Renal Physiology
PART ONE
Renal Physiology
Overview
PART TWO
Renal Clearance
PART THREE
Renal Acid-Base
Balance
1
Role of the kidney in maintaining water,
electrolytes, and pH balance
 Plasma leaks out of the capillaries in the
glomerulus. The kidneys return the nutrients to
the plasma, while removing the waste products.
This also maintains the pH balance, since some
of the wastes are acids and bases.
 Under the direction of aldosterone, they keep
the balance between electrolytes, especially
sodium and potassium.
 This keeps the plasma volume constant to
maintain BP.
2
Role of Kidneys
 The kidneys can adjust blood volume, blood pressure, and
blood composition
 BLOOD VOLUME
 Adjusts the volume of water lost in urine by
responding to ADH, aldosterone, and renin
 BLOOD PRESSURE
 Releasing renin and adenosine (increases blood
pressure)
 BLOOD COMPOSITION
 Releasing erythropoietin (increases RBC production)
3
Sympathetic Nervous
System Effect on Kidneys
Decreases the rate of blood flow (and
therefore, the pressure) to the glomerulus
by telling the precapillary sphincters to
contract.
Sympathetic nervous system is stimulated
by renin, which is released by the kidney.
Causes changes in water and sodium
reabsorption by the nephron
4
Hypothalamus
 The hypothalamus monitors the concentration of water in the
plasma.
 If the plasma is too concentrated (high osmotic pressure), it means
there are many electrolytes and not enough water inside the blood
vessels (the person is dehydrated, and blood pressure will drop).
 Since water goes to the area that has the most particles (particles
SUCK water!), water will be drawn out of the nearby cells, which
will cause them to shrink.
 If the plasma is too dilute (low osmotic pressure), it means there is
too much water and too few electrolytes inside the blood vessels
(the person is over-hydrated, and blood pressure will rise).
 Water will be drawn out of the blood vessels to enter the nearby
cells (causing them to swell) or the space between them (interstitial
space, causing edema).
5
Video
z Osmotic Pressure
z http://www.showme.com/sh/?h=P2a0rWi
6
Hypothalamus and Adrenal Gland
 When a person is dehydrated and has low blood pressure, the
hypothalamus will sense that the osmotic pressure of the plasma is
too high (above homeostatic levels; plasma is too concentrated: too
many electrolytes and not enough water is in the plasma), it tells
the pituitary gland to release ADH (antidiuretic hormone) to cause
the kidneys to retain additional water to dilute the plasma. This will
make the low blood pressure go back up.
 The adrenal cortex will also release aldosterone, which causes
sodium ions to be reabsorbed by the kidneys, and water will follow.
This will also increase the plasma volume (which will dilute it), and
also help the low blood pressure to go back up.
 If the osmotic pressure is too low (plasma is too dilute: too much
water and not enough electrolytes in the plasma), ADH and
aldosterone are not released, and excess water will pass out of the
body as urine. This will make the high blood pressure go back
down.
7
Quiz Yourself
 What does it mean when the osmotic pressure is too
high? Too low?
 What are the causes of each of these situations?
 How does the body compensate for each of these
situations?
 What does it mean when the plasma is too dilute? Too
concentrated?
 What are the causes of each of these situations?
 How does the body compensate for each of these
situations?
8
pH Imbalances
Many things can alter the pH of the blood
Beverages we drink
Acids produced by metabolism
Breathing rate
Vomiting (loss of acid)
Diarrhea (loss of base)
pH imbalances are dangerous because
many enzymes only function within a
narrow pH range.
9
Renal Physiology
Basic Mechanisms
of Urine Formation
1) Glomerular filtration
2) Tubular reabsorption
3) Tubular secretion
4) Excretion
How do we determine
these rates?
Master formula
10
Glomerular Filtration
 The capillaries in the glomerulus contain many
holes, called fenestrations. As blood passes
through the glomerulus, the plasma passes
through the fenestrations. Proteins and other
large substances do not cross through; they
stay in the bloodstream.
 The filtered plasma leaves the bloodstream in
this way, and enters the glomerular capsule,
and then enters the proximal convoluted tubule.
11
Glomerular Filtration
 In a sprinkler hose, the higher the water pressure, the faster the water squirts
through its holes. The same process is also true for the glomerulus.
 The blood pressure inside the glomerulus affects how fast the fluid can filter through
the fenestrations. Therefore, blood pressure affects the glomerular filtration rate
(GFR). The higher the blood pressure, the higher the GFR.
 The pre-capillary sphincters can also control how much pressure is in the glomerulus,
much like the water faucet controls the pressure in a hose.
12
Glomerular Filtration Rate
 GFR is used as a measure of kidney function.
 Normal GFR is 125 ml per minute for both kidneys
combined.
 That means 7.5 liters per hour, or 180 liters per day.
 That is 45 gallons of filtrate produced per day!
 Of course, most of that is reabsorbed.
 Average urine output is about 1.2 liters per day.
 That means you need to drink 1.2 liters of fluid per day
(remember that caffeine and alcohol are diuretics, so
you need more than that to compensate if you drink
those beverages). You need to drink more (about 2
liters per day) if you are getting a cold or flu.
13
Altering GFR
Several different mechanisms can change
the diameter of the afferent and efferent
arterioles to alter the GFR:
Hormonal (hormones)
Autonomic (nervous system)
Autoregulation or local (smooth muscle
sphincters around the arterioles or
capillaries near the glomerulus)
14
Remember the route the fluid takes:
Glomerulus 
Proximal convoluted tubule (PCT) 
Descending limb of LOH 
Ascending limb of LOH 
Distal Convoluted tubule (DCT) 
Collecting duct (CT)
Tubular Reabsorption
 This is the process by which substances in the renal tubules are
transferred back into the bloodstream. Reabsorption is the removal
of water and solute molecules from filtrate after it enters the renal
tubules.
 Fluid goes from the glomerulus to the proximal convoluted tubule
(PCT), down the loop of Henle and back up, then into the distal
convoluted tubule (DCT), and into the collecting duct.
 In the PCT, the nutrients are reabsorbed. If there are more
nutrients than can be reabsorbed (such as excess sugar), it will be
excreted in the urine.
 When the nutrients are reabsorbed (in the PCT), the inside of the
tubule will have more water and less nutrients. Since water goes to
the area that has a higher concentration of particles (osmosis),
water will also leave the tubules; this occurs mostly in the PCT.
 By the time the fluid has reached the collecting duct, nothing but
16
waste products are left, such as urea, ammonia, and bilirubin.
Tubular Reabsorption
 Capillaries follow the renal
tubules and wrap around them.
 The straight capillaries that travel
longitudinally next to the tubules
are called vasa recta, and the
capillaries that wrap around the
tubule are called peritubular
capillaries.
 There is a space between the
capillaries and the tube, called
the peritubular space.
17
Tubular
Reabsorption
Tubular
Cells
Peritubular
Capillaries
Filtrate arriving from
Bowman’s Capsule
Lumen of
Tubule
 The peritubular capillaries are nearby, and the particle
concentration is high inside of them. Therefore, the water in the
peritubular space (lower concentration of particles) will leave that
space and enter into the peritubular capillaries by osmosis.
 That is how the nutrients are reabsorbed from the tubules back into
the bloodstream.
18
Tubular Reabsorption
 The ascending limb of the Loop of Henle and the DCT are
impermeable to water unless hormones cause substances to be
moved through their walls.
 If the blood is low in sodium, (after excessive sweating),
aldosterone (from the adrenal cortex) will cause more sodium to be
pumped out of the tubule and into the peritubular space. The
sodium will then enter the capillaries.
 Since water follows where salt goes, whenever the body needs
more water (such as dehydration), ADH is released (from the
neurohypophysis = posterior pituitary). The synthetic form of ADH
is vasopressin (a medicine).
 Aldosterone and ADH will increase blood volume, increasing blood
pressure.
 These two hormones begin their action in the ascending limb and
continue to work in the DCT.
19
Tubular Secretion
 Some substances are unable to filter through
the glomerulus, but are not wanted by the
body.
 Examples are pollutants like pesticides, and
many drugs, such as penicillin and non-steroidal
anti-inflammatory drugs (NSAID’s).
 As blood passes through the peritubular
capillaries, those substances are moved from
the capillaries directly into the PCT and DCT.
 This is called tubular secretion.
20
Juxtaglomerular Apparatus
 The distal end of the
renal tubule passes
next to the
glomerulus to form
the juxtaglomerular
apparatus (juxta
means “next to”).
21
Juxtaglomerular Apparatus:
Alters BP and GFR by autoregulation
 Two types of cells:
 1) Macula densa cells
 2) Juxtaglomerular cells
22
Juxtaglomerular Apparatus:
Macula Densa Cells
 If blood pressure is
too low, the macula
densa releases
adenosine, which
causes
vasoconstriction
of the afferent
arteriole. This will
slow the GFR, so
less water is lost,
and blood
pressure
increases.
23
Juxtaglomerular Apparatus:
Macula Densa Cells
 If blood pressure is
too high, the
macula densa
stops releasing
adenosine, which
allows the sphincters
to relax.
 This will increase
GFR so more water
is lost, and blood
pressure
decreases.
24
Juxtaglomerular Apparatus:
Juxtaglomerular Cells
 Juxtaglomerular
cells secrete renin if
the blood pressure is
still too low after
adenosine has caused
vasoconstriction.
 Renin causes more
sodium to be
reabsorbed, and water
follows, so blood
volume increases, so
blood pressure
increases.
25
Summary of Autoregulation
 The nephron can alter the blood pressure and flow into the
glomerulus by autoregulation.
 The JGA senses the blood pressure going into the glomerulus and
the flow rate of the fluid going through the renal tubule. If the GFR
is too low, the JGA (macula densa) will cause the pre-capillary
sphincters on the nearby arterioles to contract, increasing blood
pressure.
 If that restores the desired filtration rate and flow, no further action
is needed. If not, the kidneys produce the enzyme renin, which cuts
angiotensinogen into A1. The lungs produce angiotensin converting
enzyme (ACE), which turns A1 into A2, which constricts blood
vessels, and also causes the release of aldosterone and ADH,
raising the blood pressure further.
26
Hormonal Regulation
 If a person sweats from activity, eats very salty food, or has
diarrhea, it changes the sodium and water content of the plasma.
 Two hormones that affect the ascending limb of the Loop of Henle
are aldosterone and antidiuretic hormone (ADH).
 Adosterone is produced by the adrenal cortex and causes additional
sodium ions to be pumped out of the tubule and into the
bloodstream. Water comes with it by osmosis, and the blood
pressure increases.
 ADH is produced by the posterior pituitary gland and causes
retention of additional water from the DCT and collecting ducts.
Sodium is not included in this process, so the result is to dilute the
plasma during dehydration from not drinking enough water.
27
How Low BP is Raised:
The renin-angiotensin system






When baroreceptors detect low blood pressure, the kidney releases an enzyme
called renin.
In the meantime, angiotensinogen is made by the liver and released into the
blood.
Renin cuts angiotensinogen into angiotensin-1 (A1), which travels through blood to
the pulmonary capillary bed, where cells have angiotensin converting enzyme (ACE)
that cuts A1 into A2 (the active form).
 Any word that ends in –ogen means it is a longer, inactive protein, called a
zymogen.
 To become activated, they need to be cut by an enzyme into a smaller segment.
A2 then causes vasoconstriction of the peripheral blood vessels so the body’s blood
will pool up to the core organs.
Also, these high levels of A2 stimulates the adrenal cortex to make more
aldosterone, and also stimulates the posterior pituitary gland to release ADH.
These events will raise the blood pressure.
When blood pressure is too high, the patient might be given an ACE inhibitor such as
Captopril, or a renin inhibitor such as Aliskiren, or an A2 antagonist, such as
Azilsartan.
28
ALDOSTERONE
WATER
RENIN
ADH
ACE
SALT
ANGIOTENSINOGEN
A1
ReninAngiotensin Kit
A2
29
Erythropoietin
The kidneys also monitor the oxygen
content of the blood.
If O2 levels are low, the JGA releases the
hormone erythropoietin to stimulate the
bone marrow to produce more red blood
cells.
31
Neural Regulation
 The kidneys receive about 22% of the blood pumped
out of the heart, so that is a substantial quantity passing
through the kidneys at any given time.
 If there is a stressor and the sympathetic nervous
system causes us to go into fight or flight mode, the
skeletal muscles need to have a maximum amount of
blood flow.
 Neurons from the sympathetic nervous system innervate
the kidneys will constrict the blood vessels entering the
kidney to decrease renal blood flow during critical
situations.
32
Urine
 Urine contains ions such as sodium, chloride, and potassium, as
well as suspended solids, known as sediments, such as cells,
mineral crystals, mucus threads, and sometimes bacteria.
 The pH of urine is normally 4.6-8
 A urinalysis can identify abnormal processes occurring in the body.
 Because urine is a waste product, its contents are influenced by the
foods and drinks we ingest.
 We may lose fluid elsewhere, such as through sweating or diarrhea,
which causes the urine to become more concentrated.
 Acids produced through metabolism can also change the pH of our
urine. Even changes in breathing rate can change the urine pH as
excess acids or bases are excreted to maintain normal plasma pH.
33
Abnormal Urinalysis
 These substances should not be in the
urine. When they are, it is abnormal.






Glucose
Blood
Protein
Pus
Bilirubin
Ketones
34
Causes of abnormal UA
Glucose: diabetes mellitus
Blood: bleeding in urinary tract from
infection or kidney stone
Protein: kidney disease, hypertension,
excessive exercise, pregnancy
Pus: bacterial infection in urinary tract
Bilirubin: liver malfunction
Ketones: excessive breakdown of lipids
35
Micturition
 Urination is technically known as micturition.
 Once the volume in the urinary bladder exceeds 200 ml
stretch receptors in its walls send impulses to the brain,
indicating the need to eliminate.
 When you make the decision to urinate, the
parasympathetic nervous system stimulates the smooth
muscle in the urinary bladder’s internal sphincter to
relax.
 Remember, the internal sphincter is smooth muscle
(involuntary) and the external sphincter is skeletal
muscle (voluntary). Both must relax for urine to exit.
36
Diuretics for hypertension and
congestive heart failure
 Diuretics decrease plasma volume. One group of these drugs are
called thiazide diuretics (such as Lasix). They inhibit the
reabsorption of sodium and potassium from the renal tubule,
causing more water to pass out as urine.
 Compared to sodium, the homeostatic range of potassium is quite
narrow. You can lose or gain much sodium without causing a
problem, but you need a fairly exact amount of potassium or all
your neurons can die.
 Lasix (Furosemide) inhibits reabsorption of potassium more than
other diuretics. Low blood levels of potassium are called
hypokalemia. It is important for someone on Lasix to take
potassium supplements or eat fruits or vegetables that have a lot of
potassium (such as cantaloupe).
 However, too much potassium from excessive supplements can
have fatal side effects.
37
Diuretics
Furosemide (Lasix)
Mannitol
Spironolactone
Amiloride
Hydrochorothyozide
38
Homeostasis
 Maintaining the proper concentration of sodium and water is
critical.
 If the plasma is too concentrated with particles, nearby cells can
shrink and lose their function.
 If the plasma is too dilute, water can enter the nearby cells and
cause them to expand, also decreasing their function.
 This is especially dangerous in the brain.
 Studies have shown a close link between obesity, diabetes, and
kidney disease. Exercise helps maintain normal kidney function by
increasing blood flow, and it decreases the incidence of high blood
pressure. People receiving dialysis and those who have had kidney
transplants especially need to exercise.
39
 The rest of this lecture is not on the test.
40
 Renal Physiology Video
41
Countercurrent exchange
You Tube Animation 1
https://www.youtube.com/watch?v
=XbI8eY-BeXY
You Tube Animation 2
https://www.youtube.com/watch?v
=AOqIlrQhqHQ
You Tube Animation 3
https://www.youtube.com/watch?v
=3THZeaMfuSw
Counter heat current
exchange: Note the
gradually declining
differential and that the once
hot and cold streams exit at
the reversed temperature
difference; the hotter
entering stream becomes
the exiting cooler stream
and vice versa.
42
Countercurrent exchange



Countercurrent exchange is a mechanism occurring in nature and
mimicked in industry and engineering, in which there is a crossover of
some property, usually heat or some component, between two flowing
bodies flowing in opposite directions to each other. The flowing bodies can
be liquids, gases, or even solid powders, or any combination of those.
The maximum amount of heat or mass transfer that can be obtained is
higher with countercurrent than co-current (parallel) exchange because
countercurrent maintains a slowly declining concentration difference or
gradient.
Countercurrent exchange, when set up in a loop (such as the Loop of
Henle), can be used for building up concentrations of solutes. When set up
in a loop with a buffering liquid between the incoming and outgoing fluid,
and with active transport pumps, the system is called a Countercurrent
multiplier, enabling a multiplied effect of many small pumps to gradually
build up a large concentration in the buffer liquid.
43
Countercurrent exchange

Countercurrent multiplication is where liquid moves in a loop followed
by a long length of movement in opposite directions with an intermediate
zone. The tube leading to the loop passively building up a gradient of
solvent concentration while the returning tube has a constant small
pumping action all along it, so that a gradual intensification of the heat or
concentration is created towards the loop. Countercurrent multiplication
has been found in the kidneys as well as in many other biological organs.
44
Countercurrent exchange
Countercurrent exchange is used extensively in biological
systems for a wide variety of purposes. For example, fish
use it in their gills to transfer oxygen from the surrounding
water into their blood, and birds use a countercurrent heat
exchanger between blood vessels in their legs to keep heat
concentrated within their bodies. Mammalian kidneys use
countercurrent exchange to remove water from urine so
the body can retain water used to move the nitrogenous
waste products.
45
Countercurrent multiplier
A countercurrent multiplier is a system where fluid flows in a loop so that the entrance
and exit are at similar low concentration of a dissolved substance but at the tip of the
loop there is a very high concentration of that substance. The system allows the
buildup of a high concentration gradually, with the use of many active transport pumps
each pumping only against a very small gradient.
The incoming flow starting at a low concentration has a semipermeable
membrane with water passing to the buffer liquid via osmosis at a small
gradient. There is a gradual buildup of concentration inside the loop until the
loop tip where it reaches its maximum.
47
In the example image, water enters at 299 mg/L (NaCL / H2O). Water passes
because of a small osmotic pressure to the buffer liquid in this example at
300 mg/L (NaCL / H2O). Further up the loop there is a continued flow of
water out of the tube and into the buffer, gradually raising the concentration
of NaCL in the tube until it reaches 1199 mg/L at the tip. The buffer liquid
between the two tubes is at a gradually rising concentration, always a bit
over the incoming fluid, in our example reaching 1200 mg/L. This is regulated
by the pumping action on the returning tube as explained immediately.
48
The tip of the loop has the highest concentration of salt (NaCL) in the incoming tube in the example 1199 mg/L, and in the buffer 1200 mg/L. The returning tube has active
transport pumps, pumping salt out to the buffer liquid at a low difference of
concentrations of up to 200 mg/L more than in the tube. Thus when opposite the 1000
mg/L in the buffer liquid, the concentration in the tube is 800 and only 200 mg/L are
needed to be pumped out. But the same is true anywhere along the line, so that at exit
of the loop also only 200 mg/L need to be pumped.
In effect, this can be seen as a gradually multiplying effect - hence the name of the
phenomena: a 'countercurrent multiplier' or the mechanism: Countercurrent
multiplication.
50
• A circuit of fluid in the Loop of Henle - an important part of
the kidneys allows for gradual buildup of the concentration of
urine in the kidneys, by using active transport on the exiting
nephrons. The active transport pumps need only to overcome
a constant and low gradient of concentration, because of the
countercurrent multiplier mechanism.
• Various substances are passed from the liquid entering the
Nephrons until exiting the loop.
51
• The sequence of flow is as follows:
• Renal corpuscle: Liquid enters the nephron system at the
Bowman's capsule.
• Proximal convoluted tubule: It then may reabsorb urea in the
thick descending limb. Water is removed from the nephrons
by osmosis (and Glucose and other ions are pumped out with
active transport), gradually raising the concentration in the
nephrons.
• Loop of Henle Descending: The liquid passes from the thin
descending limb to the thick ascending limb. Water is
constantly released via osmosis. Gradually, there is a buildup
of osmotic concentration, until 1200 mOsm is reached at the
loop tip, but the difference across the membrane is kept small
and constant.
52
• For example, the liquid at one section inside the thin
descending limb is at 400 mOsm while outside it's 401.
Further down the descending limb, the inside concentration is
500 while outside it is 501, so a constant difference of 1
mOsm is kept all across the membrane, although the
concentration inside and outside are gradually increasing.
• Loop of Henle Ascending: after the tip (or 'bend') of the loop,
the liquid flows in the thin ascending limb. Salt - Sodium and
Chlorine ions are pumped out of the liquid, gradually lowering
the concentration in the exiting liquid, but, using the
countercurrent multiplier mechanism, always pumping
against a constant and small osmotic difference.
53
• For example, the pumps at a section close to the bend pump
out from 1000 mOsm inside the ascending limb to 1200
mOsm outside it, with a 200 mOsm across. Pumps further up
the thin ascending limb, pump out from 400 mOsm into liquid
at 600 mOsm, so again the difference is retained at 200 mOsm
from the inside to the outside, while the concentration both
inside and outside are gradually decreasing as the liquid flow
advances.
• The liquid finally reaches a low concentration of 100 mOsm
when leaving the thin ascending limb and passing through the
thick one.
• Distal convoluted tubule: Once leaving the loop of Henle the
thick ascending limb can optionally reabsorb and increase the
concentration in the nephrons.
54
•
•
Collecting duct: The collecting duct receives liquid between 100 mOsm if no reabsorption is done, to 300 or above if re-absorption was used. The collecting duct
may continue raising the concentration if required, by gradually pumping out the
same ions as the Distal convoluted tubule, using the same gradient as the
ascending limbs in the loop of Henle, and reaching the same concentration.
Ureter: The liquid urine leaves to the Ureter.
55
Renal Solutes








Amino Acids
Ammonia
Bicarbonate
Calcium
CO2
Chloride
Creatine
Creatinine

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

Hydrogen
Magnesium
Nitrogen
Phosphate
Potassium
Sodium
Urea
Uric Acid
Urea Cycle
56
Amino Acids








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


Amino acid definition and classifications
Essential vs. Non-Essential Standard Amino Acids
Essential vs. Non-Essential AA List
Function of Standard and Non-Standard amino acids
Discovery of Amino Acids
Branched-chain amino acids
Amino Acids in human nutrition
Non-protein functions
Uses in technology
Biodegradable plastics
Peptide bond formation
Amino Acid Breakdown
Deamination
Deamination reactions in DNA
Catabolism
57
Amino Acids


Amino acid definition and classifications
Amino acids are made from an amine group (-NH2) and a carboxylic acid
group (-COOH), along with a side-chain specific to each amino acid. About
500 amino acids are known and can be classified in many ways. They can
be classified according to the location of their functional groups, polarity,
pH level, and side chain group type. The side-chain can make an amino
acid a weak acid or a weak base, and hydrophilic if the side-chain is polar
or hydrophobic if it is nonpolar.
58
Amino Acids


Essential vs. Non-Essential Standard Amino Acids
There are 20-22 amino acids in humans which form proteins, and are
known as "standard" amino acids. The amino acid Phenylalanine breaks
down into the amino acid tryptophan, and arginine breaks down into
ornithine, so some people count tryptophan and ornithine as the 21st and
22nd standard amino acids, while others just count the original 20. Nine of
the standard amino acids are known as “essential” because they cannot be
created from other compounds by the human body, and so must be taken
in as food on a daily basis (we cannot store up any excess amino acids).
The other 11 standard amino acids are called non-essential because the
body can make them. There are many other amino acids that are nonstandard because they do not make proteins. Many amino acids also play
other critical roles in the body that are not related to protein synthesis. For
example: in the brain, glutamate (glutamic acid) and gamma-amino-butyric
acid ("GABA") are the main excitatory and inhibitory neurotransmitters.
Proline is a major component of collagen. Glycine makes up red blood cells.
59
Amino Acids
Essential
Nonessential
Histidine
Alanine
Isoleucine
Arginine
Leucine
Asparagine
Lysine
Aspartic acid
Methionine
Cysteine
Phenylalanine
(breaks down to tyrosine)
(breaks down to ornithine)
Glutamic acid (glutamate)
Threonine
Glutamine
Tryptophan
Glycine
Valine
Proline
Serine
Tyrosine
60
Amino Acids
Function of Standard amino acids
The process of making proteins is called translation and involves the step-by-step
addition of amino acids to a growing protein chain. The order in which the amino
acids are added is read through the genetic code from an mRNA template, which is
a RNA copy of one of the organism's genes.
Function of Non-standard amino acids
Non-standard amino acids are those that do not make proteins (for example
carnitine, GABA), or are not produced directly by the cell (for example,
hydroxyproline and selenomethionine). They often function to modify proteins after
they are made. For example, glutamate allows for better binding of calcium ions,
and proline is critical for maintaining connective tissues. Modifications can also
determine where proteins will bind, such as the addition of long hydrophobic groups
can cause a protein to bind to a phospholipid membrane. Some nonstandard amino
acids do not modify the function of proteins. Examples include the neurotransmitter
GABA. They also might occur as intermediates in the metabolic pathways for
standard amino acids — for example, ornithine and citrulline occur in the urea cycle,
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which is part of amino acid catabolism.
Amino Acids
Discovery of Amino Acids
In the 1800’s, proteins were found to yield amino acids after enzymatic
digestion. It was therefore realized that proteins are formed when amino
acids are linked together. A short protein (less than 70 amino acids in
length) is called a peptide. The first amino acid was discovered in 1806,
when two French chemists isolated a compound in asparagus that was
subsequently named asparagine. Glycine and leucine were discovered in
1820. Cystine was discovered in 1810, although its monomer, cysteine,
remained undiscovered until 1884. Cystine is produced in the body from
two cysteine molecules. Despite this, cysteine and cystine work differently
to maintain health. Cysteine helps promote skin protection through white
blood cell and collagen production and assists in the production of an
antioxidant known as gluthathione, while cystine can aid in surgery
recovery, hair growth, and treatment of anemia.
z Amino acids are usually classified by the properties of their side-chain into
four groups.
z
z
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Amino Acids
z
z
Branched-chain amino acids
The phrase "branched-chain amino acids" or BCAA refers to the amino
acids having side-chains that are non-linear; these are leucine, isoleucine,
and valine. Branched-chain amino acids are essential nutrients that the
body obtains from proteins found in food, especially meat, dairy products,
and legumes. Branched-chain amino acids are used to treat amyotrophic
lateral sclerosis (ALS, Lou Gehrig's disease), brain conditions due to liver
disease (chronic hepatic encephalopathy, latent hepatic encephalopathy), a
movement disorder called tardive dyskinesia, a genetic disease called
McArdle's disease, a disease called spinocerebellar degeneration, and poor
appetite in elderly, kidney failure patients and cancer patients. Branchedchain amino acids are also used to help slow muscle wasting in people who
are confined to bed. Some people use branched-chain amino acids to
help symptoms of chronic fatigue syndrome and to improve
concentration. Athletes use branched-chain amino acids to improve
exercise performance and reduce protein and muscle breakdown during
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intense exercise.
Amino Acids
z
z
In human nutrition
When taken up into the human body from the diet, the standard amino
acids either are used to synthesize proteins or are oxidized to urea and
carbon dioxide as a source of energy. The oxidation pathway starts with
the removal of the amino group by a transaminase, the amino group is
then fed into the urea cycle. The other product of transamination is a keto
acid that enters the citric acid cycle. Glucogenic amino acids can also be
converted into glucose, through gluconeogenesis.
64
Amino Acids
z
z
z
z
z
z
z
Non-protein functions
In humans, non-protein amino acids also have important roles as metabolic
intermediates, such as synthesizing other molecules, for example:
Tryptophan is a precursor of the neurotransmitter serotonin.
Tyrosine (and its precursor phenylalanine) are precursors of the
catecholamine neurotransmitters dopamine, epinephrine and
norepinephrine.
Glycine is a precursor of porphyrins such as heme
Arginine is a precursor of nitric oxide.
Aspartate, glycine, and glutamine are precursors of nucleotides.
65
Amino Acids
z
z
Uses in technology
Amino acids are used for a variety of applications in industry, but their
main use is as additives to animal feed. This is necessary, since many of
the bulk components of these feeds, such as soybeans, lack some of the
essential amino acids: Lysine, methionine, threonine, and tryptophan are
most important in the production of these feeds. The food industry is also
a major consumer of amino acids, in particular, glutamic acid, which is
used as a flavor enhancer, and Aspartame as a low-calorie artificial
sweetener. Some amino acids are used in the synthesis of drugs and
cosmetics.
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Amino Acids
z
z
Biodegradable plastics
Amino acids are under development as components of a range of
biodegradable polymers for use as environmentally friendly packaging and
in medicine in drug delivery, the construction of prosthetic implants, and
use of polyaspartate, a water-soluble biodegradable polymer that may have
applications in disposable diapers and agriculture.
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Amino Acids
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z
Peptide bond formation
The condensation of two amino acids to form a dipeptide through a peptide
bond. This polymerization of amino acids is what creates proteins. This
condensation reaction yields the newly formed peptide bond and a
molecule of water.
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Amino Acids
Amino Acid Breakdown
Degradation of an amino acid often involves deamination by moving its amino
group to alpha-ketoglutarate, forming glutamate. This process involves
transaminase enzymes. The amino group is then removed through the urea
cycle and is excreted in the form of urea. However, amino acid degradation
can produce uric acid or ammonia instead. For example, serine is converted to
pyruvate and ammonia. After removal of one or more amino groups, the
remainder of the molecule can sometimes be used to synthesize new amino
acids, or it can be used for energy by entering glycolysis or the citric acid
cycle.
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Amino Acids
Deamination is the removal of an amine group from a molecule. Enzymes
which catalyse this reaction are called deaminases. There are 4 types of
deamination: intramolecular, resulting in the formation of unsaturated fatty
acid; restorative, with formation of saturated fatty acid; hydrolytic, with
formation of hydroxy carboxylic, and oxidative, with formation of a keto acid.
In the human body, deamination takes place primarily in the liver, however
glutamate is also deaminated in the kidneys. Deamination is the process by
which amino acids are broken down if there is an excess of protein intake. The
amino group is removed from the amino acid and converted to ammonia. The
rest of the amino acid is made up of mostly carbon and hydrogen, and is
recycled or oxidized for energy. Ammonia is toxic to the human system, and
enzymes convert it to urea or uric acid by addition of carbon dioxide molecules
in the urea cycle, which also takes place in the liver. Urea and uric acid can
safely diffuse into the blood and then be excreted in urine.
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Amino Acids
Deamination reactions in DNA
Spontaneous deamination of cytosine into uracil, releasing ammonia in the
process. In DNA, this spontaneous deamination is corrected for by the removal
of uracil (product of cytosine deamination and not part of DNA.
Cytosine
Uracil
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Amino Acids
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Catabolism
Catabolism of proteinogenic amino acids. Amino acids can be classified according to the
properties of their main products as either of the following:
* Glucogenic, with the products having the ability to form glucose by gluconeogenesis
* Ketogenic, with the products not having the ability to form glucose. These products may still be
used for ketogenesis or lipid synthesis.
* Amino acids catabolized into both glucogenic and ketogenic products.
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Ammonia
Ammonia is a compound of nitrogen and hydrogen with
the formula NH3 , while ammonium is NH4. Ammonia is a
colorless gas with a characteristic pungent smell. Ammonia
contributes significantly to the nutritional needs of
terrestrial organisms by serving as a precursor to food and
fertilizers. Ammonia is also a building-block for the
synthesis of many pharmaceuticals and is used in many
commercial cleaning products. Although in wide use,
ammonia is both caustic and hazardous. Household
ammonia is a solution of NH3 in water.
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Ammonia
Natural occurrence
Ammonia is found in trace quantities in the atmosphere, being produced from
the putrefaction (decay process) of animal and vegetable matter. When we
consume those foods, the nitrogen is taken into our body and used to make
amino acids and other important substances. When amino acids are broken
down, NH3 is the toxic waste product, and has an alkaline pH. The kidneys
excrete or reabsorb NH3 to keep the blood plasma at neutral pH. Dilute
aqueous ammonia can be applied on the skin to lessen the effects of acidic
animal venoms, such as from insects and jellyfish. The basic pH of ammonia
also is the basis of its toxicity and its use as a cleaner. By creating a solution
with a pH much higher than a neutral water solution, proteins (enzymes) will
denature, leading to cell damage, death of the cell, and eventually death of
the organism. Dirt often consists of fats and oils, which are not very soluble in
water. Ammonia causes them to dissolve in water. This will allow the ammonia
and water, with its dissolved dirty oils to evaporate completely, leaving a clean
surface.
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Ammonia
History
The Romans called the ammonium chloride deposits they collected from near
the Temple of Amun in ancient Libya 'sal ammoniacus' (salt of Amun).
Toxicity
The toxicity of ammonia solutions does not usually cause problems for humans
and other mammals, as a specific mechanism exists to prevent its build-up in
the bloodstream. Ammonia is converted to carbamoyl phosphate by an
enzyme, and then enters the urea cycle to be either incorporated into amino
acids or excreted in the urine. However, fish and amphibians lack this
mechanism, as they can usually eliminate ammonia from their bodies by direct
excretion. Ammonia even at dilute concentrations is highly toxic to aquatic
animals, and for this reason it is classified as dangerous for the environment.
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Ammonia
Formation and elimination in the body
Ammonia is a metabolic product of amino acid deamination
catalyzed by enzymes. Ammonia is quickly converted to
urea, which is much less toxic, particularly less basic. This
urea is a major component of the dry weight of urine. The
liver converts ammonia to urea through a series of
reactions known as the urea cycle. Liver dysfunction, such
as that seen in cirrhosis, may lead to elevated amounts of
ammonia in the blood (hyperammonemia). Likewise,
defects in the enzymes responsible for the urea cycle,
leads to this disorder. It causes confusion and coma,
neurological problems, and aciduria (acid in the urine).
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Ammonia
Acid base balance
Ammonia is important for normal animal acid/base
balance. After formation of ammonium from glutamine, αketoglutarate may be degraded to produce two molecules
of bicarbonate, which are then available as buffers for
acids. Ammonium is excreted in the urine, resulting in net
acid loss. Ammonia may itself diffuse across the renal
tubules, combine with a hydrogen ion, and thus allow for
further acid excretion.
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Bicarbonate
Bicarbonate has the chemical formula HCO3−. Bicarbonate serves a crucial biochemical role in the
physiological pH buffering system.
Bicarbonate participates in this equilibrium reaction.
CO2 + H2O ↔ H2CO3 ↔ HCO3− + H+
Bicarbonate is alkaline, and a vital component of the pH buffering system of the human body
(maintaining acid-base homeostasis). 70-75% of CO2 in the body is converted into carbonic acid
(H2CO3), which can quickly turn into bicarbonate (HCO3−). Bicarbonate – in conjunction with water,
hydrogen ions, and carbon dioxide forms a buffering system, which provides prompt resistance to
drastic pH changes in both the acidic and basic directions. This is especially important for protecting
tissues of the central nervous system, where pH changes too far outside of the normal range in
either direction could prove disastrous. Bicarbonate also acts to regulate pH in the small intestine. It
is released from the pancreas in response to the hormone secretin to neutralize the acidic chyme
entering the duodenum from the stomach.
The most common salt of the bicarbonate ion is sodium bicarbonate, NaHCO3, which is commonly
known as baking soda. When heated or exposed to an acids, such as acetic acid (vinegar), sodium
bicarbonate releases carbon dioxide. This is used as a leavening agent in baking.
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Calcium
Calcium is the fifth-most-abundant element by mass in the
Earth's crust. Calcium is essential for living organisms, where
movement of the calcium ion Ca2+ into and out of the
cytoplasm functions as a signal for many cellular processes. It
is the major material used in mineralization of bone, and
teeth. It is the relatively high-atomic-number of calcium that
causes bone to be radio-opaque (can see bone on x-rays). Of
the human body's solid components after cremation, about a
third of the total "mineral" mass is the approximately one
kilogram of calcium that composes the average skeleton (the
remainder being mostly phosphorus and oxygen). Calcium,
combined with phosphate forms hydroxyapatite, which is the
mineral portion of human and animal bones and teeth.
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Calcium
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Calcium compounds
Calcium carbonate (CaCO3) is used in manufacturing cement and
mortar, lime, limestone, and in toothpastes.
Calcium hydroxide solution (Ca(OH)2) (also known as limewater) is used to detect
the presence of carbon dioxide by being bubbled through a solution. It turns cloudy
where CO2 is present.
Calcium arsenate (Ca3(AsO4)2) is used in insecticides.
Calcium carbide (CaC2) is used to make acetylene gas (for torches for welding) and
in the manufacturing of plastics.
Calcium chloride (CaCl2) is used in ice removal and dust control on dirt roads, in
conditioner for concrete, as an additive in canned tomatoes, and to provide body
for automobile tires.
Calcium cyclamate (Ca(C6H11NHSO3)2) is used as a sweetening agent in several
countries. In the United States it is no longer permitted for use because of suspected
cancer-causing properties.
Calcium gluconate (Ca(C6H11O7)2) is used as a food additive and in vitamin pills.
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Calcium
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Calcium compounds
Calcium hypochlorite (Ca(OCl)2) is used as a swimming pool disinfectant, as
a bleaching agent, as an ingredient in deodorant, and in algaecide and fungicide.
Calcium permanganate (Ca(MnO4)2) is used in liquid rocket propellant, and as a
water sterilizing agent and in dental procedures.
Calcium phosphate (Ca3(PO4)2) is used as a supplement for animal feed, fertilizer,
in commercial production for dough and yeast products, in the manufacture of glass,
and in dental products.
Calcium phosphide (Ca3P2) is used in fireworks, rodenticide, torpedoes and flares.
Calcium stearate (Ca(C18H35O2)2) is used in the manufacture
of wax crayons, cements, plastics and cosmetics, as a food additive, and in paints.
Calcium sulfate (CaSO4·2H2O) is used as common blackboard chalk, and Plaster of
Paris.
Calcium tungstate (CaWO4) is used in luminous paints, fluorescent lights and in Xray studies.
Hydroxylapatite (Ca5(PO4)3(OH), makes up seventy percent of bone. Also
carbonated-calcium deficient hydroxylapatite is the main mineral of which dental
enamel and dentin are comprised.
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Calcium
Calcium is an important component of a healthy diet and a mineral necessary for life.
Approximately 99 percent of the body's calcium is stored in the bones and teeth. The
rest of the calcium in the body has other important uses, such as some exocytosis,
especially neurotransmitter release, and muscle contraction. In the electrical conduction
system of the heart, calcium replaces sodium as the mineral that depolarizes the cell,
proliferating the action potential. Long-term calcium deficiency can lead to rickets and
poor blood clotting and in case of a menopausal woman, it can lead to osteoporosis, in
which the bone deteriorates and there is an increased risk of fractures. While a lifelong
deficit can affect bone and tooth formation, over-retention can
cause hypercalcemia (elevated levels of calcium in the blood), impaired kidney function
and decreased absorption of other minerals. Several sources suggest a correlation
between high calcium intake (2000 mg per day, or twice the U.S. recommended daily
allowance, equivalent to six or more glasses of milk per day) and prostate cancer. High
calcium intakes or high calcium absorption were previously thought to contribute to the
development of kidney stones. However, a high calcium intake has been associated with
a lower risk for kidney stones in more recent research. Vitamin D is needed to absorb
calcium.
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Calcium
Dairy products, such as milk and cheese, are a well-known source of calcium.
Some individuals are allergic to dairy products and even more people, in
particular those of non Indo-European descent, are lactose-intolerant, leaving
them unable to consume non-fermented dairy products in quantities larger
than about half a liter per serving. Others, such as vegans, avoid dairy
products for ethical and health reasons.
Many good vegetable sources of calcium exist, including seaweeds such as
kelp, and nuts and seeds like almonds, hazelnuts, sesame, and pistachio;
molasses; beans (especially soy beans); figs; rutabaga; broccoli; dandelion
leaves; and kale. In addition, some drinks are often fortified with calcium (like
soy milk or orange juice).
Numerous vegetables, notably spinach and rhubarb, have a high calcium
content, but they may also contain varying amounts of oxalic acid that binds
calcium and reduces its absorption. An overlooked source of calcium is
eggshell, which can be ground into a powder and mixed into food or a glass of
water.
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Calcium
Dietary supplements
Most experts recommend that supplements be taken with
food and that no more than 600 mg should be taken at a
time because the percent of calcium absorbed decreases as
the amount of calcium in the supplement increases. It is
recommended to spread doses throughout the day.
Recommended daily calcium intake for adults ranges from
1000 to 1500 mg. It is recommended to take supplements
with food to aid in absorption.
Vitamin D is added to some calcium supplements. Proper
vitamin D status is important because vitamin D is converted
to a hormone in the body, which then induces the synthesis
of intestinal proteins responsible for calcium absorption. 84
Calcium
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The absorption of calcium from most food and commonly used dietary supplements is
very similar. This is contrary to what many calcium supplement manufacturers claim in
their promotional materials.
Calcium carbonate is the most common and least expensive calcium supplement. It
should be taken with food, and depends on low pH levels (acidic) for proper absorption
in the intestine. While most people digest calcium carbonate very well, some might
develop gastrointestinal discomfort or gas. Taking magnesium with it can help to avoid
constipation. Calcium carbonate is 40% elemental calcium. 1000 mg will provide
400 mg of calcium. However, supplement labels will usually indicate how much calcium
is present in each serving, not how much calcium carbonate is present.
Antacids frequently contain calcium carbonate, and are a commonly used, inexpensive
calcium supplement.
Coral calcium is a salt of calcium derived from fossilized coral reefs. Coral calcium is
composed of calcium carbonate and trace minerals.
Calcium citrate can be taken without food and is the supplement of choice for
individuals with achlorhydria or who are taking histamine-2 blockers or proton-pump
inhibitors due to gastric ulcers. Calcium citrate is about 21% elemental calcium.
1000 mg will provide 210 mg of calcium. It is more expensive than calcium carbonate
and more of it must be taken to get the same amount of calcium.
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Calcium
 Calcium phosphate costs more than calcium carbonate, but less than
calcium citrate. Microcrystalline Hydroxyapatite (MH) is one of several
forms of calcium phosphate used as a dietary supplement.
Hydroxyapatite is about 40% calcium.
 Calcium lactate has similar absorption as calcium carbonate, but is
more expensive. Calcium lactate and calcium gluconate are less
concentrated forms of calcium and are not practical oral supplements.
 Calcium chelates are synthetic calcium compounds in which calcium is
bound to an organic molecule, such as malate, aspartate, or
fumarate. These forms of calcium may be better absorbed on an
empty stomach. However, in general they are absorbed similarly to
calcium carbonate and other common calcium supplements when
taken with food. The "chelate" mimics the action that natural food
performs by keeping the calcium soluble in the intestine. Thus, on an
empty stomach, in some individuals, chelates might, in theory, be
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absorbed better.
Calcium
Hazards and toxicity
Excessive consumption of calcium carbonate
antacids/dietary supplements (such as Tums) over a period
of weeks or months can cause milk-alkali syndrome, with
symptoms ranging from hypercalcemia to potentially
fatal renal failure. Persons consuming more than
10 grams/day of CaCO3 (=4 g Ca) are at risk of developing
milk-alkali syndrome. Oral calcium supplements diminish
the absorption of thyroxine when taken within four to six
hours of each other. Thus, people taking both calcium and
thyroxine run the risk of inadequate thyroid hormone
replacement and thence hypothyroidism if they take them
simultaneously or near-simultaneously.
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Carbon dioxide
Carbon dioxide is an important greenhouse gas, warming the Earth's
surface to a higher temperature by reducing outward radiation.
Atmospheric carbon dioxide is the primary source of carbon in life on
Earth and its concentration in Earth's pre-industrial atmosphere since
late in the Precambrian eon has been regulated by photosynthetic
organisms. Burning of carbon-based fuels since the industrial
revolution has rapidly increased concentrations of atmospheric carbon
dioxide, increasing the rate of global warming and causing
anthropogenic climate change. It is also a major source of ocean
acidification since it dissolves in water to form carbonic acid, which is a
weak acid as its ionization in water is incomplete.
CO2 + H2O
H2CO3
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Carbon dioxide
History
Carbon dioxide was one of the first gases to be described as a
substance distinct from air. In the seventeenth century,
the Flemish chemist Jan Baptist van Helmont observed that when he
burned charcoal in a closed vessel, the mass of the resulting ash was
much less than that of the original charcoal. His interpretation was
that the rest of the charcoal had been transmuted into an invisible
substance he termed a "gas" or "wild spirit" (spiritus sylvestre). Carbon
dioxide is used by the food industry, the oil industry, and the chemical
industry.
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Carbon dioxide
Foods
A candy called Pop Rocks is pressurized with carbon dioxide gas.
Leavening agents cause dough to rise by producing carbon
dioxide. Baker's yeast produces carbon dioxide by fermentation of
sugars within the dough, while chemical leaveners such as baking
powder and baking soda release carbon dioxide when heated or if
exposed to acids.
Beverages
Carbon dioxide is used to produce carbonated soft drinks and soda
water. Traditionally, the carbonation in beer and sparkling wine came
about through natural fermentation, but many manufacturers
carbonate these drinks with carbon dioxide recovered from the
fermentation process.
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Carbon dioxide
Wine making
Carbon dioxide in the form of dry ice is often used in the wine
making process to cool down bunches of grapes quickly after picking to
help prevent spontaneous fermentation by wild yeast. The main
advantage of using dry ice over regular water ice is that it cools the
grapes without adding any additional water that may decrease
the sugar concentration in the grape, and therefore also decrease
the alcohol concentration in the finished wine.
Biological applications
In medicine, up to 5% carbon dioxide (130 times atmospheric
concentration) is added to oxygen for stimulation of breathing
after apnea and to stabilize theO2/CO2 balance in blood.
It has been proposed that carbon dioxide from power generation be
bubbled into ponds to grow algae that could then be converted
into biodiesel fuel.
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Carbon dioxide
Biological role
Carbon dioxide is an end product in organisms that obtain energy from
breaking down sugars, fats and amino acids with oxygen as part of
their metabolism, in a process known as cellular respiration. This includes
all plants, animals, many fungi and some bacteria. In higher animals, the
carbon dioxide travels in the blood from the body's tissues to the lungs
where it is exhaled. In plants using photosynthesis, carbon dioxide is
absorbed from the atmosphere.
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Carbon dioxide
Toxicity
Acute carbon dioxide physiological effect is hypercapnia or asphyxiation
sometimes known by the names given to it by miners: blackdamp.
Blackdamp is primarily nitrogen and carbon dioxide and kills via
suffocation (having displaced oxygen). Miners would try to alert
themselves to dangerous levels of blackdamp and other gases in a mine
shaft by bringing a caged canary with them as they worked. The canary
is more sensitive to environmental gases than humans and as it became
unconscious would stop singing and fall off its perch. The Davy lamp
could also detect high levels of blackdamp (which collect near the floor)
by burning less brightly, while methane, another suffocating gas and
explosion risk would make the lamp burn more brightly).
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Carbon dioxide
Human physiology
The body produces approximately 2.3 pounds (1 kg) of carbon dioxide
per day per person, containing 0.63 pounds (290 g) of carbon. In
humans, this carbon dioxide is carried through the venous system and is
breathed out through the lungs. Therefore, the carbon dioxide content in
the body is high in the venous system, and decreases in the respiratory
system, resulting in lower levels along any arterial system. Carbon
dioxide content in this sense is often given as the partial pressure, which
is the pressure which carbon dioxide would have had if it alone occupied
the volume.
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Carbon dioxide
Transport in the blood
CO2 is carried in blood in three different ways.
70% to 80% is converted to bicarbonate ions HCO3− by the
enzyme carbonic anhydrase in the red blood cells, by the reaction
CO2 + H2O → H2CO3 → H+ + HCO3−
5% – 10% is dissolved in the plasma
5% – 10% is bound to hemoglobin
Hemoglobin, the main oxygen-carrying molecule in red blood cells, carries both oxygen and
carbon dioxide. However, the CO2 bound to hemoglobin does not bind to the same site as
oxygen. Instead, it combines with the N-terminal groups on the four globin chains.
However, because of its effects on the hemoglobin molecule, the binding of CO2 decreases
the amount of oxygen that is bound for a given partial pressure of oxygen. The decreased
binding to carbon dioxide in the blood due to increased oxygen levels is known as
the Haldane Effect, and is important in the transport of carbon dioxide from the tissues to
the lungs. Conversely, a rise in the partial pressure of CO2 or a lower pH will cause
offloading of oxygen from hemoglobin, which is known as the Bohr Effect.
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Carbon dioxide
Regulation of respiration
Carbon dioxide is one of the mediators of local autoregulation of blood
supply. If its levels are high, the capillaries expand to allow a greater
blood flow to that tissue.
Bicarbonate ions are crucial for regulating blood pH. A person's breathing
rate influences the level of CO2 in their blood. Breathing that is too slow
or shallow causes respiratory acidosis, while breathing that is too rapid
leads to hyperventilation, which can cause respiratory alkalosis.
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Carbon dioxide
Regulation of respiration
Although the body requires oxygen for metabolism, low oxygen levels
normally do not stimulate breathing. Rather, breathing is stimulated by
higher carbon dioxide levels. As a result, breathing low-pressure air or a
gas mixture with no oxygen at all (such as pure nitrogen) can lead to loss
of consciousness without ever experiencing air hunger. This is especially
perilous for high-altitude fighter pilots. It is also why flight attendants
instruct passengers, in case of loss of cabin pressure, to apply the
oxygen mask to themselves first before helping others; otherwise, one
risks losing consciousness.
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Carbon dioxide
Regulation of respiration
The respiratory centers try to maintain an arterial CO2 pressure of 40
mm Hg. With intentional hyperventilation, the CO2 content of arterial
blood may be lowered to 10–20 mm Hg (the oxygen content of the blood
is little affected), and the respiratory drive is diminished. This is why one
can hold one's breath longer after hyperventilating than without
hyperventilating. This carries the risk that unconsciousness may result
before the need to breathe becomes overwhelming, which is why
hyperventilation is particularly dangerous before free diving.
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Chloride
The chloride ion and its salts, such as sodium chloride, are
very soluble in water. It is an essential electrolyte located
in all body fluids responsible for maintaining acid/base
balance, transmitting nerve impulses and regulating fluid in
and out of cells. The amount of chloride in the blood is
carefully controlled by the kidneys. Chloride is used to form
salts that can preserve food such as sodium chloride.
Other salts such as calcium chloride, magnesium chloride,
potassium chloride have varied uses ranging from medical
treatments to cement formation.
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Creatine
Not to be confused with creatinine.
Creatine is a nitrogenous organic acid that occurs
naturally in vertebrates and helps to supply
energy to all cells in the body, primarily muscle.
This is achieved by increasing the formation of
ATP. Creatine was identified in 1832 when Michel
Eugène Chevreul discovered it as a component of
skeletal muscle, which he later named after the
Greek word for meat (kreas). In solution, creatine
is in equilibrium with creatinine.
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Creatine
Biosynthesis
Creatine is naturally produced in the human body from
amino acids primarily in the kidney and liver. It is
transported in the blood for use by muscles. Approximately
95% of the human body's total creatine is located in
skeletal muscle. Creatine is not an essential nutrient, as it
can be manufactured in the human body from arginine,
glycine, and methionine. In humans and animals,
approximately half of stored creatine originates from food
(about 1 g/day, mainly from meat). Genetic deficiencies in
the creatine biosynthetic pathway lead to various severe
neurological defects.
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Creatine
The phosphocreatine system
Creatine, synthesized in the liver and kidney, is transported
through the blood and taken up by tissues with high
energy demands, such as the brain and skeletal muscle,
through an active transport system. The concentration of
ATP in skeletal muscle is usually 2-5 mM, which would
result in a muscle contraction of only a few seconds.
Fortunately, during times of increased energy demands,
the phosphagen (or ATP/PCr) system rapidly resynthesizes
ATP from ADP with the use of phosphocreatine (PCr)
through a reversible reaction with the enzyme creatine
kinase (CK).
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Creatine
Use as a supplement
Creatine supplements are used by athletes, bodybuilders,
wrestlers, sprinters, and others who wish to gain muscle
mass, typically consuming 2 to 3 times the amount that
could be obtained from a very-high-protein diet. The Mayo
Clinic states that creatine has been associated with
asthmatic symptoms and warns against consumption by
persons with known allergies to creatine.
104
Creatine
Use as a supplement
There are reports of kidney damage with creatine use, such as
nephritis; patients with kidney disease should avoid use of this
supplement. In similar manner, liver function may be altered, and
caution is advised in those with underlying liver disease. Long-term
administration of large quantities of creatine is reported to increase
the production of formaldehyde, which has the potential to cause
serious unwanted side-effects. In 2004 the European Food Safety
Authority (EFSA) published a record which stated that oral long-term
intake of 3g pure creatine per day is risk-free. Other research has
shown that oral creatine supplementation at a rate of 5 to 20 grams
per day appears to be very safe and largely devoid of adverse sideeffects, while at the same time effectively improving the physiological
response to resistance exercise, increasing the maximal force
production of muscles in both men and women.
105
Creatine
Pharmacokinetics
To maintain an elevated plasma level it is necessary to
take small oral doses every 3–6 hours throughout the day.
After the "loading dose" period (1–2 weeks, 12-24 g a
day), it is no longer necessary to maintain a consistently
high serum level of creatine. Creatine is consumed by the
body fairly quickly, and if one wishes to maintain the high
concentration of creatine, Post-loading dose, 2-5 g daily is
the standard amount to intake.
106
Creatine
Treatment of diseases
Creatine has been demonstrated to cause modest
increases in strength in people with a variety of
neuromuscular disorders. Creatine supplementation has
been, and continues to be, investigated as a possible
therapeutic approach for the treatment of muscular,
neuromuscular, neurological and neurodegenerative
diseases (arthritis, congestive heart failure, Parkinson's
disease, disuse atrophy, gyrate atrophy, McArdle's disease,
Huntington's disease, miscellaneous neuromuscular
diseases, mitochondrial diseases, muscular dystrophy, and
neuroprotection), and depression.
107
Creatine
Improved cognitive ability
A placebo-controlled double-blind experiment found that a group of
subjects composed of vegetarians and vegans who took 5 grams of
creatine per day for six weeks showed a significant improvement on
two separate tests of fluid intelligence, Raven's Progressive Matrices,
and the backward digit span test from the WAIS. The treatment group
was able to repeat longer sequences of numbers from memory and
had higher overall IQ scores than the control group. The researchers
concluded that "supplementation with creatine significantly increased
intelligence compared with placebo." A subsequent study found that
creatine supplements improved cognitive ability in the elderly. A study
on young adults (0.03 g/kg/day for six weeks, e.g., 2 g/day for a 70kilogram (150 lb) individual) failed to find any improvements. Perhaps
this improvement is only seen in those who are creatine deficient.
108
Creatine
Creatine phosphate (CP) or PCr (Pcr), also known as
Phosphocreatine, is a phosphorylated creatine molecule
that serves as a rapidly mobilizable reserve of high-energy
phosphates in skeletal muscle and the brain.
109
Creatine
Chemistry
Phosphocreatine is formed from parts of three amino
acids: arginine (Arg), glycine (Gly), and methionine (Met).
It can be synthesized by formation of guanidinoacetate
from Arg and Gly (in kidney) followed by methylation (Sadenosyl methionine is required) to creatine (in liver), and
phosphorylation by creatine kinase (ATP is required) to
phosphocreatine (in muscle); catabolism: dehydration to
form the cyclic Schiff base creatinine. Phosphocreatine is
synthesized in the liver and transported to the muscle
cells, via the bloodstream, for storage. The creatine
phosphate shuttle facilitates transport of high energy
phosphate from mitochondria.
110
Creatine
Function
Phosphocreatine can anaerobically donate a phosphate
group to ADP to form ATP during the first 2 to 7 seconds
following an intense muscular or neuronal effort.
Conversely, excess ATP can be used during a period of low
effort to convert creatine to phosphocreatine. The
reversible phosphorylation of creatine (i.e., both the
forward and backward reaction) is catalyzed by several
creatine kinases. The presence of creatine kinase (CK-MB,
MB for muscle/brain) in blood plasma is indicative of tissue
damage and is used in the diagnosis of myocardial
infarction.
111
Creatine
Function
The cell's ability to generate phosphocreatine from excess
ATP during rest, as well as its use of phosphocreatine for
quick regeneration of ATP during intense activity, provides
a spatial and temporal buffer of ATP concentration. In
other words, phosphocreatine acts as high-energy reserve
in a coupled reaction; the energy given off from donating
the phosphate group is used to regenerate the other
compound - in this case, ATP. Phosphocreatine plays a
particularly important role in tissues that have high,
fluctuating energy demands such as muscle and brain.
112
Creatinine
Creatinine (from the Greek “flesh”) is a
breakdown product of creatine
phosphate in muscle, and is usually
produced at a fairly constant rate by the
body (depending on muscle mass).
113
Creatinine
Biological relevance
Serum creatinine (a blood measurement) is an important
indicator of renal health because it is an easily-measured
by-product of muscle metabolism. Creatinine itself is an
important biomolecule because it is a major by-product of
energy usage in muscle, via a biological system involving
creatine, phosphocreatine (also known as creatine
phosphate), and adenosine triphosphate (ATP, the body's
immediate energy supply).
114
Creatinine
Biological relevance
Creatine is primarily synthesized in the liver. It is then
transported through blood to the other organs, muscle,
and brain where it is converted into the high energy
compound phosphocreatine. Creatinine is chiefly filtered
out of the blood by the kidneys (glomerular filtration and
proximal tubular secretion). There is little or no tubular
reabsorption of creatinine. If the filtering of the kidney is
deficient, creatinine blood levels rise. Therefore, creatinine
levels in blood and urine may be used to calculate the
creatinine clearance (CrCl), which reflects the glomerular
filtration rate (GFR).
115
Creatinine
Biological relevance
The GFR is clinically important because it is a
measurement of renal function. A more complete
estimation of renal function can be made when
interpreting the blood (plasma) concentration of creatinine
along with that of urea. BUN-to-creatinine ratio (the ratio
of blood urea nitrogen to creatinine) can indicate other
problems besides those intrinsic to the kidney; for
example, a urea level raised out of proportion to the
creatinine may indicate a pre-renal problem such as
volume depletion.
116
Creatinine
Diagnostic use
Serum creatinine
Measuring serum creatinine is a simple test and it is the most
commonly used indicator of renal function.
A rise in blood creatinine level is observed only with marked damage
to functioning nephrons. Therefore, this test is unsuitable for detecting
early-stage kidney disease. A better estimation of kidney function is
given by the creatinine clearance (CrCl) test. Creatinine clearance can
be accurately calculated using serum creatinine concentration and
some or all of the following variables: sex, age, weight and race, as
suggested by the American Diabetes Association without a 24-hour
urine collection.
117
Creatinine
Urine creatinine
Creatinine concentration is also checked during
standard urine drug tests. Normal creatinine levels
indicate the test sample is undiluted, whereas low
amounts of creatinine in the urine indicate either a
manipulated test or low individual baseline
creatinine levels. Test samples considered
manipulated due to low creatinine are not tested,
and the test is sometimes considered failed.
118
Creatinine
Urine creatinine
Diluted samples may not always be due to a conscious
effort of subversion, and diluted samples cannot be proved
to be intentional, but are only assumed to be. Diuretics,
such as coffee and tea, cause more frequent urination,
thus potently decreasing creatinine levels. They are usually
used with other tests to reference levels of other
substances measured in the urine. A decrease in muscle
mass will also cause a lower reading of creatinine, as will
pregnancy.
119
Creatinine
Interpretation
The trend of serum creatinine levels over time is more
important than absolute creatinine level.
Creatinine levels may increase when ACE inhibitors (ACEI)
or angiotensin II receptor antagonists (or angiotensin
receptor blockers, ARBs) are taken. Using both ACEI and
ARB concomitantly will increase creatinine levels to a
greater degree than either of the two drugs would
individually. An increase of <30% is to be expected with
ACEI or ARB use.
120
Hydrogen
 Hydrogen is a chemical element with chemical symbol H and atomic
number 1. It is the most abundant chemical substance, constituting
roughly 75% of the Universe's mass. It readily forms covalent
(shares an electron orbital) bonds with most non-metallic elements.
 Hydrogen plays a particularly important role in acid-base chemistry
with many reactions exchanging protons between soluble
molecules.
 Protons and acids
 Oxidation of hydrogen removes its electron and gives H+, which
contains no electrons and a nucleus which is usually composed of
one proton. Acids are proton donors, while bases are proton
acceptors.
 A bare proton, H+, cannot exist in solution or in ionic crystals,
because of its unstoppable attraction to other atoms or molecules
with electrons.
121
Hydrogen
History
In 1671, Robert Boyle discovered and described the reaction
between iron filings and dilute acids, which results in the production of
hydrogen gas. In 1766,Henry Cavendish was the first to recognize
hydrogen gas as a discrete substance, by naming the gas from
a metal-acid reaction "flammable air". He is usually given credit for its
discovery as an element. In 1783, Antoine Lavoisier gave the element
the name hydrogen (from the Greek hydro meaning water
and genes meaning creator) when he and Laplace reproduced
Cavendish's finding that water is produced when hydrogen is burned.
122
Hydrogen
Applications
H2 has several other important uses. H2 is used as a hydrogenating
agent, particularly in increasing the level of saturation of unsaturated
fats and oils (found in items such as margarine), and in the production
of methanol.
Energy carrier
Hydrogen is not an energy resource, except in the hypothetical context
of commercial nuclear fusion power plants using deuterium or tritium,
a technology presently far from development. The Sun's energy comes
from nuclear fusion of hydrogen, but this process is difficult to achieve
controllably on Earth. Elemental hydrogen from solar, biological, or
electrical sources require more energy to make it than is obtained by
burning it, so in these cases hydrogen functions as an energy carrier,
like a battery. Hydrogen may be obtained from fossil sources (such as
methane), but these sources are unsustainable.
123
Hydrogen
Biological reactions
H2 is a product of some types of anaerobic metabolism and is
produced by several microorganisms, usually via reactions catalyzed by
enzymes called hydrogenases. These enzymes catalyze the reversible
redox reaction between H2 and its component two protons and two
electrons. Creation of hydrogen gas occurs in the transfer of reducing
equivalents produced during pyruvate fermentation to water.
124
Hydrogen
Biological reactions
Water splitting, in which water is decomposed into its component
protons, electrons, and oxygen, occurs in the light reactions in all
photosynthetic organisms. Some such organisms, including the alga
Chlamydomonas reinhardtii and cyanobacteria, have evolved a second
step in the dark reactions in which protons and electrons are reduced
to form H2 gas by specialized hydrogenases in the chloroplast. Efforts
have been undertaken to genetically modify cyanobacterial
hydrogenases to efficiently synthesize H2 gas even in the presence of
oxygen. Efforts have also been undertaken with genetically modified
alga in a bioreactor.
125
Magnesium
Magnesium is a chemical element with the symbol Mg and
atomic number 12. Its common oxidation number is +2. It
is an alkaline earth metal and the eighth most abundant
element in the Earth's crust and ninth in the known
universe as a whole. Magnesium is the fourth most
common element in the Earth as a whole (behind iron,
oxygen and silicon), making up 13% of the planet's mass.
Due to magnesium ion's high solubility in water, it is the
third most abundant element dissolved in seawater.
126
Magnesium
The free metal burns with a characteristic brilliant white light, making
it a useful ingredient in flares. The metal is now mainly obtained by
electrolysis of seawater. In human biology, magnesium is the eleventh
most abundant element by mass in the human body. Its ions are
essential to all living cells, where they play a major role in
manipulating important biological polyphosphate compounds like ATP,
DNA, and RNA. Hundreds of enzymes thus require magnesium ions to
function. Magnesium compounds are used medicinally as common
laxatives, antacids (e.g., milk of magnesia), and in a number of
situations where stabilization of abnormal nerve excitation and blood
vessel spasm is required (e.g., to treat eclampsia). In vegetation,
magnesium is the metallic ion at the center of chlorophyll, and is thus
a common additive to fertilizers.
127
Magnesium
History
The name magnesium originates from the Greek word for
a district in Thessaly called Magnesia. It is related to
magnetite and manganese, which also originated from this
area, and required differentiation as separate substances.
Magnesium is the eighth most abundant element in the
Earth's crust by mass. In 1618, a farmer at Epsom in
England attempted to give his cows water from a well
there. The cows refused to drink because of the water's
bitter taste, but the farmer noticed that the water seemed
to heal scratches and rashes. The substance became
known as Epsom salts and its fame spread. It was
eventually recognized as hydrated magnesium sulfate.
128
Magnesium
Biological role
Because of the important interaction between phosphate and
magnesium ions, magnesium ions are essential to the basic nucleic
acid chemistry of life, and thus are essential to all cells of all known
living organisms. Over 300 enzymes require the presence of
magnesium ions for their catalytic action, including all enzymes
utilizing or synthesizing ATP, or those that use other nucleotides to
synthesize DNA and RNA. ATP exists in cells normally as a chelate of
ATP and a magnesium ion. Plants have an additional use for
magnesium in that chlorophylls are magnesium-centered porphyrins.
Magnesium deficiency in plants causes late-season yellowing between
leaf veins, especially in older leaves, and can be corrected by applying
Epsom salts (which is rapidly leached).
129
Magnesium
Biological role
Magnesium is a vital component of a healthy human diet. Human
magnesium deficiency (including conditions that show few overt
symptoms) is relatively rare, although only 32% of people in the
United States meet the RDA-DRI; low levels of magnesium in the body
has been associated with the development of a number of human
illnesses such as asthma, diabetes, and osteoporosis. Taken in the
proper amount, magnesium plays a role in preventing both stroke and
heart attack. The symptoms of people with fibromyalgia, migraines,
and girls going through their premenstrual syndrome are less severe
and magnesium can shorten the length of the migraine symptoms.
130
Magnesium
Biological role
Adult human bodies contain about 24 grams of magnesium, with 60%
in the skeleton, 39% intracellular (20% in skeletal muscle), and 1%
extracellular. Serum magnesium levels may appear normal even in
cases of underlying intracellular deficiency, although no known
mechanism maintains a homeostatic level in the blood other than renal
excretion of high blood levels.
131
Magnesium
Biological role
Intracellular magnesium is correlated with intracellular potassium.
Magnesium is absorbed in the gastrointestinal tract, with more
absorbed when status is lower. In humans, magnesium appears to
facilitate calcium absorption. Low and high protein intake inhibit
magnesium absorption, and other factors such as phosphate and fat
affect absorption. Absorbed dietary magnesium is largely excreted
through the urine, although most magnesium "administered orally" is
excreted through the feces. Magnesium status may be assessed
roughly through serum and erythrocyte Mg concentrations and urinary
and fecal excretion, but intravenous magnesium loading tests are likely
the most accurate and practical in most people. In these tests,
magnesium is injected intravenously; a retention of 20% or more
indicates deficiency. Other nutrient deficiencies are identified through
biomarkers, but none are established for magnesium.
132
Magnesium
Biological role
Spices, nuts, cereals, coffee, cocoa, tea, and vegetables are rich
sources of magnesium. Green leafy vegetables such as spinach are
also rich in magnesium as they contain chlorophyll. Observations of
reduced dietary magnesium intake in modern Western countries
compared to earlier generations may be related to food refining and
modern fertilizers that contain no magnesium.
133
Magnesium
Excess magnesium in the blood is freely filtered at the
kidneys, and for this reason it is difficult to overdose on
magnesium from dietary sources alone. With supplements,
overdose is possible, however, particularly in people with
poor renal function; occasionally, with use of high cathartic
doses of magnesium salts, severe hypermagnesemia has
been reported to occur even without renal dysfunction.
Alcoholism can produce a magnesium deficiency, which is
easily reversed by oral or parenteral administration,
depending on the degree of deficiency.
134
Magnesium
Detection in biological fluids
Magnesium concentrations in plasma or serum may be
measured to monitor for efficacy and safety in those
receiving the drug therapeutically, to confirm the diagnosis
in potential poisoning victims or to assist in the forensic
investigation in a case of fatal overdosage. The newborn
children of mothers who received parenteral magnesium
sulfate during labor may exhibit toxicity at serum
magnesium levels that were considered appropriate for the
mothers.
135
Magnesium
Magnesium in treatment-resistant depression (TRD)
There has been some speculation that magnesium deficiency
can lead to depression. Cerebral spinal fluid (CSF)
magnesium has been found low in treatment-resistant
suicidal depression and in patients that have attempted
suicide. Brain magnesium has been found low in TRD using
phosphorus nuclear magnetic resonance spectroscopy, an
accurate means for measuring brain magnesium. Blood and
CSF magnesium do not appear well-correlated with major
depression. Magnesium chloride in relatively small doses was
found as effective in the treatment of depressed elderly type
2 diabetics with hypomagnesemia as imipramine 50 mg
daily.
136
Magnesium
Magnesium in disease
Results from a meta-analysis of randomized clinical trials
demonstrated that magnesium supplementation lowers high
blood pressure in a dose dependent manner. Low serum
magnesium levels are associated with metabolic syndrome,
diabetes mellitus type 2 and hypertension. Magnesium
therapy is recommended for Management of Patients With
Ventricular Arrhythmias and the Prevention of Sudden
Cardiac Death as well as for the treatment of patients with
digoxin intoxication-induced arrhythmias.
137
Magnesium
Magnesium in disease
Magnesium is also the drug of choice in the management of
pre-eclampsia and eclampsia.
Besides its therapeutic role, magnesium has an additional
beneficial effect on calcification. Patients with chronic kidney
disease have a high prevalence of vascular calcification, and
cardiovascular disease is the leading cause of death in this
population. Magnesium is a natural calcium antagonist and
low circulating magnesium levels are associated with
vascular calcification.
138
Magnesium
Magnesium in disease
Magnesium supplementation might be useful in reducing the
progression of atherosclerosis in chronic dialysis patients.
Low serum magnesium may be an independent risk factor
for death in patients with chronic kidney disease, and
patients with mildly elevated serum magnesium levels could
have a survival advantage over those with lower magnesium
levels.
139
Nitrogen
Nitrogen is a chemical element with symbol N and atomic number 7.
Elemental nitrogen is a colorless, odorless, tasteless gas, constituting
78% by volume of Earth's atmosphere. The element nitrogen was
discovered as a separable component of air, by Scottish physician
Daniel Rutherford, in 1772. Nitrogen is a common element in the
universe, estimated at about seventh in total abundance in our galaxy
and the Solar System. It is synthesized by fusion of carbon and
hydrogen in supernovas. Due to the volatility of elemental nitrogen
and its common compounds with hydrogen and oxygen, nitrogen is far
less common on the rocky planets of the inner Solar System, and it is
a relatively rare element on Earth as a whole. However, as on Earth,
nitrogen and its compounds occur commonly as gases in the
atmospheres of planets and moons that have atmospheres.
140
Nitrogen
Many industrially important compounds, such as ammonia, nitric acid,
organic nitrates (propellants and explosives), and cyanides, contain
nitrogen. The extremely strong bond in elemental nitrogen dominates
nitrogen chemistry, causing difficulty for both organisms and industry
in converting the N2 into useful compounds, but at the same time
causing release of large amounts of often useful energy when the
compounds burn, explode, or decay back into nitrogen gas.
Synthetically-produced ammonia and nitrates are key industrial
fertilizers and fertilizer nitrates are key pollutants in causing the
eutrophication (overabundance of algae) of water systems.
141
Nitrogen
Nitrogen occurs in all organisms, primarily in amino acids (and thus
proteins) and also in the nucleic acids (DNA and RNA). The human
body contains about 3% by weight of nitrogen, the fourth most
abundant element in the body after oxygen, carbon, and hydrogen.
The nitrogen cycle describes movement of the element from the air,
into the biosphere and organic compounds, then back into the
atmosphere.
142
Nitrogen
History and etymology
Nitrogen is formally considered to have been discovered by Scottish
physician Daniel Rutherford in 1772, who called it noxious air or fixed
air. The fact that there was constituent of air that does not support
combustion was clear to Rutherford. Nitrogen was also studied at
about the same time by Carl Wilhelm Scheele, Henry Cavendish, and
Joseph Priestley, who referred to it as burnt air or phlogisticated air.
Nitrogen gas was inert enough that Antoine Lavoisier referred to it as
"mephitic air" or azote, from the Greek word ἄζωτος (azotos) meaning
"lifeless". In it, animals died and flames were extinguished. Lavoisier's
name for nitrogen is used in many languages and still remains in
English in the common names of many compounds, such as hydrazine
and compounds of the azide ion.
143
Nitrogen
History and etymology
The English word nitrogen (1794) entered the language from the
French nitrogène, coined in 1790 by French chemist Jean-Antoine
Chaptal (1756–1832), from the Greek "nitron" (sodium carbonate) and
the French gène (producing). The gas had been found in nitric acid.
Chaptal's meaning was that nitrogen gas is the essential part of nitric
acid, in turn formed from saltpetre (potassium nitrate), then known as
nitre. This word in the more ancient world originally described sodium
salts that did not contain nitrate, and is a cognate of natron.
144
Nitrogen
Biological role
Nitrogen is an essential building block of amino and nucleic acids,
essential to life on Earth.
Elemental nitrogen in the atmosphere cannot be used directly by either
plants or animals, and must be converted to a reduced (or 'fixed')
state to be useful for higher plants and animals. Precipitation often
contains substantial quantities of ammonium and nitrate, thought to
result from nitrogen fixation by lightning and other atmospheric
electric phenomena. This was first proposed by Liebig in 1827 and
later confirmed. However, because ammonium is preferentially
retained by the forest canopy relative to atmospheric nitrate, most
fixed nitrogen reaches the soil surface under trees as nitrate. Soil
nitrate is preferentially assimilated by tree roots relative to soil
ammonium.
145
Nitrogen
Biological role
Specific bacteria (e.g., Rhizobium trifolium) possess nitrogenase
enzymes that can fix atmospheric nitrogen (see nitrogen fixation) into
a form (ammonium ion) that is chemically useful to higher organisms.
This process requires a large amount of energy and anoxic conditions.
Such bacteria may live freely in soil but normally exist in a symbiotic
relationship in the root nodules of leguminous plants (e.g. clover, or
soybean). Nitrogen-fixing bacteria are also symbiotic with a number of
unrelated plant species such as lichens.
As part of the symbiotic relationship, the plant converts the 'fixed'
ammonium ion to nitrogen oxides and amino acids to form proteins
and other molecules, (e.g.,alkaloids). In return for the 'fixed' nitrogen,
the plant secretes sugars to the symbiotic bacteria. Legumes maintain
an anaerobic (oxygen free) environment for their nitrogen-fixing
bacteria.
146
Nitrogen
Biological role
Plants are able to assimilate nitrogen directly in the form of nitrates
that may be present in soil from natural mineral deposits, artificial
fertilizers, animal waste, or organic decay (as the product of bacteria,
but not bacteria specifically associated with the plant). Nitrates
absorbed in this fashion are converted to nitrites by the enzyme nitrate
reductase, and then converted to ammonia by another enzyme called
nitrite reductase.
Nitrogen compounds are basic building blocks in animal biology as
well. Animals use nitrogen-containing amino acids from plant sources
as starting materials for all nitrogen-compound animal biochemistry,
including the manufacture of proteins and nucleic acids. Plant-feeding
insects are dependent on nitrogen in their diet, such that varying the
amount of nitrogen fertilizer applied to a plant can affect the
reproduction rate of insects feeding on fertilized plants.
147
Phosphate
A phosphate is a salt of phosphoric acid.
The phosphate ion has the empirical formula PO4. It consists of one
central phosphorus atom surrounded by four oxygen atoms.
Phosphates are most commonly found in the form of adenosine
phosphates, (AMP, ADP and ATP) and in DNA and RNA and can be
released by the hydrolysis of ATP or ADP. The bonds in ADP and ATP
contain high amounts of energy which give them their vital role in all
living organisms. The addition and removal of phosphate from proteins
in all cells is a pivotal strategy in the regulation of metabolic processes.
Phosphate is useful in animal cells as a buffering agent. An important
occurrence of phosphates in biological systems is as the structural
material of bone and teeth. These structures are made of crystalline
calcium phosphate in the form of hydroxyapatite. The hard dense
enamel of mammalian teeth consists of fluoroapatite, an hydroxy
calcium phosphate where some of the hydroxyl groups have been
replaced by fluoride ions.
148
Potassium
Potassium is a chemical element with symbol K (from Neo-Latin
kalium). Because potassium and sodium are chemically very similar,
their salts were not at first differentiated. Potassium ions are necessary
for the function of all living cells. Potassium ion diffusion is a key
mechanism in nerve transmission, and potassium depletion in animals,
including humans, results in various cardiac dysfunctions. Potassium
accumulates in plant cells, and thus fresh fruits and vegetables are a
good dietary source of it. Heavy crop production rapidly depletes soils
of potassium, and agricultural fertilizers consume 95% of global
potassium chemical production.
149
Potassium
History
Kalium was taken from the word "alkali", which in turn came from
Arabic: "plant ashes." The similar-sounding English term alkali is from
this same root – potassium in Modern Standard Arabic is būtāsyūm.
The English name for the element potassium comes from the word
"potash", and refers to the method by which potash was obtained –
leaching the ash of burnt wood or tree leaves and evaporating the
solution in a pot.
150
Potassium
Biological role
The action of the sodium-potassium pump is an example of primary
active transport. The two carrier proteins on the left are using ATP to
move sodium out of the cell against the concentration gradient. The
proteins on the right are using secondary active transport to move
potassium into the cell.
Potassium is the eighth or ninth most common element by mass
(0.2%) in the human body, so that a 60 kg adult contains a total of
about 120 g of potassium. The body has about as much potassium as
sulfur and chlorine, and only the major minerals calcium and
phosphorus are more abundant.
151
Potassium
Biological role
Potassium cations are important in neuron (brain and nerve) function,
and in influencing osmotic balance between cells and the interstitial
fluid, with their distribution mediated in all animals by the Na+/K+ATPase pump. This ion pump uses ATP to pump three sodium ions out
of the cell and two potassium ions into the cell, thus creating an
electrochemical gradient over the cell membrane. In addition, the
highly selective potassium ion channels are crucial for the
hyperpolarization, in for example neurons, after an action potential is
fired.
152
Potassium
Membrane polarization
Potassium is also important in preventing muscle contraction and the
sending of all nerve impulses in animals through action potentials. A
shortage of potassium in body fluids may cause a potentially fatal
condition known as hypokalemia, typically resulting from vomiting,
diarrhea, and/or increased diuresis. Deficiency symptoms include
muscle weakness, paralytic ileus, ECG abnormalities, decreased reflex
response and in severe cases respiratory paralysis, alkalosis and
cardiac arrhythmia.
153
Potassium
Filtration and excretion
Potassium is an essential macromineral in human nutrition; it is the
major cation (positive ion) inside animal cells, and it is thus important
in maintaining fluid and electrolyte balance in the body. Sodium makes
up most of the cations of blood plasma at a reference range of about
145 mmol/L (3.345 g)(1mmol/L = 1mEq/L), and potassium makes up
most of the cell fluid cations at about 150 mmol/L (4.8 g). Plasma is
filtered through the glomerulus of the kidneys in enormous amounts,
about 180 liters per day. Thus 602 g of sodium and 33 g of potassium
are filtered each day. All but the 1–10 g of sodium and the 1–4 g of
potassium likely to be in the diet must be reabsorbed. Sodium must be
reabsorbed in such a way as to keep the blood volume exactly right
and the osmotic pressure correct; potassium must be reabsorbed in
such a way as to keep serum concentration as close as possible to 4.8
mmol/L (about 0.190 g/L).
154
Potassium
Filtration and excretion
Sodium pumps in the kidneys must always operate to conserve
sodium. Potassium must sometimes be conserved also, but, as the
amount of potassium in the blood plasma is very small and the pool of
potassium in the cells is about thirty times as large, the situation is not
so critical for potassium. Since potassium is moved passively[ in
counter flow to sodium in response to an apparent (but not actual)
Donnan equilibrium, the urine can never sink below the concentration
of potassium in serum except sometimes by actively excreting water at
the end of the processing. Potassium is secreted twice and reabsorbed
three times before the urine reaches the collecting tubules. At that
point, it usually has about the same potassium concentration as
plasma. At the end of the processing, potassium is secreted one more
time if the serum levels are too high.
155
Potassium
Filtration and excretion
If potassium were removed from the diet, there would remain a
minimum obligatory kidney excretion of about 200 mg per day when
the serum declines to 3.0–3.5 mmol/L in about one week, and can
never be cut off completely, resulting in hypokalemia and even death.
The potassium moves passively through pores in the cell membrane.
When ions move through pumps there is a gate in the pumps on either
side of the cell membrane and only one gate can be open at once. As
a result, approximately 100 ions are forced through per second. Pores
have only one gate, and there only one kind of ion can stream
through, at 10 million to 100 million ions per second. The pores
require calcium in order to open although it is thought that the calcium
works in reverse by blocking at least one of the pores.
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Potassium
In diet
Adequate intake
A potassium intake sufficient to support life can in general be
guaranteed by eating a variety of foods. Clear cases of potassium
deficiency (as defined by symptoms, signs and a below-normal blood
level of the element) are rare in healthy individuals. Foods rich in
potassium include parsley, dried apricots, dried milk,chocolate, various
nuts (especially almonds and pistachios), potatoes, bamboo shoots,
bananas, avocados, soybeans, and bran, although it is also present in
sufficient quantities in most fruits, vegetables, meat and fish.
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Potassium
In diet
Optimal intake
Epidemiological studies and studies in animals subject to hypertension
indicate that diets high in potassium can reduce the risk of
hypertension and possibly stroke (by a mechanism independent of
blood pressure), and a potassium deficiency combined with an
inadequate thiamine intake has produced heart disease in rats. There
is some debate regarding the optimal amount of dietary potassium.
For example, the 2004 guidelines of the Institute of Medicine specify a
DRI of 4,000 mg of potassium (100 mEq), though most Americans
consume only half that amount per day, which would make them
formally deficient as regards this particular recommendation.
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Potassium
Medical supplementation and disease
Supplements of potassium in medicine are most widely used in
conjunction with loop diuretics and thiazides, classes of diuretics that
rid the body of sodium and water, but have the side-effect of also
causing potassium loss in urine. A variety of medical and non-medical
supplements are available. Potassium salts such as potassium chloride
may be dissolved in water, but the salty/bitter taste of high
concentrations of potassium ion make palatable high concentration
liquid supplements difficult to formulate. Typical medical supplemental
doses range from 10 mmol (400 mg, about equal to a cup of milk or 6
fl oz of orange juice) to 20 mmol (800 mg) per dose.
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Potassium
Medical supplementation and disease
Potassium salts are also available in tablets or capsules, which for
therapeutic purposes are formulated to allow potassium to leach slowly
out of a matrix, as very high concentrations of potassium ion (which
might occur next to a solid tablet of potassium chloride) can kill tissue,
and cause injury to the gastric or intestinal mucosa. For this reason,
non-prescription supplement potassium pills are limited by law in the
US to only 99 mg of potassium.
Individuals suffering from kidney diseases may suffer adverse health
effects from consuming large quantities of dietary potassium. End
stage renal failure patients undergoing therapy by renal dialysis must
observe strict dietary limits on potassium intake, as the kidneys control
potassium excretion, and buildup of blood concentrations of potassium
(hyperkalemia) may trigger fatal cardiac arrhythmia.
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Sodium
Sodium is a chemical element with the symbol Na (from Latin:
natrium). Sodium is the sixth most abundant element in the Earth's
crust. Chloride and sodium are the most common dissolved elements
by weight in the Earth's bodies of oceanic water. In animals, sodium
ions are used against potassium ions to build up charges on cell
membranes, allowing transmission of nerve impulses when the charge
is dissipated. The consequent need of animals for sodium causes it to
be classified as a dietary inorganic macro-mineral.
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Sodium
History
Salt has been an important commodity in human activities, as shown
by the English word salary, which derives from salarium, the wafers of
salt sometimes given to Roman soldiers along with their other wages.
In medieval Europe, a compound of sodium with the Latin name of
sodanum was used as a headache remedy. The name sodium is
thought to originate from the Arabic suda, meaning headache. The
chemical abbreviation for sodium was first published by Jöns Jakob
Berzelius in his system of atomic symbols, and is a contraction of the
element's new Latin name natrium, which refers to the Egyptian
natron, a natural mineral salt.
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Sodium
Biological role
In humans, sodium is an essential nutrient that regulates blood
volume, blood pressure, osmotic equilibrium and pH; the minimum
physiological requirement for sodium is 500 milligrams per day.
Sodium chloride is the principal source of sodium in the diet, and is
used as seasoning and preservative, such as for pickling and jerky;
most of it comes from processed foods. The DRI for sodium is 2.3
grams per day, but on average people in the United States consume
3.4 grams per day, the minimum amount that promotes hypertension;
this in turn causes 7.6 million premature deaths worldwide.
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Sodium
Biological role
The renin-angiotensin system regulates the amount of fluids and
sodium in the body. Reduction of blood pressure and sodium
concentration in the kidney result in the production of renin, which in
turn produces aldosterone and angiotensin, retaining sodium in the
urine. Because of the increase in sodium concentration, the production
of renin decreases, and the sodium concentration returns to normal.
Sodium is also important in neuron function and osmoregulation
between cells and the extracellular fluid, their distribution mediated in
all animals by Na+/K+-ATPase; hence, sodium is the most prominent
cation in extracellular fluid.
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Urea
Urea is an organic compound with the chemical formula CO(NH2)2.
Urea serves an important role in the metabolism of nitrogen-containing
compounds by animals and is the main nitrogen-containing substance
in the urine of mammals. It is a colorless, odorless solid, highly soluble
in water and practically non-toxic. Dissolved in water, it is neither
acidic nor alkaline. The body uses it in many processes, the most
notable one being nitrogen excretion. Urea is widely used in fertilizers
as a convenient source of nitrogen. Urea is also an important raw
material for the chemical industry. The discovery by Friedrich Wöhler
in 1828 that urea can be produced from inorganic starting materials
was an important conceptual milestone in chemistry, as it showed for
the first time that a substance previously known only as a byproduct of
life could be synthesized in the lab without any biological starting
materials, contradicting the widely held doctrine of vitalism.
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Urea
History
Urea was first discovered in urine in 1727 by the Dutch scientist
Herman Boerhaave, though this discovery is often attributed to the
French chemist Hilaire Rouelle. In 1828, the German chemist Friedrich
Wöhler obtained urea by treating silver cyanate with ammonium
chloride. For this discovery, Wöhler is considered by many to be the
father of organic chemistry.
AgNCO + NH4Cl → (NH2)2CO + AgCl
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Urea
Physiology
Urea is synthesized in the body of many organisms as part of the urea
cycle, either from the oxidation of amino acids or from ammonia. In
this cycle, amino groups (NH2) donated by ammonia and aspartate are
converted to urea. Urea production occurs in the liver. Urea is found
dissolved in blood (in the reference range of 2.5 to 6.7 mmol/liter) and
is excreted by the kidney as a component of urine. In addition, a small
amount of urea is excreted in sweat.
Amino acids from ingested food that are not used for the synthesis of
proteins and other biological substances are oxidized by the body,
yielding urea and carbon dioxide, as an alternative source of
energy.The oxidation pathway starts with the removal of the amino
group by a transaminase; the amino group is then fed into the urea
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cycle.
Urea
In humans
The handling of urea by the kidneys is a vital part of human
metabolism. Besides its role as carrier of waste nitrogen, urea also
plays a role in the countercurrent exchange system of the nephrons, in
that it allows for re-absorption of water and critical ions from the
excreted urine. Urea is reabsorbed in the nephrons, thus raising the
osmolarity in the thin ascending limb of the loop of Henle, which in
turn causes water to be reabsorbed. By action of the urea transporter
2, some of this reabsorbed urea will eventually flow back into the thin
ascending limb of the tubule, through the collecting ducts, and into the
excreted urine. This mechanism, which is controlled by the antidiuretic
hormone, allows the body to create hyperosmotic urine, which has a
higher concentration of dissolved substances than the blood plasma.
This mechanism is important to prevent the loss of water, to maintain
blood pressure, and to maintain a suitable concentration of sodium
ions in the blood plasmas.
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Urea
In humans
The equivalent nitrogen content (in gram) of urea (in mmol) can be
estimated by the conversion factor 0.028 g/mmol. Furthermore, 1
gram of nitrogen is roughly equivalent to 6.25 grams of protein, and 1
gram of protein is roughly equivalent to 5 grams of muscle tissue. In
situations such as muscle wasting, 1 mmol of excessive urea in the
urine (as measured by urine volume in liters multiplied by urea
concentration in mmol/l) roughly corresponds to a muscle loss of 0.67
gram.
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Urea
In other species
In aquatic organisms the most common form of nitrogen waste is
ammonia, whereas land-dwelling organisms convert the toxic ammonia
to either urea or uric acid. Urea is found in the urine of mammals and
amphibians, as well as some fish. Birds and saurian reptiles have a
different form of nitrogen metabolism, which requires less water and
leads to nitrogen excretion in the form of uric acid.
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Urea
Agriculture Uses
More than 90% of world production of urea is destined for use as a
nitrogen-release fertilizer. Urea has the highest nitrogen content of all
solid nitrogenous fertilizers in common use. Therefore, it has the
lowest transportation costs per unit of nitrogen nutrient. The standard
crop-nutrient rating of urea is 46-0-0.
Many soil bacteria possess the enzyme urease, which catalyzes the
conversion of the urea molecule to two ammonia molecules and one
carbon dioxide molecule, thus urea fertilizers are very rapidly
transformed to the ammonium form in soils. Excess nitrogen that runs
from soils into water is a major cause of water pollution from
agriculture. Ammonia and nitrate are readily absorbed by plants, and
are the dominant sources of nitrogen for plant growth. Urea is also
used in many multi-component solid fertilizer formulations. Urea is
highly soluble in water and is, therefore, also very suitable for use in
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fertilizer solutions.
Uric Acid
Uric acid has the formula C5H4N4O3. Uric acid is a product of the
metabolic breakdown of purine nucleotides (found in high quantities in
red meat, red wine, aged cheese). High blood concentrations of uric
acid can lead to gout, diabetes and kidney stones.
Chemistry
Uric acid was first isolated from kidney stones in 1776 by
Scheele.Generally, the water solubility of uric acid is rather low. It has
greater solubility in hot water than cold, allowing for easy
recrystallization. This low solubility is significant for the etiology of
gout. Uric acid precipitates in cooler areas of the body. Therefore, uric
acid crystals may form in the 1st metatarsal phalangeal joint, causing
the symptoms of gout.
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Uric Acid
Biology
The enzyme xanthine oxidase makes uric acid from xanthine and
hypoxanthine, which in turn are produced from other purines. In
humans and higher primates, uric acid is the final oxidation
(breakdown) product of purine metabolism and is excreted in urine.
Both uric acid and ascorbic acid are strong reducing agents (electron
donors) and potent antioxidants. In humans, over half the antioxidant
capacity of blood plasma comes from uric acid.
The Dalmatian dog has a genetic defect in uric acid uptake by the liver
and kidneys, so this breed excretes uric acid directly into the urine.
In humans, about 70% of daily uric acid disposal occurs via the
kidneys, and in 5-25% of humans, impaired renal (kidney) excretion
leads to hyperuricemia.
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Uric Acid
Genetics
A proportion of people have mutations in the proteins responsible for
the excretion of uric acid by the kidneys. This is what causes them to
have the error in purine metabolism, causing gout.
Medicine
Uric acid concentrations in blood plasma above and below the normal
range are known, respectively, as hyperuricemia and hypouricemia.
Similarly, uric acid concentrations in urine above and below normal are
known as hyperuricosuria and hypouricosuria. Such abnormal
concentrations of uric acid are not medical conditions, but are
associated with a variety of medical conditions.
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Uric Acid
High uric acid
High levels of uric acid is called hyperuricemia.
Causes of high uric acid
In many instances, people have elevated uric acid levels for hereditary
reasons.
Diet may be a factor. High intake of dietary purine, high fructose corn
syrup, and table sugar can cause increased levels of uric acid.
Serum uric acid can be elevated due to reduced excretion by the
kidneys.
Fasting or rapid weight loss can temporarily elevate uric acid levels.
Certain drugs, such as thiazide diuretics, can increase uric acid levels
in the blood by interfering with renal clearance.
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Uric Acid
Gout
Excess serum accumulation of uric acid in the blood can lead to a type
of arthritis known as gout. This painful condition is the result of
needle-like crystals of uric acid precipitating in joints, capillaries, skin,
and other tissues. Kidney stones can also form through the process of
formation and deposition of sodium urate microcrystals.
A study found that men who drank two or more sugar-sweetened
beverages a day have an 85% higher chance of developing gout than
those who drank such beverages infrequently.
Inflammation during attacks is commonly treated with NSAIDs or
corticosteroids, and urate levels are managed with allopurinol, which
inhibits xanthine oxidase and thus inhibits uric acid synthesis.
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Uric Acid
Lesch-Nyhan syndrome
Lesch-Nyhan syndrome, an extremely rare inherited disorder, is also
associated with very high serum uric acid levels. Spasticity, involuntary
movement and cognitive retardation as well as manifestations of gout
are seen in cases of this syndrome.
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Uric Acid
Cardiovascular disease
Although uric acid can act as an antioxidant, excess serum
accumulation is often associated with cardiovascular disease. It is not
known whether this is causative (e.g., by acting as a prooxidant ) or a
protective reaction taking advantage of urate's antioxidant properties.
The same may account for the putative role of uric acid in the etiology
of stroke.
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Uric Acid
Type 2 diabetes
The association of high serum uric acid with insulin resistance has
been known since the early part of the 20th century, nevertheless,
recognition of high serum uric acid as a risk factor for diabetes has
been a matter of debate. In fact, hyperuricemia has always been
presumed to be a consequence of insulin resistance rather than its
precursor. However, a prospective follow-up study showed high serum
uric acid is associated with higher risk of type 2 diabetes, independent
ofobesity, dyslipidemia, and hypertension.
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Uric Acid
Metabolic syndrome
Hyperuricemia is associated with components of metabolic syndrome.
A study has suggested fructose-induced hyperuricemia may play a
pathogenic role in the metabolic syndrome. This is consistent with the
increased consumption in recent decades of fructose-containing
beverages (such as fruit juices and soft drinks sweetened with sugar
and high-fructose corn syrup) and the epidemic of diabetes and
obesity.
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Uric Acid
Uric acid stone formation
Saturation levels of uric acid in blood may result in one form of kidney
stones when the urate crystallizes in the kidney. These uric acid stones
are radiolucent and so do not appear on an abdominal plain X-ray, and
thus their presence must be diagnosed by ultrasound for this reason.
Very large stones may be detected on X-ray by their displacement of
the surrounding kidney tissues.
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Uric Acid
Uric acid stone formation
Uric acid stones, which form in the absence of secondary causes such
as chronic diarrhea, vigorous exercise, dehydration, and animal protein
loading, are felt to be secondary to obesity and insulin resistance seen
in metabolic syndrome. Increased dietary acid leads to increased
endogenous acid production in the liver and muscles, which in turn
leads to an increased acid load to the kidneys. This load is handled
more poorly because of renal fat infiltration and insulin resistance,
which are felt to impair ammonia excretion (a buffer). The urine is
therefore quite acidic, and uric acid becomes insoluble, crystallizes and
stones form. In addition, naturally present promoter and inhibitor
factors may be affected. This explains the high prevalence of uric
stones and unusually acidic urine seen in patients with type 2 diabetes.
Uric acid crystals can also promote the formation of calcium oxalate
stones, acting as "seed crystals" (heterogeneous nucleation).
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Uric Acid
Low uric acid (hypouricemia)
Causes of low uric acid
 Low dietary zinc intakes cause lower uric acid levels. This effect can
be even more pronounced in women taking oral contraceptive
medication.
 Xanthine oxidase is an Fe (iron) enzyme, so people with Fe
deficiency (the most common cause of anemia in young women)
can experience hypouricemia.
 Xanthine oxidase loses its function and gains ascorbase function
when some of the Fe atoms in XO are replaced with Cu atoms.
Accordingly, people with high Cu/Fe can experience hypouricemia
and vitamin C deficiency, resulting in oxidative damage. Since
estrogen increases the half-life of Cu, women with very high
estrogen levels and intense blood loss during menstruation are
likely to have a high Cu/Fe and present with hypouricemia.
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Uric Acid
Sevelamer, a drug indicated for prevention of hyperphosphataemia in
patients with chronic renal failure, can significantly reduce serum uric
acid.
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Uric Acid
Multiple sclerosis
Lower serum values of uric acid have been associated with multiple
sclerosis (MS). A 2006 study found elevation of serum uric acid values
in multiple sclerosis patients, by oral supplementation with inosine,
resulted in lower relapse rates, and no adverse effects.
Normalizing low uric acid
Correcting low or deficient zinc levels can help elevate serum uric acid.
Inosine can be used to elevate uric acid levels. Zn inhibits Cu
absorption, helping to reduce the high Cu/Fe in some people with
hypouricemia. Fe supplements can ensure adequate Fe reserves
(ferritin above 25 ng/dl), also correcting the high Cu/Fe.
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Uric Acid
Oxidative stress
Uric acid may be a marker of oxidative stress, and may have a
potential therapeutic role as an antioxidant. On the other hand, like
other strong reducing substances such as ascorbate, uric acid can also
act as a prooxidant. Thus, it is unclear whether elevated levels of uric
acid in diseases associated with oxidative stress such as stroke and
atherosclerosis are a protective response or a primary cause. For
example, some researchers propose hyperuricemia-induced oxidative
stress is a cause of metabolic syndrome. On the other hand, plasma
uric acid levels correlate with longevity in primates and other
mammals. This is presumably a function of urate's antioxidant
properties.
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Uric Acid
Sources
Purines are found in high amounts in animal food products, such as
liver and sardines. A moderate amount of purine is also contained in
beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach,
mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat
bran and wheat germ.
Examples of high purine and Fe sources include: sweetbreads,
anchovies, sardines, liver, beef kidneys, brains, herring, mackerel,
scallops, game meats, and gravy.
One serving of meat or seafood (3 oz = 85 g) mildly increases risk of
gout, while two servings increase risk by at least 40%. Milk products
reduce the risk of gout notably, whereas total protein intake has no
effect.
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Urea Cycle
The urea cycle is a series of biochemical reactions occurring in many
animals that produces urea from ammonia(NH3). In mammals, the
urea cycle takes place primarily in the liver, and to a lesser extent in
the kidney.
Function
Organisms that cannot easily and quickly remove ammonia usually
have to convert it to some other substance, like urea or uric acid,
which are much less toxic. Insufficiency of the urea cycle occurs in
some genetic disorders (inborn errors of metabolism), and in liver
failure. The result of liver failure is accumulation of nitrogenous waste,
mainly ammonia, which leads to hepatic encephalopathy.
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Urea Cycle
Reactions
The urea cycle consists of five reactions: two are in the mitochondria
and three are in the cytoplasm. The cycle converts two amino groups,
one from NH4+ and one from Aspartate (an amino acid), and a carbon
atom from HCO3−, to the relatively nontoxic excretion product urea at
the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2
ADP and one AMP). Ornithine is the carrier of these carbon and
nitrogen atoms.
The overall formula for the urea cycle is this:
2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi + AMP
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Urea Cycle
This process requires energy, but it is necessary to convert the toxic
ammonia into non-toxic urea to transport it to the kidneys to remove
the nitrogen waste.
Note that reactions related to the urea cycle also cause the production
of 2 NADH, so the urea cycle releases slightly more energy than it
consumes.
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Urea Cycle
Inherited deficiencies in the cycle enzymes do not result in a decrease
in urea.
Rather, the deficient enzyme's substrate builds up all the way back up
the cycle to NH4+, resulting in hyperammonemia (elevated [NH4+]).
A high [NH4+] puts an enormous strain on the NH4+-clearing system,
especially in the brain (symptoms of urea cycle enzyme deficiencies
include mental retardation and lethargy).
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