Week # 13: Lipid Metabolism and Protein Metabolism
Lectures - 35, 36, 37
http://www.elmhurst.edu/~chm/vchembook/620fattyacid.html
Concepts:
Uses of Lipids in the Body
Fatty Acid Sprial
Ketone Bodies
Fatty Acid Synthesis
Protein Metabolism - Transamination, Oxidative Deamination
Urea Cycle
Synthesis of Amino Acids
Ques. 1. List the functions of lipids in the body.
Ques. 2. List the order in which the energy reserves of the body are depleted.
Include protein, fat, glucose, and glycogen.
Ques. 3:. What are the two possible metabolic fates for glycerol.
Ques. 4. Complete the following reactions which are part of the fatty acid spiral.
Use the general name of each reaction to write out the specific structures
involved. Start with CH3 (CH2) 10COOH and follow the example in the text.
a. Oxidative deydrogenation using FAD.
b. Hydration
c. Oxidative deydrogenation using NAD+.
d. Hydrolysis or cleavage of acetyl CoA.
Ques. 5. Which is the final product of the fatty acid spiral? __________
How many of the these are made for CH3(CH2) 10COOH? _______
How many turns of the fatty acid spiral are required? _______
Ques. 6: Use the diagram above to answer the following questions:
a. Name the reactions: 1 =
4=
2=
3=
b. Write the structure in the boxes above for: Rx 2 =
Rx 3 =
Ques. 7. Calculate the total ATP produced from the fatty acid spiral of CH 3(CH2)
14COOH. Show your work.
Ques. 8. Calculate the total ATP produced from the complete metabolism of
CH3(CH2)14COOH using both the fatty acid spiral and on into the citric acid cycle.
Show your work.
Ques. 9. Calculate the total ATP produced from the fatty acid spiral of CH 3(CH2)
10COOH. Show your work.
Ques. 10. Calculate the total ATP produced from the complete metabolism of
CH3(CH2)10COOH using both the fatty acid spiral and on into the citric acid cycle.
Show your work.
Ques. 11. Explain how the lipogenesis spiral differs from fatty acid oxidation
spiral? Just give general information. How are they similar?
Ques. 12. List the major steps in the conversion of a lipid into CO2 and water.
Ques. 13. List the major steps in the conversion of a carbohydrate into a lipid.
Ques. 14. List four or five uses for acetyl CoA.
http://www.elmhurst.edu/~chm/vchembook/623acetylCoAfate.html
Ques. 15. Describe how the condition of ketosis develops.
Ques. 16. List the names of three ketone bodies. Which one is not really a
ketone?
Info in Lipids, Diabetes in Virtual Chembook for the rest of the questions.
http://www.elmhurst.edu/~chm/vchembook/624diabetes.html
Ques. 17. Define hyperglycemia and hypoglycemia. What is the relation to
insulin
Ques. 18. Using the urine tests for glucose and ketones, how could you
distinguish between diabetes insipidus, renal diabetes, and diabetes mellitus?
Ques. 19. What is meant by the renal threshold?
Ques. 20. Explain the metabolic disorders associated with diabetes mellitus.
Include the following terms: glucosuria, ketosis, acidosis, hyperglycemia,
hypoinsulinism, polyuria, and acetonuria.
Ques. 21. How is the glucose tolerance test used to identify diabetes mellitus and
distinguish it from renal diabetes?
Glucose Tolerance Test: In order to measure the metabolic response of a
patient to glucose, the glucose tolerance test was devised. The test consists of
giving 100 g of glucose in place of breakfast and then testing the concentrations
of glucose in the blood and urine at specific timed intervals. This test establishes
when the blood glucose reaches its highest concentration, when glucosuria
occurs, and how rapidly the blood glucose concentration returns to normal.
In normal persons, the venous blood sugar value usually does not exceed 200
mg/100 ml blood and returns below 120 mg in two hours. In diabetes mellitus, the
glucose level peaks above 200 mg and does not return below 120 mg after two
hours. In renal diabetes, the blood glucose curve is normal. Glucose tolerance
curves may produce different results at different times on the same person.
Protein Metabolism:
http://www.elmhurst.edu/~chm/vchembook/631transam.html
Transamination
Transamination as the name implies, refers to the transfer of an amine group
from one molecule to another. This reaction is catalyzed by a family of enzymes
called transaminases. Actually, the transamination reaction results in the
exxhange of an amine group on one acid with a ketone group on another acid. It
is analogous to a double replacement reaction.
The general reaction is:
Amino acid + ketoacid  new ketoacid
+ new amino acid
The most usual and major keto acid involved with transamination reactions is ketoglutaric acid, an intermediate in the citric acid cycle. A specific example is
the transamination of alanine - below.
Ques. 22: Transamination:
O
H2N
CH
H3C
O
HO
+
C
OH
H2
C
C
O
C
C
H2
OH
C
O
b. What are the common names of products formed?
Ques. 23: Finish the transamination with aspartic acid.
NH2
HO
O
CH
C
O
+
C
C
H2
O
H2
C
HO
OH
aspartic acid
C
O
C
C
H2
OH
C
O
Other Transamination Reactions:
Aspartic acid can be converted into oxaloacetic acid, another intermediate of the
citric acid cycle. Other amino acids such as glutamine, histidine, arginine, and
proline are first converted into glutamic acid.
Glutamine and asparagine are converted into glutamic acid and aspartic acid by
a simple hydrolysis of the amide group.
All of the amino acids can be converted through a variety of reactions and
transamination into a keto acid which is a part of or feeds into the citric acid
cycle. The interrelationships of amino acids with the citric acid cycle are
illustrated in the graphic on the left.
Ques. 24a: List the amino acids that can be converted into glucose.
b: List the amino acids that can be converted into lipids.
Synthesis of New Amino Acids
In addition to the catabolic function of transamination reactions, these reactions
can also be used to synthesize amino acids needed or not present in the diet.
An amino acid may be synthesized if there is an available "root" ketoacid with a
synthetic connection to the final amino acid. Since an appropriate "root" ketoacid
does not exist for eight amino acids, (lys, leu, ile, met, thr, try, val, phe), they are
essential and must be included in the diet because they cannot be synthesized.
Glutamic acid usually serves as the source of the amine group in the
transamination synthesis of new amino acids. The reverse of the reactions
mentioned earlier are the most obvious methods for producing the amino acids
alanine and aspartic acid
Ques. 25: Write the transamination reaction for the synthesis of the following
new amino acids.
O
C
H3C
NH2
OH
C
+
O
H2
C
HO
C
CH
C
H2
O
pyruvic acid
OH
C
O
glutamic acid
Oxidative Deamination Reaction
Deamination is also an oxidative reaction that occurs under aerobic conditions in
all tissues but especially the liver. During oxidative deamination, an amino acid
is converted into the corresponding keto acid by the removal of the amine
functional group as ammonia and the amine functional group is replaced by the
ketone group. The ammonia eventually goes into the urea cycle.
Oxidative deamination occurs primarily on glutamic acid because glutamic acid
was the end product of many transamination reactions.
Ques. 26: Oxidative Deamination:
NH2
H2
C
HO
C
CH
C
H2
O
OH
C
O
glutamic acid
NAD+
+
HOH
Central Role for Glutamic Acid:
Apparently most amino acids may be deaminated but this is a significant reaction
only for glutamic acid. If this is true, then how are the other amino acids
deaminated? The answer is that a combination of transamination and
deamination of glutamic acid occurs which is a recycling type of reaction for
glutamic acid. The original amino acid loses its amine group in the process. The
general reaction sequence is shown on the left.
Urea Cycle
Urea is the major end product of nitrogen metabolism in humans and mammals.
Ammonia, the product of oxidative deamination reactions, is toxic in even small
amounts and must be removed from the body. The urea cycle or the ornithine
cycle describes the conversion reactions of ammonia into urea. Since these
reactions occur in the liver, the urea is then transported to the kidneys where it is
excreted. The overall urea formation reaction is: (Memorize it)
O
NH3
ammonia
+
O
C
O
carbon dioxide
+
C
H2 N
HOH
NH2
urea
The step wise process of the urea cycle is summarized in the graphic below. One
amine group comes from oxidative deamination of glutamic acid while the other
amine group comes from aspartic acid. Aspartic acid is regenerated from fumaric
acid produced by the urea cycle. The fumaric acid first undergoes reactions
through a portion of the citric acid cycle to produce oxaloacetic acid which is then
changed by transamination into aspartic acid.
Urea is routinely measured in the blood as: Blood Urea Nitrogen (BUN). BUN
levels may be elevated (a condition called uremia) in both acute and chronic
renal (kidney) failure. Various diseases damage the kidney and cause faulty
urine formation and excretion. Congestive heart failure leads to a low blood
pressure and consequent reduced filtration rates through the kidneys, therefore,
BUN may be elevated. Urinary tract obstructions can also lead to an increased
BUN. In severe cases, hemodialysis is used to remove the soluble urea and
other waste products from the blood. Waste products diffuse through the
dialyzing membrane because their concentration is lower in the dialyzing
solution. Ions, such as Na+ and Cl- which are to remain in the blood, are
maintained at the same concentration in the dialyzing solution - no net diffusion
occurs.
As stated previously, high ammonia levels are toxic to humans. A complete block
of any step in the urea cycle is fatal since there is no known alternative pathway
for the synthesis of urea. Inherited disorders from defective enzymes may cause
a partial block in some of the reactions and results in hyperammonemia which
can lead to mental retardation. Extensive ammonia accumulation leads to
extensive liver damage and death. Liver cirrhosis caused by alcoholism creates
an interference in the enzymes which produce carbamyl phosphate in the first
step on the cycle.
Hemoglobin Catabolism and Bilirubin
The catabolism of hemoglobin is outlined in the graphic on the left. Red blood
cells are continuously undergoing a hemolysis (breaking apart) process. The
average life-time of a red blood cell is 120 days. As the red blood cells
disintegrate, the hemoglobin is degraded or broken into globin, the protein part,
iron (conserved for latter use), and heme. The heme initially breaks apart into
biliverdin, a green pigment which is rapidly reduced to bilirubin, an orange-yellow
pigment (see middle graphic). These processes all occur in the
reticuloendothelial cells of the liver, spleen, and bone marrow. The bilirubin is
then transported to the liver where it reacts with a solubilizing sugar called
glucuronic acid. This more soluble form of bilirubin (conjugated) (see bottom
graphic) is excreted into the bile.
The bile goes through the gall bladder into the intestines where the bilirubin is
changed into a variety of pigments. The most important ones are stercobilinogen,
which is excreted in the feces, and urobilinogen, which is reabsorbed back into
the blood. The blood transports the urobilinogen back to the liver where it is
either re-excreted into the bile or into the blood for transport to the kidneys.
Urobilinogen is finally excreted as a normal component of the urine.
Types of Jaundice:
Various conditions of jaundice result from the accumulation of bilirubin in the
blood. A jaundice condition is characterized by yellow colored skin due to the
presence of bilirubin.
Hemolytic Jaundice:
Excessive hemolysis or breakdown of red blood cells causes the formation of
higher than normal amounts of bilirubin. Bilirubin made in the liver goes into bile
and then into the gall bladder and into the intestines where most is excreted. The
liver works normally, but could eventually be damaged from overwork. Usually
the liver can handle the excess and the bilirubin is excreted via intestines and
does not usually spill over into the kidneys. Urobilinogen levels are likely to be
elevated in the blood and urine.
Hepatic Jaundice:
Hepatic jaundice is caused by damage or disease in the liver. Heme enters the
liver but it does not take out as much bilirubin as is normal. Bilirubin builds up in
the blood and spills over into the kidneys which filter it out into the urine. The
amount of urobilinogen in the urine will be either normal or low if not enough
bilirubin is being removed by the liver into bile and the intestines.
Biliary Obstruction:
If bilirubin cannot reach the intestinal area because of a blockage in the bile duct,
than bilirubin builds up in the blood because it cannot get out of the liver. Bilirubin
is then removed by the kidneys into the urine. Little if any, urobilinogen will be
found in the urine since little or no bilirubin is reaching the intestines.
Ques. 27: Lab tests on urine may be made for both bilirubin and urobilinogen.
Complete the types of results expected for the various jaundice conditions.
Answer with positive, negative, lower, higher, etc.
LAB TEST
Normal
Bilirubin: neg.
Urobilinogen : pos.
Biliary Obstruction Hepatic Disease
Hemolytic Disease
Review Metabolism
By this time in your study you should have a pretty good knowledge of the
individual metabolic relationships in carbohydrates, lipids, and protein. Hopefully,
you have also begun to see that there are numerous interconnecting points
between all three types of metabolism. This should be particularly evident in the
considerations of diabetes, the amino acid transaminations, and the urea cycle.
As a further exercise in summarizing the metabolic interrelationships, you may be
asked to do "road map" problems for pieces of the overall metabolism
sequences.
A "road map" problem is merely the diagramming of a particular metabolic
pathway. The pathways described should be at least as detailed as that shown
on the graphic on the left. In all cases, the starting point is the ingestion of the
particular food listed.
Ques. 28: You should be able to diagram road maps for:
a) carbohydrate to CO2 and H2O
b) carbohydrate to lipid
c) protein to lipid
d) protein to CO2, H2O, urea
e) protein to glucose or glycogen
f) carbohydrate to glycogen
g) lipid to CO2 and H2O
h) lipid to protein
Alcohol Metabolism Effects
http://www.elmhurst.edu/~chm/vchembook/642alcoholmet.html
(Adapted from C.S. Lieber, Sci. Am. 234(3), 25(1976)
Alcohol is the favorite mood-altering drug in the United States and its effects, both pleasant and
unpleasant, are well-known. What may not be well known is the fact that alcohol is a toxic drug
that produces pathological changes (cirrhosis) in liver tissue and can cause death.
Alcohol is readily absorbed from the gastrointestinal tract; however, alcohol cannot be stored and
therefore, the body must oxidize it to get rid of it. Alcohol can only be oxidized in the liver, where
enzymes are found to initiate the process.
In addition, alcohol directly contributes to malnutrition since a pint of 86 proof alcohol (not an
unusual daily intake for an alcoholic) represents about half of the daily energy requirement.
However, ethanol does not have any minerals, vitamins, carbohydrates, fats or protein associated
with it. Alcohol causes inflammation of the stomach, pancreas, and intestines which impairs the
digestion of food and absorption into blood. Moreover, the acetaldehyde (the oxidation product)
can interfere with the activation of vitamins.
The first step in the metabolism of alcohol is the oxidation of ethanol to acetaldehyde catalyzed
by alcohol/dehydrogenase containing the coenzyme NAD+. The acetaldehyde is further oxidized
to acetic acid and finally CO2 and water through the citric acid cycle. A number of metabolic
effects from alcohol are directly linked to the production of an excess of both NADH and
acetaldehyde.
CH3CH2OH + NAD+ ---> CH3CH=O + NADH + H+
Metabolic Fates of NADH:
The metabolic pathways for the disposal of excess NADH and the consequent blocking of other
normal metabolic pathways is shown in the graphic on the left.
1. Pyruvic Acid to Lactic Acid:
The conversion of pyruvic acid to lactic acid requires NADH:
Pyruvic Acid + NADH + H+ ---> Lactic Acid + NAD+
This pyruvic acid normally made by transamination of amino acids, is intended for conversion into
glucose by gluconeogenesis. This pathway is inhibited by low concentrations of pyruvic acid,
since it has been converted to lactic acid. The final result may be acidosis from lactic acid buildup and hypoglycemia from lack of glucose synthesis.
2. Synthesis of Lipids:
Excess NADH may be used as a reducing agent in two pathways--one to synthesize glycerol
(from a glycolysis intermediate) and the other to synthesis fatty acids. As a result, heavy drinkers
may initially be overweight.
3. Electron Transport Chain:
The NADH may be used directly in the electron transport chain to synthesize ATP as a source of
energy. This reaction has the direct effect of inhibiting the normal oxidation of fats in the fatty acid
spiral and citric acid cycle. Fats may accumulate or acetyl CoA may accumulate with the resulting
production of ketone bodies. Accumulation of fat in the liver can be alleviated by secreting lipids
into the blood stream. The higher lipid levels in the blood may be responsible for heart attacks.