METABOLISM
OBJECTIVES
At the end of these lectures the student should :1. Understand the meaning of and importance of a balanced diet
2. Understand the concept of metabolic balance
3. Recognise the meaning of anabolism and catabolism
4. Have a basic understanding of the mechanisms of
carbohydrate breakdown and assembly glycolysis and
gluconeogenesis, and the metabolic pathways associated with
these processes.
5. Have a basic understanding of the mechanism for ATP
production in the mitochondrion.
6. Understand at the basic level lipid and protein metabolism.
NUTRIENTS
These are substances in food used by the body for growth,
maintenance, and repair.
6 categories :1-3 Carbohydrates, lipids, and proteins the major nutrients and
bulk of what we eat.
4 & 5 Vitamins and minerals, though crucial for health, are only
required in minute amounts.
6 Water, 60 % by volume of the food we eat, is also a major
nutrient.
Most foods provide a combination of nutrients. A diet consisting of
foods from each of the five main food groups - grains, fruits,
vegetables, meats and fish, and milk products - normally provides
all necessary nutrients.
The ability of cells (particularly liver) to convert one type of
molecule to another enables the body to use a wide range of the
chemicals found in foods and to adjust to varying food intakes.
There are limits to this ability to interconvert between molecules.
Some 45 molecules, called - essential nutrients, cannot be made
by the body or interconverted and must be contained in the diet.
As long as these essential nutrients are present, the body can
synthesize the hundreds of other molecules required for life,
growth and good health.
Carbohydrates
Except for milk sugar (lactose) and small amounts of glycogen in
meat, carbohydrates are derived from plants.
Monosaccharides and disaccharides (sugars) - come from fruits,
sugar cane, sugar beet, honey, and milk.
Polysaccharides (starch) are found in grains, legumes, and root
vegetables. Cellulose, present in most vegetables, cannot be
digested but provides roughage, or fibre, which increases the bulk
of the stool and facilitates defaecation.
The monosaccharide glucose is the carbohydrate molecule that is
ultimately used by body cells.
Carbohydrate digestion also yields the monosaccharides fructose
and galactose that are converted to glucose by the liver before
entering the general circulation.
Glucose is a major body fuel and used to make ATP.
Many cells can use fat as an energy source, however neurons and
red blood cells are almost entirely dependent on glucose for their
energy needs. Consequently a shortage of blood glucose can
affect brain function and lead to neuronal death. Hence the need
for blood glucose levels to be carefully regulated. Glucose excess
is converted to glycogen or fat and stored.
Carbohydrates are also used in; the synthesis of nucleic acids
(pentose sugars -fructose) and attachment to externally facing
plasma membrane proteins and lipids (Ag, signal molecules).
Monosaccharides - the basic subunits of –CHO’s. Usually have a
5 or 6 carbon backbone that forms into a ring structure, e.g.
glucose, fructose.
Dissacharides – dimers of monosacharides. Can have different
monosaccharides e.g. sucrose, maltose. Broken down into
monosaccharides for absorption.
Polysaccharides -polymers of monosaccharides. Can be chains
of one monosaccharide (cellulose), different monosaccharides,
branched (glycogen) or unbranched. Broken down into
monosaccharides for absorption.
Lipids
Dietary lipid is typically in the form of neutral fats - triglycerides or
triacylglycerols.
Saturated fats are present in animal products (meat and dairy
products) and in a few plant products (coconut).
Unsaturated fats are in seeds, nuts, and most vegetable oils.
Cholesterol is found in egg yolk, meats, and milk products.
Fats are digested to fatty acids and monoglycerides and
reconverted to triglycerides for transport in the lymph.
Although the liver is able to convert one fatty acid to another, it is
unable to synthesize linoleic acid, a fatty acid component of
lecithin. Linoleic acid is thus an essential fatty acid that must be
ingested. Linoleic acid is found in most vegetable oils.
Dietary fats are needed for several reasons :-
a) they help the body absorb fat-soluble vitamins
b) triglycerides are the major energy fuel of hepatocytes and
skeletal muscle
c) phospholipids are an integral component of myelin sheaths and
cellular membranes
d) the fatty deposits of adipose tissue provide a protective cushion
around body organs, an insulating layer beneath the skin, and
an store of energy fuel
e) regulatory molecules called prostaglandins, formed from
linoleic acid via arachidonic acid play a role in smooth muscle
contraction, control of blood pressure, and inflammation.
Unlike fats, cholesterol is not used for energy. It stabilises plasma
membranes and is a precursor of bile salts, steroid hormones, and
many other essential molecules.
Most fats have the general structure of a glycerol molecule with 3
fatty acid side chains attached. The side chains can be of different
lengths, straight (saturated) or kinked (unsaturated).
Proteins
Animal products contain proteins with the greater proportion of
essential amino acids. Proteins in eggs, milk, and most meats
meet all the body's amino acid requirements for tissue
maintenance and growth.
Legumes (beans and peas), nuts, and cereals are protein-rich but
nutritionally incomplete because they are low in one or more of the
essential amino acids. Leafy green vegetables are well balanced in
all essential amino acids except methionine, but contain only small
amounts of protein.
Strict vegetarians must carefully plan their diets to obtain all the
essential amino acids and prevent protein malnutrition. When
ingested together, cereal grains and legumes provide all the
essential amino acids.
Proteins are important structural materials of the body comprising
for example; keratin in skin, collagen and elastin in connective
tissue, muscle protein. They also have functional roles as,
enzymes and hormones.
Whether amino acids are used to synthesize new proteins or are
burned for energy depends on a number of factors:-
The all-or-none rule – all amino acids needed to make a particular
protein must be present in a cell at the same time and in sufficient
quantity. If one is missing, the protein cannot be made. Because
essential amino acids cannot be stored, those not used
immediately to build proteins are oxidized for energy or converted
to carbohydrates or fats.
Adequacy of caloric intake - for protein synthesis the diet must
provide sufficient carbohydrate or fat for ATP production. If
insufficient is available dietary and tissue proteins are used for
energy.
Nitrogen balance - in healthy adults the rate of protein synthesis
equals the rate of protein breakdown and loss. This homeostatic
state is called the body's nitrogen balance. The body is in nitrogen
balance when the amount of nitrogen ingested in proteins equals
the amount excreted in urine and faeces.
PROTEINS are polymers of amino acids (of which there are 20)
and must be broken down into their component AA’s for
absorption.
R and R’ are side
groups that differ
for each AA
When AA’s are joined together to construct proteins H2O is
released (hydrolysis). The protein will end up with an AMINO end
(-NH2) and a CARBOXYL end (-COOH). Protein characteristics
are dependent on the length of the chain, the component AA’s and
importantly the bends and twists that the different AA’s induce,
called secondary and tertiary structure.
Vitamins
Are essential organic compounds but needed only in minute
amounts. They usually function as coenzymes (or parts of
coenzymes), which act along side other enzymes to carry out a
particular chemical task.
e.g. the B vitamins riboflavin and niacin act as coenzymes in the
breakdown (oxidation) of glucose for energy.
Because they are essential they must be taken in via foods. The
exceptions are Vitamin D which is made in the skin, and Vitamin
K synthesized by intestinal bacteria. The body can convert beta –
carotene (the orange pigment in carrots and other foods) to
vitamin A.
Vitamins are found in all major food groups, but no one food
contains all the required vitamins. A balanced diet is required to
ensure a full vitamin complement.
Vitamins are fat soluble or water soluble.
Water-soluble vitamins – B and C are absorbed along with water
from the gastrointestinal tract (except for vitamin B12, which must
bind to gastric intrinsic factor to be absorbed). Not stored and
excess lost in urine
Fat-soluble vitamins - A, D, E, and K bind to ingested lipid and are
absorbed along with their digestion products. Anything that
interferes with fat absorption will affect uptake of fat-soluble
vitamins. Except for Vitamin K, fat-soluble vitamins are stored in
the body. Excesses may cause problems.
Minerals
The body requires moderate amounts of particular minerals;
calcium, phosphorus, potassium, sulphur, sodium, chlorine and
magnesium. It also needs trace amounts of a number of others (F,
Co, Cr, Cu, I, Fe, Mn, Se, Zn.
METABOLISM
Cells are chemical factories that break down organic molecules to
obtain energy, typically in the form of ATP. These reactions take
place in the mitochondrion and provide most of the energy needed
by a typical cell.
To carry out these metabolic reactions, cells need a good supply
of oxygen and nutrients. Oxygen is absorbed at the lungs, other
materials from the digestive tract and the cardiovascular system
ensures effective delivery throughout the body.
Energy released from breakdown supports growth, cell division,
contraction, secretion, as well as a number of other special
functions that vary from cell to cell and tissue to tissue.
As a result the energy requirements of different tissues is highly
variable.
When supply exceeds demand nutrients are stored in specialised
tissues – adipose tissue, glycogen deposits, where they remain
until needed. .
The endocrine system along with the nervous system, adjusts and
coordinates the metabolic activity of tissues and controls the
use, storage and remobilization of nutrient reserves.
The term metabolism describes all of the chemical reactions that
take place in an organism.
At the cellular level these chemical reactions provide the energy
needed to maintain homeostasis and to perform essential
functions such as :1) the periodic breakdown and replacement of the organic
components of a cell
2) growth and cell division
3) special processes, such as secretion, contraction, and action
potential propagation.
Catabolism – describes the breakdown of organic substrates to
release energy that is used to make ATP or other high-energy
compounds.
Catabolism takes place in a series of steps, beginning in the
cytoplasm, where enzymes break down large organic molecules
into smaller fragments. E.g. carbohydrates are broken down to
short carbon chains, triglycerides are split into fatty acids and
glycerol, and proteins are broken down to individual amino acids.
Relatively little ATP is produced during these preparatory steps
However, the simple molecules formed can be absorbed and
processed by mitochondria, and the mitochondrial steps release
significant amounts of energy. As mitochondrial enzymes break the
covalent bonds that hold these molecules together, they capture
roughly 40 percent of the energy released. The captured energy is
used to convert ADP to ATP. The other 60 percent escapes as heat
that warms the interior of the cell and the surrounding tissues.
The ATP produced in the mitochondrion provides energy to support
anabolism (the synthesis of new organic molecules), as well as
functions like cell movement, muscle contraction and active
transport.
The molecules produced by the anabolic processes are used in a
number of ways:To perform structural maintenance or repairs - cells must expend
energy to carry out ongoing maintenance and repair (metabolic
turnover).
To support growth – dividing cells increase in size and produce
extra proteins and organelles.
To produce secretions - secretory cells must make their products
To build nutrient reserves - cells constantly lay down reserved
when nutrient supply allows, carbohydrate typically as
glycogen, lipid as triglyceride.
In general, when a cell has free access to carbohydrates, lipids,
and amino acids, it will break down carbohydrates first, lipids as
second choice and only use amino acids when other sources
are unavailable.
Catabolic and Anabolic Reactions
CARBOHYDRATE METABOLISM
Most cells generate ATP and other high-energy compounds by
breaking down carbohydrates, especially glucose. A summary of
the reactions can be given as :C6H12O6 + 6O2  6CO2 + 6 H2O
The breakdown occurs in a series of enzyme catalysed steps,
some of which release energy that is used to convert ADP to ATP.
The complete catabolism of one molecule of glucose provides a
cell with a net gain of 36 molecules of ATP.
Although most of the actual ATP production occurs inside
mitochondria, the early steps take place in the cytoplasm. These
early steps do not require oxygen so are said to be anaerobic,
these cytoplasmic steps are called GLYCOLYSIS. The steps that
take place in the mitochondrion require oxygen and are aerobic.
They are called aerobic metabolism, or cellular respiration.
GLYCOLYSIS
Is the name for the series of steps that breakdown the 6 carbon
glucose molecule into 2 X the 3 carbon molecule pyruvic acid
(which at the normal pH inside the cell is in the form of the
negatively charged ion pyruvate).
For glycolysis to take place there must be present :(1) glucose molecules,
(2) appropriate cytoplasmic enzymes
(3) ATP and ADP
(4) inorganic phosphates
(5) NAD (nicotinamide adenine dinucleotide), a coenzyme that is
reduced to NADH as part of the breakdown process (the NAD
effectively holds on the H+ and releases it later to contribute to
ATP production in the mitochondrion).
Glycolysis begins when an enzyme phosphorylates (attaches a
phosphate group to the glucose molecule to make glucose-6phosphate.
This effectively “uses up” one ATP molecule, it is advantageous
however because it :1) traps the glucose molecule within the cell, because
phosphorylated glucose cannot cross the cell membrane
2) prepares the glucose molecule for further biochemical
reactions.
A second phosphorylation occurs in the cytosol before the sixcarbon chain is broken into two three-carbon pieces.
Energy benefits appear when the pieces are converted to
pyruvate with production of ATP and NADH. The net reaction is:-
Glucose + 2NAD + 2ADP + 2Pi  2Pyruvate + 2NADH + 2ATP
The “anaerobic” glycolysis reaction sequence provides a net gain
of 2 ATP for each glucose molecule converted to 2 pyruvic acid
molecules.
More energy can be gained from the further breakdown of
pyruvate, however these reactions require oxygen and take place
in the mitochondrion.
Because the supply of NAD is limited, glycolysis can only continue
if NADH is relieved of its extra H. When oxygen is available NADH
delivers its burden of H atoms to the enzymes of the electron
transport chain in the mitochondria, which add them to O2 to form
water.
If oxygen is not available (as might occur during strenuous
exercise) NADH unloads its H back to pyruvic acid, reducing it to
lactic acid which diffuses out of the cells and is transported to the
liver. When oxygen is available the lactic acid is oxidized back to
pyruvic acid and enters the aerobic pathways within the
mitochondria to be completely oxidized to H2O and CO2.
The Krebs cycle, Tricarboxylic Cycle, Citric Acid cycle - is the next
stage of breakdown.
It takes place in the matrix of the mitochondrion and breaks down
pyruvate produced during glycolysis or fatty acids produced by
breakdown of fats.
The pyruvate is firstly converted into acetyl CoA by a 3 step
process.
Acetyl coA then enters the TCA cycle and a series of reactions
takes place that results in the production of :CO2 + H2O + ATP + reduced coenzymes NADH + FADH
The coenzymes then enter the final step in the production of ATP
which is the electron transport chain.
The energy contained in the reduced coenzymes (H) is used to
move H+ across the mitochondrial membrane. Dissipation of the H+
gradient through an ATP synthase generates ATP from ADP + Pi.
The purpose of the electron transport chain is to take the H on the
coenzymes (NADH and FADH) and combine them with oxygen in
a controlled manner such that the energy released is gathered
and then used to ATP from ADP + Pi.
The components are complex, but most are proteins bound to
metal atoms (cofactors), flavins (contain flavin mononucleotide,
FMN, derived from the vitamin riboflavin) and cytochromes (ironcontaining pigments.
In the steps of the chain electrons are passed from one cofactor
to the next and hydrogen ions are moved across the membrane of
the mitochondrion. Eventually H+ re-enters the matrix through an
ATP synthase and ATP is formed and O2 reacts with H+ to form
water.
Glycogenesis and Glycogenolysis
Although most glucose is used to generate ATP, unlimited supply
of glucose do not result in unlimited ATP, because cells cannot
store large amounts of ATP.
When more glucose is available than can be used, rising ATP
inhibits glucose catabolism and initiates storage of glucose as
either glycogen or fat. Because the body can store much more fat
than glycogen, fats account for 80 - 85 % of stored energy.
Glycogenesis (glycogen storage) takes place typically in the liver
and muscles. Reversal and glucose production occurs when
required.
LIPID CATABOLISM
Fats are the body's most concentrated source of energy. The
energy yield from fat catabolism is nearly twice that from either
glucose or protein catabolism - 9 kcal.g-1. Fat in the blood (in the
form of chylomicrons) is hydrolyzed by plasma enzymes to fatty
acids and glycerol that are taken up by body cells and processed
in various ways.
Neutral fats are routinely oxidized for energy, with the separate
oxidation of their two components glycerol and fatty acid chains.
Glycerol is converted to glyceraldehyde phosphate (a glycolysis
intermediate) that can enter the TCA cycle. Glyceraldehyde is
effectivelyl half a glucose molecule and will enable 18 ATP’s to be
made.
Fatty acid oxidation occurs in the mitochondrion. The fatty acid
chain is broken into 2C acetic acid fragments, and reduction of
coenzymes are reduced. The acetic acid molecule then binds to
coenzyme A to form acetyl CoA and onward to the TCA cycle.
Lipogenesis
Neutral fats are continuously turned over in adipose tissue.
Glycerol and fatty acids not needed for energy are recombined
into triglycerides and stored usually in subcutaneous tissue
Lipogenesis occurs when cellular ATP and glucose levels are
high. Excess ATP leads to an accumulation of acetyl CoA and
glyceraldehyde-PO 4 that are channeled into triglyceride
synthesis pathways.
Acetyl CoA molecules are condensed together, forming fatty acid
chains that grow two carbons at a time (hence almost all fatty
acids in the body contain an even number of carbon atoms).
Glyceraldehyde-PO 4 is converted to glycerol, which condenses
with the fatty acids to reform triglycerides.
Protein Metabolism
Proteins like other molecules wear out and must be broken down
and replaced.
Amino acids gained from the diet and transported in the blood are
taken up by cells by active transport processes and used to
rebuild and replace these worn out proteins.
If more protein is ingested than needed for anabolic purposes,
they are oxidized for energy or converted to fat.
In order to be oxidized for energy amino acids must have their
amine group (-NH2) removed. The resulting molecule is then
converted to pyruvic acid or to one of the keto acid intermediates
in the TCA cycle. The steps include:Transamination - the amine group is removed from the AA by
reaction with ketoglutaric acid. The ketoglutaric acid becomes
glutamic acid and the original AA becomes a keto acid (oxygen
swapped for NH2).
Oxidative deamination - the amine group of glutamic acid is
removed as ammonia (NH3) and ketoglutaric acid is regenerated.
NH3 combines with CO2 to yield urea and water that is excreted in
the urine.
Keto acid modification - the keto acid is then modified so it can
enter the TCA.
Amino Acid Metabolism
Absorptive State
Anabolism exceeds catabolism. Glucose is the major energy
fuel. Dietary amino acids and fats are used to remake degraded
body protein or fat, and small amounts are oxidized to provide
ATP. Excess metabolites, regardless of source, are transformed
to fat if not used for anabolism.
Insulin essentially directs all of the events of the absorptive
state. Rising blood glucose act as a humoral stimulus for the
beta cells of the pancreatic islets to secrete more insulin.
Insulin binds to membrane receptors of its target cells, activates
carrier-mediated facilitated diffusion of glucose into the cells
enhancing glucose oxidation for energy, stimulating its
conversion to glycogen (in adipose tissue, to triglycerides) and
promoting protein synthesis and inhibiting the liver enzymes that
promote gluconeogenesis.
Postabsorptive State
In the postabsorptive state, between meals when blood glucose
levels are dropping, the aim is to maintain blood glucose levels
within the homeostatic range (80 - 100 mg glucose/100 ml).
Constant blood glucose is required to “feed” the brain. The
events of the postabsorptive state either make glucose available
to the blood or save glucose for the organs that need it most.
The sympathetic nervous system and several hormones interact
to control events of the postabsorptive state. As a result
regulation is much more complex than in the absorptive state
where insulin rules.
A trigger for initiating postabsorptive events is the reduction in
insulin release that occurs when blood glucose falls. Declining
glucose levels stimulate the alpha cells of the pancreatic islets to
release the insulin antagonist glucagon.
Glucagon promotes a rise in blood glucose levels, targetting the
liver and adipose tissue.
Hepatocytes accelerate glycogenolysis and gluconeogenesis.
Adipose cells mobilize fat stores (lipolysis), releasing fatty acids
and glycerol to the blood.
Glucagon release is inhibited after the next meal or whenever
blood glucose levels rise and insulin secretion begins again.