INTEGRATION OF METABOLISM

DEFINITION
• The various metabolism pathways by which
carbohydrates, lipids and proteins are
processed as metabolic fuel for energy supply
or as precursors in the biosynthesis of
compounds required by the cell. This
coordination between three metabolites is
called integration of metabolism.
 SIGNIFICANCE
• Integration of metabolism ensures a supply of
suitable fuel for all tissues, at all times from
the fully fed state to the totally starved state.
 Central Themes of Metabolism
1. ATP is the universal energy carrier.
2. ATP is generated by the oxidation of metabolic fuels
• Glucose
• Fatty Acids
• Amino Acids
3. NADPH is the redox agent for reductive biosynthesis.
4. Biomolecules are constructed from a small set of
building blocks.
5. Biosynthetic and Degradation pathways are distinct.
 Major Metabolic Pathways
1. Glycolysis
2. Gluconeogenesis
3. Glycogen Metabolism
4. Fatty Acid Metabolism
5. Citric Acid Cycle
6. Oxidative Phosphorylation
7. Amino Acid Metabolism
 Cont---
• Only the liver can carry out all of the reaction
Of the major pathways.
• The key junction points are Glucose-6-
phosphate, Pyruvate and Acetyl CoA.
 Glucose-6-phosphate
• When glucose is transported into the cell it is
rapidly phosphorylated to glucose-6-phosphate.
• Glucose-6- phosphate may be catabolized into
pyruvate, stored as glycogen or converted into
ribose 5-phosphate by the pentose phosphate
pathway.
• Glucose 6-phosphate can be generated from
glycogen stores or by gluconeogenesis.
 Pyruvate
• Pyruvate is generated from glucose 6-
phosphate by glycolysis.
• Pyruvate is converted into lactate under
anaerobic conditions to regenerate NAD+.
• Pyruvate is also transaminated to form
alanine. Several amino acids are degraded into
pyruvate.
 Cont---
• Pyruvate may be carboxylated to form
oxaloacetate in the matrix of the
mitochondria. This is the first step of
gluconeogenesis.
• The fourth fate of pyruvate is the oxidation of
pyruvate into acetyl CoA by the pyruvate
dehydrogenase complex. This is an irreversible
step committing the pyruvate for oxidation
 Acetyl CoA
• Produced by the oxidative decarboxylation of
pyruvate , by the β-oxidation of fatty acids and
by the degradation of ketogenic amino acids.
• Acetyl CoA may be completely oxidized into
CO2 via the citric acid cycle, converted into
ketone bodies or cholesterol.
• Acetyl CoA may be exported into the cytosol
and converted into fatty acids
 Organ Specialization

1. Brain
• Glucose is the primary fuel for the brain. Only
under prolonged starvation does the brain use
ketone bodies as fuel.
• The brain has no capacity to store fuels and
needs a continuous supply of glucose.
• Fatty acids cannot fuel the brain because they
cannot traverse the brain blood barrier.
 2. Muscle
• The muscles can use glucose, fatty acids and
ketone bodies for fuel.
• Unlike the brain the muscles have stores of
glycogen. This glycogen is readily converted
into glucose when needed for bursts of activity.
• During fasting or during excessive activity,
muscle tissue is degraded into amino acids and
the carbon skeletons are used for fuel.
 Cont----
• Muscle tissues lack the enzymes to convert
ammonia into urea. Instead Alanine
transaminase transfers the amino group to
pyruvate to form alanine.
• Alanine is released by the muscle tissue into
the blood stream where it is absorbed by the
liver, deaminated to reform pyruvate
 Cont----
• pyruvate is then converted into glucose by
gluconeogenesis.
• The amino group of alanine is converted into
urea by the urea cycle.
• In the resting state, the major source of fuel
for the muscles is fatty acids. 85% of the
resting muscle tissue’s needs are met by fatty
acid catabolism.
Pyruvate-Alanine cycle
 3. Heart Muscle
• The heart muscle always functions aerobically
and has virtually no glycogen reserves.
• Fatty acids are the fuel of choice for heart
muscle;
• ketone bodies may also be the fuel for heart
tissue. The heart will use ketone bodies over
glucose as a source of fuel.
• Lactate can also serve as a fuel for the heart.
 4. Adipose Tissue
• The function of the adipose tissue is to store
triacylglycerol and release fatty acids as
needed.
• Adipose tissue needs a steady supply of
glucose to generate glycerol 3-phosphate
needed for triacylglycerol synthesis.
 Cont----
• When the blood glucose concentration is low,
glucagon activates a lipase which hydrolyzes
the triacylglycerol stores in the adipose tissue.
• The free fatty acids and glycerol are released
into the bloodstream. Serum albumin carries
the fatty acids to the tissues and the glycerol is
absorbed by the liver and used for
gluconeogenesis.
 5. The Kidney
• The major role of the kidney is to produce
urine which is a vehicle for excreting water
soluble waste products.
• During starvation the kidney becomes an
important site of gluconeogenesis and may
produce up to half of the blood’s glucose.
 6. The Liver
• The liver is the center of metabolism. The liver
maintains the blood glucose level and regulates
the concentration of metabolites in the blood.
• The liver stores a day supply of glucose as
glycogen.
• During the fasting state the liver produces
ketone bodies which fuel the heart and muscles
preserving glucose for the brain.
 Cont---
• When the blood glucose concentration is high,
fatty acids are synthesized by the liver,
converted into triacylglycerols and packaged
as very low density lipoproteins which are
secreted into blood.
• The liver synthesizes fatty acids, cholesterol
and bile salts.
 Cont----
• The majority of amino acids are catabolized in
the liver. The reason is that only the liver and
kidneys can convert the ammonia produced
by the catabolism of amino acids into urea.
 Metabolic States
1. Fed State
Dietary Carbohydrates.
• Insulin activates the liver to transport a good
portion of the dietary glucose into the liver cells.
• Insulin activates glycolysis, so some of the
glucose is used to generate ATP.
• The remainder of the glucose is converted into
glycogen or triacylglycerols.
 Cont----
• When the liver glycogen reaches its maximum,
all of the excess glucose is diverted towards
triacylglycerols. The liver synthesizes both the
fatty acids and the glycerol from glucose.
• The remainder of the glucose travels to the
peripheral tissues. Insulin activates the uptake
of glucose by the muscle tissue and the
adipose tissue.
 Dietary Lipids
• The intestinal mucosa cells absorb cholesterol,
fatty acids and monoacylglycerols from the
small intestine.
• They then reassemble the triacylglycerols and
package them with cholesterol, phospholipids
and lipoproteins to form chylomicrons.
• The chylomicrons are released into the blood
stream, where tissues absorb the fatty acids.
 Cont----
• The fatty acids carried in the triacylglycerols in
the chylomicrons are absorbed by the adipose
tissue, reconverted into triacylglycerols and
stored.
• The remnants of chylomicrons are absorbed
by the liver cells.
 Dietary Amino Acids
• The intestinal mucosa cells absorb amino acids
and release them into the blood stream where
they are absorbed by the tissues that need
them.
• They may be used for protein biosynthesis,
converted into hemes and other cofactors or
degraded and used for energy.
 2. Fasting State
• Within one hour of a meal the blood glucose
level begins to fall. The insulin concentration
also begins to fall and the glucagon
concentration begins to rise.
• These changes in hormone concentrations
trigger the release of metabolic fuels from the
body stores.
 Cont----
• Glucagon stimulates glycogenolysis, the break
down of liver glycogen to maintain the blood
glucose concentration.
• Glucagon also stimulates gluconeogenesis,
synthesizing glucose from lactate, alanine, and
glycerol.
• As fasting progresses, gluconeogenesis
becomes more important to maintain the blood
glucose
 Cont----
• After 30 hours of fasting, the liver glycogen
stores are depleted, and gluconeogenesis is
generating all of the blood glucose.
• Only the glycerol moiety of triacylglycerols can
be used as source of glucose.
• Glucagon also stimulates the break down of
proteins and the catabolism of amino acids.
• This generates ammonia which the liver converts
into urea to be excreted.
 Cont----
• During fasting the triacylglycerols stored in the
adipose tissue become the major energy
source.
• The glycerol component is used for
gluconeogenesis and the fatty acids released
are oxidized by tissues such as muscle and
heart tissue.
 Cont----
• The liver absorbs these fatty acids and
converts them into ketone bodies which are
released in the blood.
• These ketone bodies can fuel the muscles and
heart saving glucose for the brain.
 3. Starvation State
• Prolong fasting produces the starvation state.
Metabolic changes have to occur because the
rate of protein catabolism would rapidly
consume all of the body’s protein.
• After 4-5 days of fasting, the body enters the
starvation state. The muscles quit relying on
ketone bodies for fuel and rely solely on fatty
acids stored in the adipose tissue for fuel.
 Cont----
• The result is a higher concentration of ketone
bodies in the blood stream.
• The brain begins to utilize these ketone bodies
as a source of fuel.
• Glucose is still required to fuel the red blood
cells, but now the liver needs to produce only
a fraction of glucose as it did in the fasting
state.
 Cont----
• The decrease in gluconeogenesis spares the
muscle tissue. The decreased rate of amino
acid catabolism reduces the rate of urea
production.
• The adipose tissue plays an important role
during starvation.
• How long you will survive starvation depends
on how much fat you have stored.
 Cont----
• During starvation fatty acids are fuelling every
tissue of the body except the red blood cells.
• When the starving person runs out of stored
triacylglycerols, Proteins become the only
source of fuel.
• Soon the proteins of the individual have
become so depleted that the heart, kidneys
and other tissues stop functioning.