BCH 303:Integration of Metabolism

Dr. MD Hassan
Content:
• Overview of metabolisms
• Integration of metabolism
3 key crossroads:
-glucose 6–phosphate
-pyruvate
-acetyl–CoA
• Metabolic regulation/controls
Enzyme levels
Compartmentalization
Organ Specialization
• Muscle metabolism:
a. Roles of creatinine and myoglobin
b. Biochemical and molecular concept, control etc.
Overview of metabolism
• Metabolism is defined as the entire set of life-sustaining chemical
reactions that occur in organisms.

• It is a continuous process, with thousands of reactions. simultaneously

occur in the living cell.

• It is classified as catabolic (catabolism) or anabolic (anabolism) reactions.

-Catabolic reactions involve the splitting of larger organic compounds into smaller
compounds.
- Anabolic reactions involve forming of larger organic compounds from smaller
• In previous lectures, we have learnt the metabolism of carbohydrates,
lipids and amino acids etc.

• We shall now consider the organism as a whole and integrate the

metabolism with particular reference to energy demands of the body.
 Integration of metabolism

What is Integration of metabolism?

It refers to the co-ordination between three metabolites (carbohydrates, lipids

and proteins)

Significance of Integration of metabolism

• It ensures a supply of suitable fuel for all tissues, at all the time (from the
fully fed state to the totally starved state)

• Under positive caloric balance, – A significant proportion of the food energy

intake is stored as either glycogen or fat

• Under negative caloric balance, – Fatty acids are oxidised in preference to

glucose, to spare glucose for those tissues (Brain & RBCs) that require it under
all conditions.
INTERRELATIONSHIP OF CARBOHYRATE, LIPID AND PROTEIN
METABOLISM

• Certain amino acids can be synthesized in the body from carbohydrates.

Conversely, most amino acids can serve as precursors for carbohydrate
(glucogenic amino acids)

• Some amino acids can serve as precursors for fat synthesis (ketogenic amino
acids)

• Carbohydrate (glucose) can be converted to fat. Glucose is the precursor for both
the glycerol and the fatty acid components of triacylglycerols. The glycerol portion
can be formed from dihydroxyacetone phosphate
INTERRELATIONSHIP OF CARBOHYRATE, LIPID AND PROTEIN METABOLISM

3 key crossroads:
-glucose 6–phosphate
-pyruvate
-acetyl–CoA
 Interplay of pathways/integration of metabolism

A. Glucose 6-phosphate
 Interplay of pathways/integration of metabolism

B. Pyruvate and Acetyl CoA

Interconnection of metabolism at cellular and organs levels

• Integration of metabolism at tissue or organ level includes the inter-

relationship of different tissues and organs to meet metabolic
demands for the whole body.
Synthesis of glucose from lactate .

• Lactate is converted
to pyruvate in the
cytosol where
pyruvate in then
converted to PEP in
the mitochondria
Integration of metabolism between Organs

Glucose-alanine cycle
Adipose tissue
 Metabolic pathways regulation/controls
Anabolism and catabolism must be precisely regulated:

 Enzyme levels
 Compartmentalization
 Specialization of organs
 Major metabolic pathways and control sites

Glycolysis
Phosphofructokinase
 Major metabolic pathways and control sites continued

Citric acid cycle and oxidative phorphorylation

Electron donors are oxidized an recycled back to the citric acid cycle only if ADP is
simultaneously phosphoryated to ATP.

ATP inhibits activity of Isocitrate dehydrogenase and Citrate synthase.

High NADH inhibits Citrate synthase, Isocitrate dehydrogenase, and a-ketoglutarate
dehydrogenase

Pentose phosphate pathway

oxidative phase produces -glucose-6-phosphate dehydrogenase

NADPH and ribose 5–phosphate

non-oxidative phase
regenerates glycolytic intermediates
 Major metabolic pathways and control sites continued

Gluconeogenesis
Glycolysis and gluconeogenesis are reciprocally regulated

i. Decreased pyruvate kinase results in the reduced conversion of phosphoenol pyruvate

to pyruvate and the former is diverted for the synthesis of glucose.
ii. Reduces the concentration of fructose 2,6-bisphosphate allosterically inhibits
phosphofructokinase and activates fructose 1,6-bisphosphatase.

Glycogen synthesis and degradation

Glycogen synthase is stimulated by Insulin,

Glycogen phosphorylase is stimulated by glucagon or epinephrine

Both enzymes undergo allosteric control: feedback inhibition by metabolites

 Major metabolic pathways and control sites continued

Fatty acid synthesis and degradation

Carnitine acyltransferase I
-Citrate increases the activity of acetyl CoA carboxylase
which increases fatty acid synthesis
Major metabolic pathways and control sites continued
 Metabolic pathways regulation/controls

COMPARTMENTATION OF
METABOLIC PATHWAYS

• In compartmentation, there is
physical separation of the
biosynthesis and catabolism of a
metabolite in different organelles.

• The aim of this concept is to avoid

furtile cycles.
 Metabolic pathways regulation/controls

Organs Specialization
• The various tissues and organs of the body work in a well
coordinated manner to meet its metabolic demands.

• The major organs along with their most important metabolic

functions will be discussed below.
Liver
• The liver is specialized to serve as the body's central
metabolic clearing house.
• lt processes and distributes the nutrients to different
tissues for utilization.
• After a meal, the liver takes up the carbohydrates, lipids
and most of the amino acids, processes them and routes to
other tissues.
• During starvation, liver act as a blood glucose buffering
organ.
The major metabolic functions of liver as shown below:
Liver tissue
In an absorptive state, In a starved state
Carbohydrate metabolism: Increased gluconeogenesis and
Carbohydrate metabolism: glycogenolysis which furnish glucose to the needy tissues
Increased glycolysis, glycogenesis (mostly brain).

and hexose monophosphate shunt Lipid metabolism: Fatty acid oxidation is increased with an
and decreased gluconeogenesis. elevated synthesis of ketone bodies. This is due to the fact
that TCA (Krebs) cycle cannot cope up with the excess
Lipid metabolism : Increased production of acetyl CoA, hence the latter is diverted for
synthesis of fatty acids and ketone body synthesis.
-Ketone bodies (primarily p-hydroxybutyrate) effectively
triacylglycerols. serve as fuel source for the peripheral tissues.
-The brain slowly adapts itself to use ketone
bodies. Thus, after a 3-day fast, about one third of the
brain's fuel demands are met by ketone bodies, while, after
40 days,
Protein starvation, Increased
metabolism: they contribute to about
degradation of 7O % acids
amino of
Protein metabolism: Decreased energy needs
and protein synthesis
degradation of amino acids but
protein synthesis is increased
Skeletal muscle
• The metabolism of skeletal muscle is rather variable
depending on its needs. For instance, the resting muscle of
the body utilizes about 3O % of body's oxygen consumption.
• However, during strenuous exercise, this may be as high as
90%.
• The important metabolic functions of skeletal muscle in an
absorptive and starved states is shown below.
Skeletal muscle
• In absorptive state • In starve state
• Carbohydrate metabolism: Glucose uptake
Carbohydrate metabolism : The and its metabolism are very much depressed.
uptake of glucose is higher, and • Lipid metabolism: Both fatty acids and ketone
bodies are utilized by the muscle as fuel
glycogen synthesis is increased. source. However, on prolonged starvation
beyond 3 weeks, the muscle adapts to
Lipid metabolism : Fatty acids exclusively utilize fatty acids. This further
taken up from the circulation increases the level of ketone bodies in the
circulation.
are also important fuel sources • Protein metabolism: During the early period
for the skeletal muscle. of starvation, muscle proteins are degraded
to liberate the amino acids which are
Protein metabolism : effectively utilized by the liver for glucose
Incorporation of amino acids synthesis (gluconeogenesis). On prolong
starvation, however, protein breakdown is
into proteins is higher. reduced.
Adipose tissue

• Adipose tissue is regarded as the energy storage tissue. As

much as 15 kg of triacylglycerol (equivalent to 135,000 Cal)
is stored in a normal adult man.

• The major metabolic functions of adipose tissue in an

absorptive and starved states are shown below.
Adipose tissue
• In absorptive state • In a starve state
Carbohydrate metabolism : Carbohydrate metabolism: Glucose
uptake and its metabolism are lowered.
The uptake of glucose is
increased. This follows an Lipid metabolism : The degradation of
triacylglycerol is elevated, leading to an
increase in glycolysis and increased release of fatty acids and
hexose monophosphate shunt. glycerols.
Lipid metabolism : The -Fatty acids serve as fuel source for
synthesis of fatty acids and various tissues (brain is an exception).
triacylglycerols is increased. -Glycerol serves as a precursor for
The degradation of glucose synthesis by liver.
triacylglycerols is inhibited. The synthesis of fatty acids and
triacylglycerols is totally stopped in
adipose tissue
Brain

• The human brain constitutes about 2% of the body's weight.

But it utilizes as much as 20 % of the oxygen consumed by
the body.
• Being a vital organ, special priority is given to the metabolic
needs of the brain.
Brain tissue
• In an absorptive state • In a starve state
Carbohydrate metabolism : In an absorptive state, glucose is the only
fuel source to the brain. About 120 g of glucose is utilized per day by
Carbohydrate metabolism: Glucose uptake and its
an adult brain. This constitutes about 6O % of the glucose consumed metabolism are very much depressed.
by the body at rest. lt is estimated that about 50 % of the energy Lipid metabolism: Both fatty acids and ketone bodies are
consumed by brain is utilized by plasma membrane Na+-K+-ATPase to utilized by the muscle as fuel source. However, on
maintain membrane potential required for nerve impulse transmission.
prolonged starvation beyond 3 weeks, the muscle adapts
Lipid metabolism : The free fatty acids cannot cross the blood-brain
barrier, hence their contribution for the supply of energy to the brain to exclusively utilize fatty acids. This further increases
is insignificant. Further, in a fed state, ketone bodies are almost the level of ketone bodies in the circulation.
negligible as fuel source to the brain. However, brain predominantly
depends on ketone bodies during prolonged starvation
Protein metabolism: During the early period of
starvation, muscle proteins are degraded to liberate the
amino acids which are effectively utilized by the liver for
glucose synthesis (gluconeogenesis). On prolong
starvation, however, protein breakdown is reduced.
As already stated, glucose is the preferred fuel source
by brain. During the first 2 weeks of starvation, the brain
is mostly dependent on glucose, supplied by liver
Protein metabolism: protein are synthesis from gluconeogenesis. This, in turn, is dependent on the amino
acids released from the muscle protein degradation.
amino acids in fed for muscle development. Starvation beyond 3 weeks generally results in a marked
increase in plasma ketone bodies. By this time, the brain
adapts itself to depend on ketone bodies for the energy
needs.