METABOLISM

DR. CHRISTIAN JAY ORTE

CARBOHYDRATE METABOLISM
Metabolism can be defined as the entire chemical reactions network of the
body. Other name often used is intermediary metabolism. Most of the chemical
reactions in the body are enzyme catalyzed. The intermediates, substrates or
products of these enzyme catalyzed reactions are called as metabolites.
MEDICAL AND BIOLOGICAL IMPORTANCE
1. Glucose is the major fuel for all types of cells in the body. Its oxidation produces
energy.
2. Glucose consumption per day varies from one organ to another.
3. Some organs like brain prefers glucose as fuel than fat and protein. Brain
consumes about 100 gm of glucose per day.
4. Rate of glucose oxidation is more in cancer cells.
5. Glucose is used for the formation of glycogen, pentoses, lactose and
mucopolysaccharides.
6. Since brain is totally dependent on glucose for its energy needs glucose is
synthesized from glycogen or other non-carbohydrates during starvation or when
food is in short supply.
MEDICAL AND BIOLOGICAL IMPORTANCE
7. Deficiency or absence of enzymes of glycogen metabolism causes glycogen
storage diseases.
8. In erythrocytes, 2, 3-BPG (Bisphosphoglycerate) is formed from glucose. 2, 3-
BPG facilitates the release of oxygen from oxyhemoglobin.
9. Dietary galactose and fructose are converted to glucose.
10.Deficiency of enzymes of galactose and fructose metabolism causes galactosemia
and fructosemia, respectively.
11.Most common metabolic disease diabetes mellitus is due to defective glucose
metabolism.
12.Diabetes mellitus in turn causes secondary diseases like hypertension, kidney
diseases and blindness.
GLYCOLYSIS
• Degradation of glucose to two molecules of pyruvate or lactate by sequence of enzyme catalyzed
reactions constitutes the process of glycolysis. It is a catabolic pathway.
• If glucose is degraded to pyruvate then it is called as aerobic glycolysis. Usually it occurs in
presence of oxygen.
• If glucose is degraded to lactate then it is anaerobic glycolysis.

Site of Glycolysis
Enzymes of glycolysis are present in the cytosol of most of the cells present in the body.
Source of Glucose
Dietary glucose formed from the digestion of dietary carbohydrates
enter liver through portal venous system after its absorption from
the intestine. Liver distributes glucose to all other organs (cells) of
the body.

Entry of the Glucose in to the Cells

Glucose enters cells by facilitated transport.
1. Liver Glucose enters liver cells by facilitated diffusion. It is an
insulin-independent transport mechanism for the transport of
glucose across liver cells.
2. Extra hepatic tissues Glucose enters adipocytes, erythrocytes,
brain and skeletal muscle by facilitated transport involving
carrier molecule. The transport of glucose across the
membranes of these tissues by carrier is dependent on insulin.
Medical and Biological Importance of Glycolysis
1. Glycolysis provides energy to cells. Anaerobic glycolysis
meets energy requirement of rapidly contracting
skeletal muscle.
2. Since heart is mainly aerobic organ, myocardial
ischemia decreases glycolytic ability of cardiac muscle.
As a result, energy or ATP production in heart is
affected.
3. Deficiency of enzymes of erythrocyte glycolysis
(pyruvate kinase) causes hemolytic anemia. This is
because erythrocytes get their energy from glycolysis.
4. Deficiency of muscle phosphofructokinase causes
decreased muscular performance and fatigue.
5. Dietary fructose and galactose are also metabolized by
this pathway.
Medical and Biological Importance of Glycolysis
6. Glycolysis has amphibolic role also. It provides precursors
for the formation of lipids and amino acids. For example,
pyruvate is converted to alanine by transamination and
dihydroxy acetone phosphate serves as precursor for
triglyceride formation.
7. Two glycolytic intermediates pyruvate and
glyceraldehydes-3-phosphate are used for the synthesis of
cholesterol, thiamine and pyridoxine in tuberculosis,
malaria and gastritis causing organisms.
8. Glycolysis is the major energy source for rapidly growing
malarial parasite in R.B.C. Lactate is the end product of
glycolysis in malarial parasite. LDH of parasite is different
from human enzyme. Unlike human LDH parasite enzyme
is not subjected to inhibition by substrate pyruvate. This
allows rapid formation of lactate from pyruvate and fast
energy production.
9. In brain tumors lactate production is 10 times more.
Citric Acid Cycle
1. Cyclic arrangement of sequence of reactions
that convert acetyl-CoA to two molecules of
CO2 is called as citric acid cycle.
2. It is also called as Tricarboxylic acid (TCA) cycle
or Krebs cycle.
3. This cyclic process starts with oxaloacetate and
completes with regeneration of oxaloacetate.
4. The conversion of acetyl-CoA to CO2 in the
citric acid cycle generates reducing equivalents
(NADH, FADH2) and GTP.
5. The reduced co-enzymes are finally oxidized in
the respiratory chain with concomitant
generation of ATP.
6. One acetyl-CoA molecule is oxidized by this
cycle at a time.
Site
Enzymes of citric acid cycle are present in
mitochondrial matrix.
Medical Importance
1. It is the final common metabolic pathway for
oxidation of carbohydrates, fats and proteins.
Some amino acids are degraded to
intermediates of TCA-cycle. Acetyl-CoA arises
from fat catabolism.
2. Amphibolic role: In the liver intermediates of
TCA cycle are used for the synthesis of (a) Fatty
acids, Cholesterol (b) Amino acids (c)
Porphyrins (d) Glucose.
3. In some liver diseases, like hepatitis and
cirrhosis amphibolic role of citric acid cycle is
affected.
GLYCOGENESIS
In cells, the rate of glucose
oxidation largely depends on
energy (ATP) demand of cell. If cell
has sufficient energy (ATP) then
glucose oxidation stops and excess
glucose is stored as glycogen.
GLYCOGENESIS
In cells, the rate of glucose oxidation largely depends on energy (ATP) demand of cell. If cell has sufficient
energy (ATP) then glucose oxidation stops and excess glucose is stored as glycogen.

Glycogenesis is the Synthesis of Glycogen from Glucose

Site Though every cell can form glycogen it chiefly occurs in liver and skeletal muscle. In the muscle, about 245
gms of glycogen and in the liver about 72 gms of glycogen is stored under well fed condition. Even though-
energy, rich fat is abundant in the body skeletal muscle prefers to store glucose (energy) as glycogen because:
1. Fat cannot be oxidized under anaerobic condition.
2. Acetyl-CoA of fat oxidation cannot be converted to glucose.
3. Skeletal muscle is unable to mobilize fat rapidly.

Medical Importance
Excess glucose is stored as glycogen under fed conditions.
GLYCOGENOLYSIS
• The process that converts glycogen to
glucose and other small molecules is called
as glycogenolysis.
• Site. Glycogenolysis occurs in liver and
muscle.
• Degradation of glycogen is not the reversal
of glycogenesis. Instead, independent
enzymes are involved in glycogen break
down. In the liver the end product of
glycogenolysis is glucose whereas in the
skeletal muscle glucose-6-phosphate or
lactate is the end product.
Lysosomal Glycogenolysis
Lysosomes degrades about 1-3% of cellular
glycogen. Lysosomes contain an enzyme known as
acidmaltase or a-glucosidase which hydrolyzes a (1, 4)
and a(1, 6) glycosidic linkages of glycogen to produce
glucose.

Medical Importance
1. In the liver, glycogenolysis contributes glucose to
maintain blood glucose level in between meals.
2. In the muscle, glycogenolysis meets its energy
requirement in between meals.
3. Glycogen metabolism is defective in several
inherited diseases.
4. Inhibition of glycogen phosphorylase (GP) decreases
glycogenolysis which leads to low blood glucose
level.
HORMONAL REGULATION OF
GLYCOGEN METABOLISM
• Epinephrine and nor epinephrine
increase glycogenolysis in muscle and
decrease glycogenesis. Likewise,
glucagon increases glycogenolysis
and decreases glycogenesis in liver.
• In contrast, insulin favors
glycogenesis and suppresses
glycogenolysis in liver and muscle.
Medical Importance of Hormonal Regulation of
Glycogen Metabolism
• In between meals hypoglycemia induces glucagon
production. Glucagon causes breakdown of
glycogen in liver to maintain supply of glucose to
brain and cardiac muscle.
• Epinephrine causes breakdown of glycogen in
skeletal muscle to maintain fuel supply for muscle
contraction.
• After a meal, hyperglycemia induces insulin
secretion. Insulin causes inactivation of enzymes of
glycogenolysis and activation of glycogen forming
enzymes. As a result, glycogenesis occurs in liver
and muscle.
LIPID METABOLISM
MEDICAL AND BIOLOGICAL IMPORTANCE
1. In fed condition, excess calories consumed in the form of
carbohydrates are conserved in the form of lipids. Of course,
dietary lipids are also stored under well-fed condition.
2. Even though excess energy may be stored in the form of
carbohydrate (glycogen) humans and other mammals prefers to
store excess energy only in the form of lipid because
(a) Energy content of lipid is 2-3 times higher.
(b) Lipid can be stored without water of hydration, which is
not possible with glycogen. For example, 1 gm of glycogen
needs 2 gm of water for storage.
(c) Oxidation of lipid produces more water. For example,
oxidation of glucose produces approximately 45 water
molecules whereas oxidation of stearic acid produces
nearly 165 water molecules.
3. Usually lipid stores are greater compared to glycogen. A 70 kg
individual may have lipid store of about 15 kg. However, his
glycogen store is about only 0.22 kg.
4. During fasting or in between meals stored lipids are used
to meet energy demands. Glycogen store get depleted
within 24 hours of fasting. Later, energy requirement of
the body is entirely met by stored lipid. Lipids can meet
body energy requirements for weeks.
5. Desert animal camel suits well to dry conditions because it
derives water and energy from large amounts of lipids
stored in hump. Hibernating and migratory birds also use
lipid stores to meet water and energy demands during
hibernation and migration, respectively.
6. Defect or changes in the pathways of lipid metabolism are
directly related to development of diseases.
7. Increased fatty acid oxidation in starvation and diabetes
leads to keto acidosis. Decreased fatty acid oxidation leads
to hypoglycemia.
8. Some drugs and poisons work by inhibiting pathways of
lipid metabolism. Aspirin an anti-inflammatory drug works
by inhibiting prostaglandin formation. Hypoglycin a toxin
causes hypoglycemia.
FATTY ACID OXIDATION
Sources of fatty acids
(a) Dietary sources: Fatty acids
formed from the digestion of dietary
lipids are carried to liver. From the
liver, they are transported to cell in
bound form with albumin.
(b) Endogenous sources: As
mentioned above, free fatty acids
formed from body triglycerides are
used for energy production.
Site
Fatty acid oxidation occurs in the mitochondria of
all types of cells like liver, heart, adipose tissue,
kidney, lung, skeletal muscle and some extent in
brain. Long chain fatty acid oxidation involves
(a) Activation in outer mitochondrial membrane
(b) Transport of activated fatty acids across inner
mitochondrial membrane
(c) Oxidation in mitochondria
The short and medium chain fatty acids are
activated and oxidized in the matrix of
mitochondria. Since these fatty acids are freely
permeable to inner mitochondrial membrane, no
transport system is required unlike long chain
fatty acids.
Disorders of Fatty acids oxidation or Medical importance
• Fatty acid oxidation is impaired in many diseases.
• Carnitine deficiency
• It occurs in premature infants and in newborns. It is due to inadequate
formation or loss in urine due to renal leakage. Lack of carnitine
results in impaired transport of acyl-CoAs into mitochondria. The
plasma-free fatty acid level raises due to decreased a-oxidation. Main
symptom is hypoglycemia, because all tissues use glucose for energy
production, other symptoms are lipid accumulation, muscle weakness
and hypoketonemia. Oral supplementation of carnitine results in
disappearance of symptoms.
• Carnitine acyl transferase deficiencies
• Hepatic carnitine acyl transferase deficiency Deficiency of CAT-I in
the liver leads to impaired fatty acid oxidation. As a result,
hypoketonemia and hypoglycemia develops.
• Muscle carnitine acyl transferase-II deficiency Due to deficiency of
CAT-II fatty acid oxidation is impaired in muscle. Muscle weakness
and myoglobinuria are the main symptoms.
• Hypoglycemic agents like sulfonylureas particularly glyburide and
tolbutamide used in diabetics inhibit transferases.
Ketogenesis
1. Synthesis of ketone bodies is called as
ketogenesis.
2. Under certain conditions, production of
acetyl-CoA either from b-oxidation or
pyruvate oxidation is more rapid than it
can be utilized for other metabolic
processes.
3. Liver converts the excess acetyl-CoA to
ketone bodies. Hence, liver can be
considered as net producer of ketone
bodies.
Ketolysis
1. Degradation of ketone bodies is called as ketolysis.
2. Ketone bodies produced in liver reaches peripheral
tissues through circulation.
3. Heart, kidney cortex, brain and to some extent
skeletal muscle uses ketone bodies for energy
production.

Biological importance
1. Heart and kidney cortex prefer to use ketone bodies
rather than glucose. During prolonged starvation,
brain derives most of energy from ketone bodies.
2. Liver is unable to use ketone bodies due to lack of
enzymes.
Medical Importance
1. Usually the utilization of ketone bodies by peripheral tissues is proportional to their formation.
Normal blood ketone bodies level is 1mg/100ml.
2. Under certain metabolic conditions, the rate of ketone body formation exceeds the rate of their
utilization by peripheral tissues. This results in accumulation of ketone bodies in blood (hyper
ketonemia) and their excretion in urine (ketonuria).
3. Ketosis Hyper ketonemia and ketonuria gives rise to ketosis. Main clinical symptoms of ketosis
are headache, nausea, vomiting and finally coma.
4. Ketoacidosis Under normal conditions, ketone bodies acetoacetate and b-hydroxy butyrate are
neutralized by blood bicarbonate to maintain constant blood pH.
5. Hypoketonemia Ketone body formation is impaired in some disease like carnitine
• deficiency and hepatic CAT-I deficiency.
Triglyceride biosynthesis
• It occurs in the liver, adipose tissue
and intestine of non-ruminants.
• Triglycerides synthesized in liver and
intestine are transported to other
tissues where as in adipose tissue
triglycerides are stored. Both
saturated and unsaturated fatty acids
having 16-18 carbon atoms are used
for triglycerides formation after
activation. They are used in the CoA
form.
Medical importance
1. Diet influences the type of fat produced in
adipose tissue. Carbohydrate or starchy diets
produce hard fat whereas diets rich are
peanut oil or corn oil produce soft fat.
2. Triglyceride formation is marked in well fed
state and decreased in starvation, diabetes.
High fat diet also decreases fat formation.
• Usually triglyceride biosynthesis is directly
related to fatty acid biosynthesis
Fatty livers
1. Liver contains about 5% lipid. Of
this, about 1/4 is triglyceride.
2. Extensive accumulation of lipid in
the liver leads to condition known as
fatty liver. In the fatty livers, the lipid
content increases to 25-30%.
Further, triglycerides and fatty acid
may occupy entire cytoplasm of
hepatocyte.
ALCOHOL METABOLISM
Sources
a)Endogenous Small amounts of alcohol
in the blood may be produced by
intestinal flora.
b)Exogenous Alcohol consumed by
pleasure seekers is absorbed easily all
along gastro intestinal tract and
reaches liver.

Site Liver is the major site of alcohol

metabolism.
Medical Importance
1. It serves as energy source like carbohydrate. However, if consumed excess
(chronic alcoholism) leads to fatty liver development.
2. Some individuals (chronic alcoholics) develop vit A and thiamin deficiency.
3. Lactic acidemia occurs due to excess NADH in the cytosol.
4. Women are more susceptible to alcohol effects than men.
5. Moderate consumption of alcohol was found to be beneficial to stroke patients.
HDL level is higher in people consuming small amount of alcohol daily.
6. Clearance of toxins from circulation by liver becomes slow and some compounds
get converted to carcinogens in chronic alcoholics.
7. Alcohol consumption aggravates gout and porphyrias.
CHOLESTEROL METABOLISM
Biosynthesis of cholesterol
1. About 1 gm of cholesterol is synthesized in
the body per day.
2. Site. Cholesterol synthesis takes place in all
nucleated cells particularly liver, adrenal
cortex, testis, ovaries, brain, placenta, aorta
and skin. The enzymes of cholesterol
biosynthesis are present in microsomes and
cytosol of the cells.
3. Precursors. Acetyl-CoAs generated from the
break-down of carbohydrates, fats and
amino acids act as precursors of cholesterol.
Formation of bile salts
• In the liver, primary bile acids are
activated to their corresponding CoAs.
• These activated bile acids undergo
conjugation with glycine and taurine to
form tauro, glycocholate and tauro,
glycochenodeoxy cholate.
• They are secreted into bile. At
physiological pH of bile, they combine
with Na+, K+ ions to form bile salts They
are secreted into intestine as bile salts of
bile.
• Bile also contains come free cholesterol.
Na+, K+ tauro and glycocholate, Na+, K+
tauro and glycochenodeoxy cholate are
called as bile salts.
Enterohepatic circulation
• Most of primary and secondary bile acids are
absorbed in ileum.
• About 99% of bile acids secreted into intestine
returns to liver through portal circulation. This is
known as enterohepatic circulation (from intestine
to liver and back).
• Only a small part of bile acids (400 mg/day)
escapes reabsorption in the ileum. Lithocholic acid
is not reabsorbed because of its less solubility. So,
it is eliminated through the feces
• along with other bile that escaped reabsorption.