Carbohydrate metabolism

BIO I BIOCHEMISTRY
Course Incharge Ms Nimra Maqsood
A sum of all catabolic and anabolic pathways of carbohydrates
occurring in a cell summarize as Carbohydrate Metabolism

 Glycogen Metabolism (Glycogenesis and Glycogenolysis)

 Glycolysis (oxidation of Glucose)
 Gluconeogenesis (production of Glucose from non carbohydrate precursors
as well)
 Hexose Monophosphate pathway (HMP) (an alternative pathway to
Glycolysis generate NADPH for reductive biosynthesis)
 Tricarboxylic Acid Cycle (TCA), Citric Acid Cycle (CAC), Krebs Cycle (so named
because of the consumption of acetate in the form of Acetyl-coA and
produce energy rich compounds or energy carriers)
CITRIC ACID CYCLE
THE CITRIC ACID CYCLE
 The citric acid cycle is the final pathway for the oxidation of carbohydrate, lipid,
and protein. Their common end metabolite, acetyl-CoA, reacts with oxaloacetate
to form citrate. By a series of dehydrogenations and decarboxylations, citrate is
degraded, reducing coenzymes, releasing two CO2, and regenerating oxaloacetate.
 The reduced coenzymes are oxidized by the respiratory chain linked to formation
ATP. Thus, the cycle is the major pathway for the formation of ATP and is located in
the matrix of mitochondria adjacent to the enzymes of the respiratory chain and
oxidative phosphorylation.
 The citric acid cycle is amphibolic, since in addition to oxidation it is important in
the provision of carbon skeletons for gluconeogenesis, acetyl CoA for fatty acid
synthesis, and interconversion of amino acids.
TEN ATP ARE FORMED PER TURN OF THE CITRIC ACID CYCLE
 As a result of oxidations catalyzed by the dehydrogenases of the citric acid cycle, three molecules of NADH
and one of FADH2 are produced for each molecule of acetyl-CoA catabolized in one turn of the cycle.
 These reducing equivalents are transferred to the respiratory chain where reoxidation of each NADH results
in formation of ∼2.5 ATP, and of FADH2 , ∼1.5 ATP.
 In addition, 1 ATP (or GTP) is formed by substrate-level phosphorylation catalyzed by succinate thiokinase.

VITAMINS PLAY KEY ROLES IN THE CITRIC ACID CYCLE

Four of the B vitamins are essential in the citric acid cycle and hence energy-yielding metabolism: riboflavin, in
the form of flavin adenine dinucleotide (FAD), Niacin, in the form of nicotinamide adenine dinucleotide (NAD+),
Thiamin (vitamin B1), as thiamin diphosphate, and pantothenic acid, as part of coenzyme A, are crucial for TCA
cycle.

THE CITRIC ACID CYCLE PLAYS A PIVOTAL ROLE IN METABOLISM

The citric acid cycle is not only a pathway for oxidation of two carbon units, but is also a major pathway for
interconversion of metabolites arising from transamination and deamination of amino acids and providing the
substrates for amino acid synthesis by transamination as well as for gluconeogenesis and fatty acid synthesis.
Because it functions in both oxidative and synthetic processes, it is amphibolic.
CLINICAL ASPECTS OF TCA

Hyperammonemia
Occurs in advanced liver disease and a number of (rare) genetic diseases of amino acid
metabolism, leads to loss of consciousness, coma and convulsions, and may be fatal. This is largely
because of the withdrawal of α-ketoglutarate to form glutamate leading to lowered
concentrations of all citric acid cycle intermediates, and hence reduced generation of ATP.
GLYCOLYSIS
GLYCOLYSIS

 Glycolysis is the cytosolic pathway of all mammalian cells for the metabolism of glucose (or
glycogen) to pyruvate and lactate.
 It can function anaerobically by regenerating oxidized NAD+ (required in the glyceraldehyde-3-
phosphate dehydrogenase reaction), by reducing pyruvate to lactate.
 Lactate is the end product of glycolysis under anaerobic conditions (eg, in exercising muscle) and in
erythrocytes, where there are no mitochondria to permit further oxidation of pyruvate.
 Glycolysis is regulated by three enzymes catalyzing non equilibrium reactions: hexokinase,
phosphofructokinase, and pyruvate kinase.
 In erythrocytes, the first site in glycolysis for generation of ATP may be bypassed, leading to the
formation of 2,3-bisphosphoglycerate, which is important in decreasing the affinity of hemoglobin
for O2.
 Pyruvate is oxidized to acetyl-CoA by a multienzyme complex, pyruvate dehydrogenase, which is
dependent on the vitamin derived cofactor thiamin diphosphate.
 Conditions that involve an impairment of pyruvate metabolism frequently lead to lactic acidosis.
BIOMEDICAL IMPORTANCE
 The ability of glycolysis to provide ATP in the absence of oxygen is especially important, because this
allows skeletal muscle to perform at very high levels of work output when oxygen supply is
insufficient, and it allows tissues to survive anoxic episodes.
 However, heart muscle, which is adapted for aerobic performance, has relatively low glycolytic
activity and poor survival under conditions of ischemia.
 Diseases in which enzymes of glycolysis (e.g., pyruvate kinase) are deficient are mainly seen as
hemolytic Anemias or, if the defect affects skeletal muscle (e.g., phosphofructokinase), as fatigue.
 In fast-growing cancer cells, glycolysis proceeds at a high rate, forming large amounts of pyruvate,
which is reduced to lactate and exported. This produces a relatively acidic local environment in the
tumor, which may have implications for cancer therapy.
CLINICAL ASPECTS OF GLYCOLYSIS

PYRUVATE DEHYDROGENASE DEFICIENCY (PDH)

Arsenite and mercuric ions inhibit pyruvate dehydrogenase, as does a dietary deficiency of thiamin,
allowing pyruvate to accumulate. Many alcoholics are thiamin deficient (both because of a poor diet
and also because alcohol inhibits thiamin absorption), and may develop potentially fatal pyruvic and
lactic acidosis. Patients with inherited pyruvate dehydrogenase deficiency, which can be the result of
defects in one or more of the components of the enzyme complex, also present with lactic acidosis,
particularly after a glucose load.

PYRUVATE KINASE DEFICIENCY

Pyruvate kinase deficiency is an inherited metabolic disorder of the enzyme pyruvate kinase which
affects the survival of red blood cells.
PENTOSE PHOSPHATE PATHWAY/
HEXOSE MONOPHOSPHATE PATHWAY/
HMP Shunt
The pentose phosphate pathway
 The pentose phosphate pathway is active in liver, adipose tissue, adrenal cortex, thyroid,
erythrocytes, testis, and lactating mammary gland.
 The pentose phosphate pathway he pentose phosphate pathway is an alternative route for the
metabolism of glucose.
 HMP does not lead to formation of ATP.
Functions of HMP
I. The formation of NADPH for synthesis of fatty acids and steroids, and maintaining reduced
glutathione for antioxidant activity.
II. The synthesis of ribose for nucleotide and nucleic acid formation.
 Like glycolysis, the enzymes of the pentose phosphate pathway are cytosolic.
 Unlike glycolysis, oxidation is achieved by dehydrogenation using NADP+, not NAD+, as the
hydrogen acceptor.
HMP divided into two phases:
An irreversible oxidative phase in which glucose6-phosphate undergoes dehydrogenation
and decarboxylation to yield a pentose, ribulose-5-phosphate.
A reversible non oxidative phase ribulose-5-phosphate is converted back to glucose-6-
phosphate by a series of reactions involving mainly two enzymes: transketolase and
transaldolase.
Impairment of the Pentose Phosphate Pathway Leads to
Erythrocyte Hemolysis

Hemolytic Anemia
Genetic defects of glucose-6-phosphate dehydrogenase, with consequent impairment
of the generation of NADPH, manifested as red cell hemolysis (hemolytic anemia)
when susceptible individuals are subjected to oxidative stress from infection, drugs
such as the antimalarial primaquine, and sulfonamides. Glutathione peroxidase is
dependent upon a supply of NADPH, which in erythrocytes can only be formed via the
pentose phosphate pathway. It reduces organic peroxides and H2O2, as part of the
body's defense against lipid peroxidation. Measurement of erythrocyte glutathione
reductase, and its activation by FAD is used to assess vitamin B2 nutritional status.
METABOLIC DISORDERS RELATED TO OTHER
HEXOSES CATABOLISM
Glucose, fructose, and galactose are the main hexoses absorbed from
the gastrointestinal tract, derived from dietary starch, sucrose, and
lactose, respectively. Fructose and galactose can be converted to
glucose, mainly in the liver.
Galactose Metabolism
 Enzyme Deficiencies in the Galactose Pathway Cause Galactosemia.
 Inability to metabolize galactose occurs in the galactosemias, which
may be caused by inherited defects of galactokinase, uridyl
transferase.
 Galactose is a substrate for aldose reductase, forming galactitol,
which accumulates in the lens of the eye, causing cataract.
SYMPTOMS
 liver failure and mental deterioration.
 Poor growth, speech abnormality and liver damage in children.
 Cataracts.
TREATMENT
Galactose-free diets.
FRUCTOSE METABOLISM
Diets high in sucrose or in high-fructose syrups (HFS) used in manufactured foods and beverages lead to large
amounts of fructose (and glucose) entering the hepatic portal vein.
Defects in Fructose Metabolism Cause Disease

Fructosuria
A lack of hepatic fructokinase causes essential fructosuria, which is a benign and asymptomatic condition.

Hereditary Fructose Intolerance

In the absences of Aldolase B, which cleaves fructose-1-phosphate, leads to hereditary fructose intolerance,
which is characterized by profound hypoglycemia and vomiting after consumption of fructose.

Treatment
Diets low in fructose, sorbitol, and sucrose are beneficial for both conditions.
GLUCONEOGENESIS
GLUCONEOGENESIS

 Gluconeogenesis is the process of synthesizing glucose or glycogen from non carbohydrate

precursors. It is of particular importance when carbohydrate is not available from the diet.
Significant substrates are amino acids, lactate, glycerol, and propionate.

 Liver and kidney are the major Gluconeogenic tissues; the kidney may contribute up to 40% of
total glucose synthesis in the fasting state and more in starvation.

 A supply of glucose is necessary especially for the nervous system and erythrocytes. After an
overnight fast, Glycogenolysis and gluconeogenesis make approximately equal contributions to
blood glucose; as glycogen reserves are depleted, so gluconeogenesis becomes progressively
more important.
REGULATION OF BLOOD GLUCOSE
 The maintenance of a stable blood glucose concentration is one of the most finely regulated of
all homeostatic mechanisms, involving the liver, extra hepatic tissues, and several hormones.

 In the post absorptive state, the concentration of blood glucose in most mammals is
maintained between 4.5 and 5.5 mmol/L. After the ingestion of a carbohydrate meal, it may
rise to 6.5 to 7.2 mmol/L, and in starvation, it may fall to 3.3 to 3.9 mmol/L.

 Insulin is secreted as a direct response to hyperglycemia; it stimulates the liver to store glucose
as glycogen and facilitates uptake of glucose into extra hepatic tissues.

 Glucagon is secreted as a response to hypoglycemia and activates both Glycogenolysis and

gluconeogenesis in the liver, causing release of glucose into the blood.
CLINICAL ASPECTS OF GLUCONEOGENESIS

Hypoglycemia May Occur During Pregnancy & in the Neonate

During pregnancy, fetal glucose consumption increases and there is a risk of maternal, and possibly fetal,
hypoglycemia, particularly if there are long intervals between meals or at night. Furthermore, premature and
low-birth-weight babies are more susceptible to hypoglycemia, since they have little adipose tissue to
provide nonesterified fatty acids. The enzymes of gluconeogenesis may not be fully developed at this time.

HYPOGLYCEMIA
Administration of insulin (as in the treatment of diabetes mellitus) lowers the blood glucose concentration
and increases its utilization and storage in the liver and muscle as glycogen. An excess of insulin may cause
hypoglycemia, resulting in convulsions and even death unless glucose is administered promptly. Increased
tolerance to glucose is observed in pituitary or adrenocortical insufficiency, attributable to a decrease in the
antagonism to insulin by the hormones normally secreted by these glands.
Diabetes mellitus (type 1, or insulin-dependent diabetes mellitus; IDDM)
It is characterized by decreased glucose tolerance as a result of decreased secretion of insulin
because of progressive destruction of pancreatic β-islet cells. Glucose tolerance is also
impaired in type 2 diabetes mellitus (noninsulin-dependent diabetes, NIDDM) as a result of
impaired sensitivity of tissues to insulin action.

METABOLIC SYNDROME
Insulin resistance associated with obesity (and especially abdominal obesity) leading to the
development of hyperlipidemia, then atherosclerosis and coronary heart disease, as well as
overt diabetes, is known as the metabolic syndrome.

Glucosuria
The capacity of the tubular system to reabsorb glucose is limited to a rate of about 2
mmol/min, and in hyperglycemia (as occurs in poorly controlled diabetes mellitus), the
glomerular filtrate may contain more glucose than can be reabsorbed, resulting in glucosuria
when the renal threshold for glucose is exceeded.
GLYCOGEN METABOLISM
GLYCOGEN METABOLISM
 Glycogen represents the principal storage carbohydrate in the body, mainly in
the liver and muscle.

 It occurs mainly in liver and muscle, with modest amounts in the brain.

 In the liver, its major function is to provide glucose for extra hepatic tissues.

 In muscle, it serves mainly as a ready source of metabolic fuel for use in

muscle. Muscle lacks glucose-6-phosphatase and cannot release free glucose
from glycogen.

 Glycogen is synthesized from glucose by the pathway of Glycogenesis. It is

broken down by a separate pathway called Glycogenolysis.
REGULATION OF BLOOD GLUCOSE

Liver glycogen functions as a reserve to maintain the blood glucose

concentration in the fasting state. The liver concentration of glycogen is
about 450 mmol /L glucose equivalents after a meal, falling to about 200
mmol /L after an overnight fast; after 12 to 18 hours of fasting, liver
glycogen is almost totally depleted. Although muscle glycogen does not
directly yield free glucose (because muscle lacks glucose-6-phosphatase),
pyruvate formed by glycolysis in muscle can undergo transamination to
alanine, which is exported from muscle and used for gluconeogenesis in
the liver.
CLINICAL ASPECT OF GLYCOGEN METABOLISM

Glycogen Storage Diseases Are Inherited

“Glycogen storage disease” is a generic term to describe a group of inherited disorders characterized by
deposition of an abnormal type or quantity of glycogen in tissues, or failure to mobilize glycogen.
Some the storage diseases are as follows;
 Von Gierke disease
 Pompe disease
 Hers disease
 Tarui disease

Clinical Features
 Liver damage
 Muscle weakness
 Hypoglycemia
 Hepatosplenomegaly
 Early death