L.1&2
Dr. Najlaa AL-Dahhan
1.The Citric Acid Cycle: The Catabolism of Acetyl-CoA
Biomedical importance: The citric acid cycle (Krebs cycle, tricarboxylic
acid cycle) is a series of reactions in mitochondria that oxidize acetyl residues
(as acetyl-CoA) and reduce coenzymes that upon reoxidation are linked to the
formation of ATP. The citric acid cycle is the final common pathway for the
aerobic oxidation of carbohydrate, lipid, and protein because glucose, fatty
acids, and most amino acids are metabolized to acetyl-CoA or intermediates
of the cycle.
The citric acid cycle provides substrate for the respiratory chain.
Reactions of The citric acid cycle liberate reducing equivalent & CO2.
(Figure 1).Twelve ATP are formed per turn of the citric acid cycle .
Vitamins play key roles in the citric acid cycle .Four of the B vitamins are
essential in the citric acid cycle and therefore in energy-yielding metabolism:
(1) riboflavin, in the form of flavin adenine dinucleotide (FAD),a cofactor in
the α-ketoglutarate dehydrogenase complex and in succinate dehydrogenase;
(2) niacin, in the form of nicotinamide adenine dinucleotide (NAD), the
coenzyme for three dehydrogenases in the cycle—isocitrate dehydrogenase, αketoglutarate dehydrogenase,and malate dehydrogenase; (3) thiamin (vitamin
B1), as thiamin diphosphate, the coenzyme for decarboxylation in the αketoglutarate dehydrogenase reaction;and (4) pantothenic acid, as part of
coenzyme A,the cofactor attached to “active” carboxylic acid residues such as
acetyl-CoA and succinyl-CoA. The citric acid cycle plays apivotal role in
metabolism.
The Citric Acid Cycle Takes Part in Gluconeogenesis, Transamination,&
Deamination.( Figure 2). The Citric Acid Cycle Takes Part in Fatty Acid
Synthesis .Regulation of the citric acid cycle depends primarily on a supply of
oxidized Cofactors.
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The citric acid cycle is the final pathway for the oxidation of carbohydrate,
lipid, and protein whose common end-metabolite, acetyl-CoA, reacts with
oxaloacetate to form citrate. By a series of dehydrogenations
and
decarboxylations, citrate is degraded,releasing reduced coenzymes and 2CO2
and regenerating oxaloacetate. The reduced coenzymes are oxidized by the
respiratory chain linked to formation of ATP. Thus, the cycle is the major
route for the generation 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, fatty acid synthesis,and interconversion of amino acids.
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2. Glycolysis & the Oxidation of Pyruvate
Biomedical importance :Most tissues have at least some requirement for
glucose. In brain, the requirement is substantial. Glycolysis, the major
pathway for glucose metabolism, occurs in the cytosol of all cells. It is unique
in that it can function either aerobically or anaerobically. Erythrocytes, which
lack mitochondria, are completely reliant on glucose as their metabolic fuel
and metabolize it by anaerobic
glycolysis. However, to oxidize glucose
beyond pyruvate (the end product of glycolysis) requires both oxygen and
mitochondrial enzyme systems such as the pyruvate dehydrogenase complex,
the citric acid cycle, and the respiratory chain . Glycolysis is both the principal
route for glucose
metabolism and the main pathway for the metabolism of fructose, galactose,
and other carbohydrates derived from the diet. Glycolysis canfunction under
anaerobic conditions.When a muscle contracts in an anaerobic medium, ie,
one from which oxygen is excluded, glycogen disappears and lactate appears
as the principal end product. The reactions of glycolysis constitute the main
pathway of glucose utllization. The overall equation for glycolysis from
glucose to lactate is as follows:All of the enzymes of glycolysis (Figure 3) are
found in the cytosol. Glucose enters glycolysis by phosphorylation to glucose
6-phosphate, catalyzed by hexokinase,using ATP as the phosphate donor.
Tissues That Function Under Hypoxic Circumstances Tend to Produce Lactate
(Figure 3).This is true of skeletal muscle, particularly the white fibers, where
the rate of work output and therefore the need for ATP formation may exceed
the rate at which oxygen can be taken up and utilized. glycolysis in
erythrocytes, even under aerobic conditions, always terminates in lactate,
because the subsequent reactions of pyruvate are mitochondrial, and
erythrocytes lack mitochondria.
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Glycolysis Is regulated at three steps involving nonequilibrium reactions .
Although most of the reactions of glycolysis are reversible, three are markedly
exergonic and must therefore be considered physiologically irreversible.These
reactions,catalyzed by hexokinase (and
glucokinase),phosphofructokinase,
and pyruvate kinase.In Erythrocytes, the First Site in Glycolysis for ATP
Generation May Be Bypassed. The oxidation of pyruvate to acetyl-ACoA is
the irreversible route from glycolysis to the citric acid cycle. Pyruvate
dehydrogenase Is
regulated
by end-product
inhibition
& covalent
modification.pyruvate dehydrogenase is inhibited by its products,acetyl- CoA
and NADH .
Oxidation of glucose yields up to 38 mol of ATP under aerobic conditions but
only 2 mol when O2 is absent. Clinical aspects: inhibition of pyruvate
metabolism leads to lactic acidosis. 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) or when the metabolic
machinery is absent for the further oxidation of pyruvate (eg, in
erythrocytes).Glycolysis
is
regulated
by
three
enzymes
catalyzing
nonequilibrium 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,
that is dependent on the vitamin cofactor thiamin diphosphate. Conditions that
involve an inability to metabolize pyruvate frequently lead to lactic acidosis.
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L.3
3.Gluconeogenesis & Control of the Blood Glucose
Gluconeogenesis is the term used to include all pathways responsible for
converting noncarbohydrate precursors to glucose or glycogen.The major
substrates are the glucogenic amino acids and lactate, glycerol, and
propionate. liver and kidney are the major gluconeogenic tissues.
Gluconeogenesis involves glycolysis ,The citric acid cycle & some special
reactions .Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis
.Three nonequilibrium reactions catalyzed by hexokinase, phosphofructo
kinase, and pyruvate kinase prevent simple reversal of glycolysis for glucose
synthesis .They are circumvented as follows:
A.
Pyruvate & Phosphoenolpyruvate.
B.
Fructose 1,6-bisphosphate & fructose 6-phosphate
C.
Glucose 6-Phosphate &glucose .
D.
Glucose lucose 1-Phosphate &glycogen.
Since glycolysis &gluconeogenesis
opposite directions ,they must be
share the same pathway but in
regulated
reciprocally. Induction &
repression of key enzyme synthesis requires several hours.covalent
modification by reversible phosphorylation Is rapid. Allosteric modification is
instantaneous.fructose 2,6-bisphosphate plays a unique role in the Regulation
of glycolysis &gluconeogenesis in liver.substrate (Futile) cycles allow fine
tuning.The
concentration
of
blood
glucose
is
regulated
within
narrowlimits.blood glucose is derived from the diet,gluconeogenesis&
glycogenolysis.metabolic &hormonal mechanisms regulate the concentration
of the blood glucose. glucokinase Is important in regulating blood glucose
after a meal. Insulin plays a central Role in regulating blood glucose. glucagon
opposes the actions of insulin.other hormones affect blood glucose.Further
cilinical aspects. glucosuria occurs when the renal threshold for glucose Is
exceeded. hypoglycemia may occur during pregnancy &in the neonate. The
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body’s ability to utilize glucose may be ascertained by measuring Its glucose
tolerance.
Gluconeogenesis is the process of converting noncarbohydrates to glucose
or glycogen. It is of particular importance when carbohydrate is not available
from the diet. Significant substrates are amino acids, lactate,glycerol, and
propionate.The pathway of gluconeogenesis in the liver and kidney utilizes
those reactions in glycolysis which are reversible plus four additional
reactions that circumvent the irreversible nonequilibrium reactions.Since
glycolysis and gluconeogenesis share the same pathway but operate in
opposite directions, their activities are regulated reciprocally. The liver
regulates the blood glucose after a meal because it contains the high-Km
glucokinase that promotes increased hepatic utilization of glucose. Insulin is
secreted as a direct response to hyperglycemia;it stimulates the liver to store
glucose as glycogen and facilitates uptake of glucose into extrahepatic 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.
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