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Citric Acid Cycle
Biochemistry
2017Hayder A Giha
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Glycolysis in erythrocytesn Mature RBCs have no mitochondrian lactate is always the end product n In RBC-glycolysis, a mutase convert some of
the 1,3 bisphosphoglycerate to 2,3-PG.n 2,3-PG decreasing the affinity of Hb to O2
(release of O2 ), But there will be No net ATP production
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Oxidation of pyruvate
n Pyruvate oxidation (under aerobic conditions) occurs within the mitochondria
n Its oxidatively decarboxylated to Acetyl-CoA, before it enter the citric acid cycle, and Co2 is liberated
n This reaction is catalyzed by a complex of enzymes (3 enzymes), designated as, pyruvate dehydrogenase complex (PDH)
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Glycolysis
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Pyruvate Dehydrogenase Complex n The complex composed of: 3 enzymes and
5 vitamins: pantothenic acid (CoA), thiamin diphosphate (TPP), lipoamide, ribofalvin (FAD) and niacin (NAD).
n 2 NADH are produced for each glucose molecule
n Also a high-energy thio ester group in acetyl-CoA is produced.
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Regulation of Pyruvate Dehydrogenase Complex
- Inhibited by: Acetyl-CoA; NADH & ATP- In starvation the enzyme is inhibited- activated by: pyruvate and insulin.
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Carbohydrate metabolism
Citric Acid Cycle Definition:Is a common pathway for catabolism of acetyl Co-A that derived from different metabolites (CHO, lipids and protein), its carried out by a series of reactions within the mitochondria. Figure 4.2 Stages of Metabolism
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IntroductionØAlso called Krebs cycle and tricarboxylic acid
cycle (TCA).ØBrings about catabolism of acetyl-CoA, liberates
reducing equivalents in a form of NADH+H, FADH2 (energy), captured as ATP.
Ø It plays major role in gluconeogenesis, transamination, deamination and lipogenesis
ØAnaplerosis: is the replacement reactions that use the glucogenic amino acid carbon skeleton to provide the intermediates of the cycle which are used in other biosynthetic reactions
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Substrates provided by TCAn The pathway commences by combination of acetyl
CoA (2 C) with oxaloacetate (4 C), resulting in tricarboxylic acid, citrate (6 C)
n During the course of the cycle, 2 CO2 are released and oxaloacetate is regenerated.
n Since only small quantity of oxaloacetate is needed, its considered to play a catalytic role.
n During oxidation, by specific dehydrogenases, reducing equivalents (H) are formed.
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Substrates provided by TCA
n These reducing equivalents, enter the respiratory chain, and generates ATP in the process of oxidative phosphorylation.
n Oxygen is needed as final oxidant for the reducing equivalents (aerobic).
n The set of citric acid cycle enzymes is located in the mitochondrial matrix
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Glycolysis
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Glycolysis
GDP+P GTP
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Glycolysis
Oxaloacetate Citrate
Cis-aconitate
Isocitrate
a-Ketoglutarate
Succinyl-CoA
Succinate
Fumarate
L-Malate
Succinate
Lipids Protein Carbohydrate
Acetyl-CoA (C2)
Cis-aconitate
NADg2
Fp
2H
H2O
Cyt aa
Cyt C
Cyt b
Q
Citric acid cycle
2H
2H
2H
p
P
P
O2
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The reactions of the citric acid cycle
n The initial reaction is condensation of acetyl CoA(2 C) with oxaloacetate (4 C), to citrate, by citrate synthase, (irreversible reaction).
n Citrate is converted to isocitrate
n Isocitrate dehydrogenase (NAD), catalyze oxidative decarboxylation (Co2 ) of isocitrate to a–ketoglutarate
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n The oxidative decarboxylation of a–ketoglutarateto succinyl-CoA is catalyzed by a–ketoglutarate dehydrogenase complex. The co-factors; thiamin diphosphate, lipoate, NAD, FAD and CoA(pantothenic acid) are needed, NADH and a high energy thioester bond (succinyl-CoA) are formed.
n This reaction is irreversible, and Co2n Succinyl-CoA is converted to succinate by
succinate thiokinase, the first & only step of GTPproduction at substrate level in the TCA cycle.
The reactions of the citric acid cycle
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The reactions of the citric acid cycle
n Succinate is dehydrogenated by succinate dehydrogenase to generate Fumarate, and FADH2 (the only FADH in the TCA cycle).
n Fumarase catalyze formation of Malate from Fumarate
n Oxaloacetate is regenerated from malate by malate dehydrogenase, a reaction that produce NADH+H.
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Energy produced per one turn of TCA cycle
n 3 NADH & 1 FADH2 produced for each acetyl-CoAn 1 NADH in the respiratory chain produce 3 ATP. n 1 FADH, produces only 2 ATPn 1 GTP (ATP) is produced at the substrate leveln Thus, 12 ATP, are produced per one turn of the
cycle (ONE acetyl-CoA), or 24 ATP molecules per ONE glucose molecule.
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Regulation of the TCA cycle
n The availability of oxidized cofactors (NAD), ADP and O2.
n Non-equilibrium reactions: NAD-linked isocitrate and a-ketoglutarate dehydrogenases and citrate synthase, these are activated by Ca2+, (exercise).
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Glycolysis
Oxaloacetate
Citrate
Alanine
a-Ketoglutarate
Succinyl-CoA
Fumarate
Tryptophan
Phosphoen-olpyruvate
Pyruvate
Lactate Hydroxyproline Serine Cysteine Threonine Glycine
Acetyl-CoA (C2)
Phosphoenolpyruvate Carboxykinase
Histidine Proline Glutamine Arginine
Aspartate
Glucose
Tyrosine Phenylalanine
Isoleucine Methionine Valine
Glutamate
CO2 CO2
Transaminase
Pyruvate carboxylase
Transaminase
Transaminase
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The End