Krebs Cycle or Tricarboxylic Acid Cycle:
The cycle was discovered by Hans Krebs. It occurs inside matrix of mitochondria. The cycle is also named as citric acid cycle (CAC) or tricarboxylic acid (TCA) cycle after the initial product. Krebs cycle is stepwise oxidative and cyclic degradation of activated acetate derived from pyruvate.
Oxidation of Pyruvate to Acetyl-CoA. Pyruvate enters mitochondria through a specific transport protein. It undergoes oxidative decarboxylation to produce CO2 and NADH. The product combines with sulphur containing coenzyme A to form acetyl CoA or activated acetate.
The reaction occurs in the presence of an enzyme complex pyruvate dehydrogenase (made up of a decarboxylase, lipoic acid, TPP, transacetylase and Mg2+). This step is called link reaction or transition reaction or gateway step as it links glycolysis with Krebs cycle.
Acetyl CoA functions as substrate entrant for Krebs cycle. It is also the connecting link between glycolysis and Krebs cycle. The acceptor molecule of Krebs cycle is a 4- carbon compound oxaloacetate. Kerbs cycle involves two decarboxylations and four dehydrogenations (oxidations).
The various components of ten stepped Krebs cycle are as follows:
1. Formation of Citrate:
Acetyl CoA (2-carbon compound) combines with oxaloacetate (4-carbon compound) in the presence of condensing enzyme citrate synthase to form a tricarboxylic 6-carbon compound called citric acid. It is the first product of Krebs cycle. CoA is liberated.
2. Formation of Isocitrate:
Citrate undergoes re-organisation in the presence of iron containing enzyme aconitase first forming cis aconitate and releasing water.
cis-aconitate is then converted into isocitrate with the addition of water while attached to enzyme aconitase. This results in interchange of hydrogen and hydroxyl groups in the molecule.
3. Formation of α-ketoglutarate:
Isocitrate undergoes oxidative decarboxylation in the presence of enzyme isocitrate dehydrogenase and Mn2+. A transient oxalosuccinate is formed as intermediate. It undergoes decarboxylation to form 5-carbon α-ketoglutarate or 2-oxoglutarate. NADH (NADPH according to some workers) is produced.
4. Oxidative Decarboxylation of α-ketoglutarate:
A third oxidative decarboxylation occurs when α- Ketoglutarate is both dehydrogenated (with the help of NAD+) and decarboxylated by an enzyme complex a-ketoglutarate dehydrogenase. The enzyme complex contains TPP and lipoic acid. The product combines with CoA to form succinyl ~ CoA.
5. Conversion of Succinyl CoA to Succinate:
Succinyl ~ CoA is acted upon by enzyme succinate or succinyl CoA synthetase thiokinase to form succinate (a 4C compound). The reaction releases sufficient energy to form ATP (in plants) or GTP (in animals). GTP can form ATP through a coupled reaction.
6. Oxidation of Succinate:
Succinate undergoes dehydrogenation to form fumarate with the help of a membrane based enzyme succinate dehydrogenase. FADH2(reduced flavin adenine dinucleotide) is produced.
7. Hydration of Fumarate:
A molecule of water gets added to fumarate to form malate. The enzyme is called fumarase.
8. Oxidation of Malate:
Malate is dehydrogenated or oxidised through the agency of malate dehydrogenase to produce oxaloacetate. Hydrogen is accepted by NADP+/NAD+.
Oxaloacetate picks up another molecule of activated acetate to repeat the cycle. A molecule of pyruvic acid that enters a mitochondrion is completely oxidized to form 3 carbon dioxide in one pre-Krebs cycle decarboxylation and two Krebs cycle decarboxylation’s.
A molecule of glucose yields two molecules of NADH2, 2ATP and two pyruvate while undergoing glycolysis. The two molecules of pyruvate are completely degraded in Krebs cycle to form two molecules of ATP, 8NADH2, and 2FADH2.
Significance of Krebs cycle and its Intermediates:
(i) Krebs cycle is the major pathway for the synthesis of reduced coenzymes and controlled release of energy during respiration.
(ii) It is a common pathway of oxidative breakdown of carbohydrates fatty acids, and amino acids (Fig. 14.7).
(iii) Amino acids enter the Krebs cycle directly as glutamate (for a-Ketoglutarate) and asparate (for oxaloacetate) after their deamination,
(iv) Fats produce fatty acids and glycerol. Glycerol is phosphorylated and oxidised to form glyceraldehyde 3-phosphate. Fatty acids undergo p-oxidation to produce acetyl CoA. Acetyl CoA enters Krebs cycle,
(v) Acetyl CoA provides 2-carbon compounds for the synthesis of atty acids, cutin, aromatic compounds and isoprenoids for forming phytol chain of chlorophyll, carotenoids, steroids, terpenes, gibberellins, etc.
(vi) a-Ketoglutarate of Krebs cycle produces an important amino acid called glutamate,
(vii) Succinyl CoA takes part in synthesis of pyrrole compounds of chlorophyll, cytochrome and phytochrome,
(viii) Oxaloacetate produces another important amino acid called aspartate. It also forms pyrimidine’s and alkaloids,
(ix) It forms GTP which is an important component of signal-transduction system,
(x) Krebs cycle is amphibolic (both catabolic and anabolic) because it provides a number of intermediates for anabolic pathways.
Krebs Cycle- An Amphibolitic Pathway:
Amphibolic pathway (Gk. amphi- both, bole- throw) is the one which is used for both breakdown (catabolism) and build-up (anabolism) reactions. Respiratory pathway is mainly a catabolic process which serves to run the living system by providing energy.
The pathway produces a number of intermediates. Many of them are raw materials for building up both primary and secondary metabolites:
(i) Acetyl CoA is helpful not only in using fatty acids in Krebs cycle but is also raw material for synthesis proteins of fatty acids, steroids, terpenes, aromatic compounds and carotenoides.
(ii) a-ketoglutarate is organic acid which forms glutamate (an important amino acid) on amination.
(iii) Oxaloacetate on amination produces aspartate (another important amino acid),
(iv) Both aspartate and glutamate are components of proteins. Pyrimidines and alkaloids are other products, and
(v) Succinyl CoA forms cytochromes and chlorophyll.
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