Friday, February 18, 2011

Kreb’s Cycle (OR) Citric Acid Cycle (OR) Tri-Carboxylic Acid Cycle (TCA)

During metabolism the synthesis and breakdown of different organic compounds takes place through various pathways like the breakdown and synthesis of proteins, carbohydrates, fats and nucleic acids. These different pathways and intermediates are also responsible for the production of energy.
Kreb’s cycle, named after Hans Krebs who began working out its details in 1930s, is a series of reactions in which the pyruvate from glycolysis is oxidized to Co2 under aerobic conditions. Kreb cycle is also known as citric acid cycle or Tri-carboxylic acid cycle (TCA).

Steps involved in the process of Kreb cycle are:
(1)        Fate of pyruvic acid:
Pyruvic acid can form different compounds by different pathways i.e. it can be converted into lactic acid. It can be converted into acetyl coenzyme A us a result of oxidation.
(2)        Fate of Acetyl CoA:
It can either undergo condensation with itself or its derivatives to form fatty acids having 14 – 20 carbons. Acetyl CoA can also go through a series of reactions in Krebs cycle.
(3)        Formation of citrate:
Acetyl CoA enzyme condenses with oxaloacetate by an enzyme citrate synthatase to form citrate with the release of acetyl CoA. If the amount of oxaloacetate is very small then small number of acetyl CoA would be reacting with oxaloacetate leaving surplus acetyl CoA to go through another pathway for the formation of long chain fatty acids.
(4)        Formation of C is – acotinate and iso-citrate:
Citrate is changed first into C is – acotinate and then to iso-citrate under the enzyme acotinase. Equilibrium is established between citrate, C is aconitate and iso-citrate. It has been observed that most of the time this equilibrium is shifted towards the iso-citrate. If the concentration of iso-citrate in increased the formation of citrate will result which also indicates that the equilibrium also shift in the reserve direction.
(5)        Formation of oxalosucinate:
Iso-citrate is acted upon by an enzyme iso-citrate dehydrogenase using nicotinamide adenine dinucleotide (NAD) as coenzyme. As a result iso-citrate is converted into oxalosucciate and NAD is reduced to NADH2. Similar reaction is carried out by same enzyme using nicotindmide adenine dinucleotide phosphate (NADP) as coenzyme which is reduced to NDAPH2.
(6)        Formation of α-Ketoglutarate:
Oxalosucciante is changed into α-ketoglutrate by iso-citrate dehydrogenase with the help of coenzyme NAD or NADP. In this reaction carbon dioxide and NADH2 or NADPH2 are also released.
(7)        Formation of succinyl CoA:
α-ketoglutarate combines with acetyl CoA in the presence of coenzyme NAD and enzyme α-keoglutarate dehyrogenase to form succinyl coenzyme a carbon dioxide and NADH2.
(8)        Formation of Succinate:
Later on coenzyme a is removed from succinyl coenzyme A in the presence of guanosine diphosphate (GDP) and inorganic phosphate to form succinate and guanosine triphosphate (GTP). This reaction is carried out by an enzyme called succinyl CoA synthatase.
(9)        Formation of Funarate:
An enzyme succinic dehydrogenase removes hydrogen from succinate to form funarate.
(10)      Formation of Malate:
Fumarate reacts with water in the presence of enzyme fumarase to form malate.
(11)      Regenration of oxaloacetate:
Malate is oxidized by malic dehydrogenase and NAD forming oxaloacetate and NADH2. Thus oxalo acetate is again available to start another cycle.

Importance of CTA Cycle:
(1) Source of energy: In addition to routine organic compounds described above, by products like nicotinanide adenine dinucleotide (NADH2) and guanosine triphosphate (GTP) are the source of biological energy. NADH2 after oxidation produce energy whereas GTP is itself high energy phosphate compound.
(2) Oxidation of organic compounds taken as food: Oxidation of fats, carbohydrates and proteins take place through it or in other words it can be said that oxidation of all compounds having carbon atoms can take place through TCA cycle. Some of amino acids like alanine, glutamic acid and aspartic acid at one stage or the other enters into TCA cycle e.g. glutamic acid enters cycle after its transformation into α-ketoglutarate. Similarly alanine enters the cycle after its conversion into pyruvate.
(3) Intermediate compounds: TCA cycle is also involved in synthesis of intermediate compounds leading to the formation of larger molecules.

Verification of Krebs Cycle:
It was done by radioactive traces like C14 as radioactive carbon dioxide of different levels and reactions. After addition of radioactive carbon dioxide different chemical compounds produced like glucose, fats, amino acids were isolated and looked for radioactive carbon. In this way whole of metabolic reaction were verified including individual reactions, alternative metabolic pathways, intermediates of fats, carbohydrates and amino acids etc in the body cells as well as in test tubes.

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