Friday, September 9, 2011

Krebs cycle (reactions) - part 1

Reaction 1: formation of citrate
This irreversible reaction is the 1st regulatory point of the Krebs cycle. It is a reaction in which an oxaloacetate molecule reacts with acetyl-CoA. In this process it is formed a very energetic intermediate (citroil-CoA) that rapidly converts into citrate. The molecule of CoA-SH liberated is recycled to participate in a new oxidative decarboxylation of pyruvate (catalyzed by pyruvate dehydrogenase complex).

Reaction 2: formation of isocitrate via cis-aconitate
This reaction occurs through the formation of an intermediate, cis-aconitate, obtained by dehydration of citrate. Thereafter, the cis-aconitate is hydrated, forming isocitrate. Thus, citrate and isocitrate are isomers. Despite that in cellular conditions the reaction produces only about 10% of isocitrate, the rapid consumption of this product in the following reaction shifts the equilibrium in the forward direction. The fluoroacetate is a toxic molecule because in physiological conditions it is transformed into fluoroacetil-CoA, which condenses with oxaloacetate to form fluorocitrate, that inhibits aconitase, causing accumulation of citrate.

Reaction 3: oxidation of isocitrate to α-ketoglutarate and CO2This reaction is an example of an irreversible oxidative decarboxylation, and it is the 2nd regulatory point in the Krebs cycle. In fact, this reaction is a set of three different reactions:
1. Dehydrogenation of isocitrate, creating oxalosuccinate and producing NADH.
2. Binding of Mn2+ to the carbonyl group of oxalosuccinate, stabilizing the enol and promoting the release of CO2.
3. Hydrogenation, with the arrangement of the resonance hybrid.

Reaction 4: Oxidation of α-ketoglutarate to succinyl-CoA and CO2This reaction, like the previous one, is another example of an irreversible oxidative decarboxylation. It is the 3rd (and the last one!) regulatory point of the Krebs cycle. This reaction is virtually identical to the oxidative decarboxylation of pyruvate, also leading to the formation of NADH. It is a very exergonic reaction due to the energy stored in the bond S-CoA.

Main bibliographic sources:
- Quintas A, Freire AP, Halpern MJ, Bioquímica - Organização Molecular da Vida, Lidel
- Nelson DL, Cox MM, Lehninger - Principles of Biochemistry, WH Freeman Publishers

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