Reaction The reaction catalyzed by this enzyme in the citric acid cycle is: :
α-ketoglutarate +
NAD+ +
CoA →
Succinyl CoA +
CO2 +
NADH This reaction proceeds in three steps: •
decarboxylation of α-ketoglutarate, •
reduction of NAD+ to NADH, • and subsequent transfer to
CoA, which forms the end product,
succinyl CoA.
ΔG°' for this reaction is -7.2 kcal mol−1. The energy needed for this oxidation is conserved in the formation of a thioester bond of
succinyl CoA.
Regulation Oxoglutarate dehydrogenase is a key control point in the citric acid cycle. It is inhibited by its products,
succinyl CoA and
NADH. A high energy charge in the cell will also be inhibitive. ADP and calcium ions are allosteric activators of the enzyme. By controlling the amount of available reducing equivalents generated by the
Krebs cycle, Oxoglutarate dehydrogenase has a downstream regulatory effect on
oxidative phosphorylation and
ATP production. Reducing equivalents (such as NAD+/NADH) supply the electrons that run through the
electron transport chain of oxidative phosphorylation. Increased Oxoglutarate dehydrogenase activation levels serve to increase the concentrations of NADH relative to NAD+. High NADH concentrations stimulate an increase in flux through oxidative phosphorylation. While an increase in flux through this pathway generates ATP for the cell, the pathway also generates
free radical species as a side product, which can cause
oxidative stress to the cells if left to accumulate. Oxoglutarate dehydrogenase is considered to be a redox sensor in the
mitochondria, and has an ability to change the functioning level of mitochondria to help prevent oxidative damage. In the presence of a high concentration of free radical species, Oxoglutarate dehydrogenase undergoes fully reversible free radical mediated inhibition. Upon consumption and removal of the free radical source, normal mitochondrial function is restored. It is believed that the temporary inhibition of mitochondrial function stems from the reversible glutathionylation of the E2-lipoac acid domain of Oxoglutarate dehydrogenase. Many of these
allosteric regulators act at the E1 domain of the enzyme complex, but all three domains of the enzyme complex can be allosterically controlled. The activity of the enzyme complex is upregulated with high levels of ADP and Pi, Ca2+, and CoA-SH. The enzyme is inhibited by high ATP levels, high NADH levels, and high Succinyl-CoA concentrations. Acute exposures to stress are usually at lower, tolerable levels for the cell. Pathophysiologies can arise when the stress becomes cumulative or develops into chronic stress. The up-regulation response that occurs after acute exposure can become exhausted if the inhibition of the enzyme complex becomes too strong. ==Pathology==