The oxoglutarate dehydrogenase complex (OGDC) or α-ketoglutarate dehydrogenase complex is an enzyme complex, most commonly known for its role in the citric acid cycle.
Units
Much like pyruvate dehydrogenase complex (PDC), this enzyme forms a complex composed of three components:
Three classes of these multienzyme complexes have been characterized: one specific for pyruvate, a second specific for 2-oxoglutarate, and a third specific for branched-chain α-keto acids. The oxoglutarate dehydrogenase complex has the same subunit structure and thus uses the same coenzymes as the pyruvate dehydrogenase complex and the branched-chain alpha-keto acid dehydrogenase complex (TTP, CoA, lipoate, FAD and NAD). Only the E3 subunit is shared in common between the three enzymes.
Properties
Metabolic pathways
This enzyme participates in three different pathways: Citric acid cycle (KEGG link: MAP00020) Lysine degradation (KEGG link: MAP00310) Tryptophan metabolism (KEGG link: MAP00380)
Kinetic properties
The following values are from Azotobacter vinelandii (1): KM: 0.14 ± 0.04 mM Vmax : 9 ± 3 μmol.min−1.mg−1
Citric acid cycle
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. In extreme cases, the enzyme can also undergo complete oxidative inhibition.
When mitochondria are treated with excess hydrogen peroxide, flux through the electron transport chain is reduced, and NADH production is halted. 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. Glutathionylation, a form of post-translational modification, occurs during times of increased concentrations of free radicals, and can be undone after hydrogen peroxide consumption via glutaredoxin. Glutathionylation “protects” the lipoic acid of the E2 domain from undergoing oxidative damage, which helps spare the Oxoglutarate dehydrogenase complex from oxidative stress.
Oxoglutarate dehydrogenase activity is turned off in the presence of free radicals in order to protect the enzyme from damage. Once free radicals are consumed by the cell, the enzyme’s activity is turned back on via glutaredoxin. The reduction in activity of the enzyme under times of oxidative stress also serves to slow the flux through the electron transport chain, which slows production of free radicals.