Oxoglutarate dehydrogenase complex

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

• 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⁾:

• K_M
  : 0.14 ± 0.04 mM
• V_max : 9 ± 3 μmol.min⁻¹.mg⁻¹

Citric acid cycle

Reaction

The reaction catalyzed by this enzyme in the citric acid cycle is:

NADH

This reaction proceeds in three steps:

• decarboxylation of α-ketoglutarate,
• reduction of NAD⁺ to NADH,
• and subsequent transfer to
  succinyl CoA
  .

Regulation

Oxoglutarate dehydrogenase is a key control point in the citric acid cycle. It is inhibited by its products,

By controlling the amount of available reducing equivalents generated by the

When mitochondria are treated with excess hydrogen peroxide, flux through the electron transport chain is reduced, and NADH production is halted.^[4][5] 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.^[5] 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.^[4] 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.

In addition to free radicals and the mitochondrial redox state, Oxoglutarate dehydrogenase activity is also regulated by ATP/ADP ratios, the ratio of Succinyl-CoA to CoA-SH, and the concentrations of various metal ion cofactors (Mg2+, Ca2+).

Oxoglutarate dehydrogenase plays a role in the cellular response to stress. The enzyme complex undergoes a stress-mediated temporary inhibition upon acute exposure to stress. The temporary inhibition period sparks a stronger up-regulation response, allowing an increased level of oxoglutarate dehydrogenase activity to compensate for the acute stress exposure.[8] 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.

In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency, mitochondrial fatty acid synthesis (mtFASII) is impaired, which is the precursor reaction of lipoic acid biosynthesis.^[13][14] The result is a reduced lipoylation degree of important mitochondrial enzymes, such as oxoglutarate dehydrogenase complex (OGDC).^[14]

References