Oxoglutarate dehydrogenase complex

Oxoglutarate Dehydrogenase Complex (OGDC or OGDH Complex) is a key enzyme complex in the tricarboxylic acid cycle (TCA cycle or Krebs cycle), which is a crucial part of cellular respiration in all aerobic organisms. This complex catalyzes the conversion of α-ketoglutarate (αKG or 2-oxoglutarate) into succinyl-CoA and CO2, a reaction that is both rate-limiting and irreversible within the TCA cycle. The activity of the OGDC is tightly regulated, as it plays a significant role in energy production, amino acid synthesis, and the regulation of glucose and fatty acid metabolism.

Structure and Function

The oxoglutarate dehydrogenase complex is a multienzyme complex that consists of multiple copies of three enzymatic components: oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2), and dihydrolipoamide dehydrogenase (E3). These components work in a sequential manner to catalyze the decarboxylation of α-ketoglutarate, the transfer of the resulting succinyl group to CoA, and the regeneration of the lipoamide cofactor, respectively.

E1: Oxoglutarate Dehydrogenase

The E1 enzyme component of the OGDC is responsible for the decarboxylation of α-ketoglutarate, a reaction that requires thiamine pyrophosphate (TPP) as a cofactor. This step is the first and rate-limiting step of the complex's catalytic cycle.

E2: Dihydrolipoamide Succinyltransferase

E2 catalyzes the transfer of the succinyl group from succinyl-dihydrolipoamide to Coenzyme A (CoA), forming succinyl-CoA. This step is crucial for the continuation of the TCA cycle and involves the coenzyme lipoic acid as a prosthetic group.

E3: Dihydrolipoamide Dehydrogenase

The E3 component regenerates the oxidized form of the lipoamide cofactor by transferring electrons to NAD+, producing NADH. This step is essential for the recycling of the lipoamide cofactor and the continuation of the complex's activity.

Regulation

The activity of the oxoglutarate dehydrogenase complex is regulated by several factors, including the availability of its substrates and products, and by allosteric effectors. High levels of ATP, NADH, and succinyl-CoA inhibit the complex, reflecting the cell's reduced demand for further energy production under these conditions. Conversely, an increase in ADP and Ca2+ levels activates the complex, indicating a higher demand for energy.

Clinical Significance

Alterations in the activity of the OGDC have been implicated in various diseases, including neurodegenerative diseases, cancer, and diabetes. Due to its central role in metabolism, the complex is considered a potential target for therapeutic interventions aimed at modulating energy production and metabolic pathways in these conditions.

See Also

• Tricarboxylic acid cycle
• Cellular respiration
• Mitochondrion
• Metabolism