Research Overview
Where 2-oxoglutarate sits in metabolism
Alpha-ketoglutarate is generated in the mitochondrial matrix when isocitrate dehydrogenase oxidatively decarboxylates isocitrate, and it is consumed by the alpha-ketoglutarate dehydrogenase complex to form succinyl-CoA. It is also the principal amino-group acceptor in transamination: glutamate dehydrogenase and the aminotransferases interconvert glutamate and 2-oxoglutarate constantly, which makes this molecule the main chemical bridge between the carbon skeleton of the TCA cycle and cellular nitrogen handling.
Dioxygenase co-substrate chemistry
A large enzyme superfamily requires 2-oxoglutarate, molecular oxygen and ferrous iron to hydroxylate their substrates, releasing succinate and carbon dioxide in the process. Members include the TET family of DNA hydroxymethylases, the JmjC-domain histone lysine demethylases, collagen prolyl and lysyl hydroxylases, and the PHD prolyl hydroxylases that mark HIF-1α for degradation under normoxia. Because these enzymes are sensitive to the ratio of 2-oxoglutarate to succinate and fumarate, researchers use that ratio as a readout linking metabolic state to chromatin and hypoxia signalling.
- Lifespan and healthspan endpoints in C. elegans, where AKG supplementation was reported to extend lifespan in a manner linked to ATP synthase and TOR signalling
- Frailty and inflammatory marker endpoints in aged mice given a calcium AKG formulation
- Effects on collagen synthesis, given the dependence of prolyl hydroxylation on 2-oxoglutarate availability
- Nitrogen balance and ammonia handling in models of amino-acid metabolism
- Bone and mineral metabolism, where both the AKG anion and the calcium counter-ion have been examined
