Octyl-α-ketoglutarate

Hypoxia-inducible factor 1α (HIF-1α) turnover is initiated by prolyl hydroxylases (PHD), which hydroxylate proline residues on HIF-1α, facilitating ubiquitination. PHD activity is linked to the tricarboxylic acid (TCA) cycle, since the intermediate α-ketoglutarate is a PHD substrate and succinate and fumarate inhibit PHD. Mutations in enzymes associated with the TCA cycle occur in certain cancers. Octyl-α-ketoglutarate is a stable, cell-permeable form of α-ketoglutarate which accumulates rapidly and preferentially in cells with a dysfunctional TCA cycle. When used at 1 mM, it stimulates PHD activity, increasing HIF-1α turnover. In addition, octyl-α-ketoglutarate competitively blocks succinate- or fumarate-mediated inhibition of PHD.