Background:

Octyl-α-ketoglutarate is a stable, cell-permeable form of α-ketoglutarate, a substrate of prolyl hydroxylases (PHD) [1][2].

The high turnover of HIFα is initiated by prolyl hydroxylases (PHD), which hydroxylate proline residues on the oxygen-dependent degradation (ODD) domain of HIFα, facilitating ubiquitination and degradation. To catalyze proline hydroxylation, PHDs convert molecular oxygen and α-ketoglutarate to carbon dioxide and succinate [2]. Loss of IDH1 activity would reduce cellular levels of α-KG [3].

Octyl-α-ketoglutarate is a cell-permeating α-ketoglutarate derivative, which built up rapidly and preferentially in cells with a dysfunctional TCA cycle. Octyl-α-ketoglutarate increased intracellular levels of freeα-ketoglutaric acid by approximately fourfold. In HEK293-derived cell lines expressing both a GFP-ODD fusion protein and HA-tagged pVHL, Octyl-α-ketoglutarate reactivated PHD activity inhibited by succinate or fumarate. Octyl-α-ketoglutarate restored hydroxylation and targeted HIF1 for ubiquitylation and proteasomally mediated degradation [2]. Octyl-α-ketoglutarate inhibited the HIF-1α induction caused by IDH1 knockdown in HeLa cells or overexpression of IDH1R132H mutant in U-87MG cells, suggesting a reduction in IDH1 activity caused a reduction in α-KG levels that in turn led to stabilization of HIF-1α [3].

参考文献:
[1].  Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005 Nov;5(11):857-66.
[2].  MacKenzie ED, Selak MA, Tennant DA, et al. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol. 2007 May;27(9):3282-9.
[3].  Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009 Apr 10;324(5924):261-5.