Succinyl phosphonate

Succinyl phosphonate is an inhibitor of the α-ketoglutarate dehydrogenase.

Succinyl phosphonate is an α-Ketoglutarate phosphoanalogue. It is found to be an effective inhibitor of α-ketoglutarate oxidative decarboxylation, catalyzed by both muscle and bacterial α-ketoglutarate dehydrogenase complexes, as well as muscle α-ketoglutarate dehydrogenase[1]. At a concentration of 0.01 mM, succinyl phosphonate completely inhibits isolated brain KGDHC even in the presence of a 200-fold higher concentration of its substrate. In cultured human fibroblasts, 0.01 mM succinyl phosphonate produced 70% inhibition of α-ketoglutarate dehydrogenase complex. DESP and TESP are also inhibitory in the cell system, but only after preincubation, suggesting the release of their charged groups by cellular esterases[2]. Succinyl phosphonate inhibits 2-Oxoglutarate dehydrogenase , the first rate-limiting component of the mitochondrial multi-enzyme complex of oxidative decarboxylation of 2-oxoglutarate, in a highly selective and efficient manner[3].

[1]. Biryukov AI, et al. Succinyl phosphonate inhibits alpha-ketoglutarate oxidative decarboxylation, catalyzed by alpha-ketoglutarate dehydrogenase complexes from E. coli and pigeon breast muscle. FEBS Lett. 1996 Mar 11;382(1-2):167-70. [2]. Bunik VI, et al. Phosphonate analogues of alpha-ketoglutarate inhibit the activity of the alpha-ketoglutaratedehydrogenase complex isolated from brain and in cultured cells. Biochemistry. 2005 Aug 9;44(31):10552-61. [3]. Bunik VI, et al. Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner. Oncotarget. 2016 May 3;7(18):26400-21.