Succinyl phosphonate inhibits α‐ketoglutarate oxidative decarboxylation, catalyzed by α‐ketoglutarate dehydrogenase complexes from E. coli and pigeon breast muscle

Abstract

Effects of a set of a-ketoglutarate phosphoanalogues on the activity of a-ketoglutarate dehydrogeoase (EC 1.2.4.2) complexes from E. coli and pigeon breast muscle, as well as on aketoglutarate dehydrogeoase isolated from the pigeon breast muscle, have been studied, a-Ketoglutarate phosphoanalogues (sueeinyl phosphonate and its monomethyl ester) were found to be effective inhibitors of a-ketoglutarate oxidative decarboxylationt catalyzed by both nmsde and bacterial a-ketuglutarate dehydrogenase complexes, as well as muscle a-ketoglutarate dehydrogenase. The ability of glutamate phosphoanalogues to Inhibit a-ketoglutarate oxidative decarboxylation has been shown in F.. coil extract and a model system. [6][7][8][9]. The feature of inhibition of pyruvate dehydrogenase was investigated by phosphoanalogaes of Pyr, modified at phosphorus containing fragment [5].In this work we have studied the effect of a set of a-Kglu phosphoanalogues (succinyl phosphonate, Sue-P, and appropriate esters) on the activity of a-ketoglutarate dehydrogenase complexes (a-KGDC) from E. coli and pigeon breast muscle, as well as on a-KGD isolated from the pigeon breast muscle. In addition, we have studied the possibility of metabolic transformation of the glutamate phosphoanalogues, l-amino-3-carboxypropyiphosphonic (Glu-P) and -phosphinic (Glu-P.) acids into dehydrogenase inhibitors in a model system and extract of E. coli.

The 2-Oxoacid Dehydrogenase Complexes in Mitochondria Can Produce Superoxide/Hydrogen Peroxide at Much Higher Rates Than Complex I

“…Substrate analogs such as succinyl phosphonate are tightly bound and highly specific competitive inhibitors of OGDH (62)(63)(64)(65). Unfortunately, succinyl phosphonate was a poor inhibitor of the OGDH complex in mitochondria from rat skeletal muscle compared with those from liver, brain, and kidney (65) (Fig.…”

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models

“…However, for OGDHC, SP binds ~ 10‐fold more tightly than its ethyl ester . The methyl ester of SP was also found to be ~ 10‐fold less efficient than SP in the overall physiological reaction catalyzed by OGDHC . It therefore appears that the esterification‐induced changes in the binding of the phosphonates within active sites are defined by the combined contributions of steric factors and any additional interactions formed with the added methyl or ethyl groups of the esters.…”

Inhibitors of the α‐ketoglutarate dehydrogenase complex alter [1‐13C]glucose and [U‐13C]glutamate metabolism in cerebellar granule neurons

“…To understand the consequences of reduced KGDHC activity on mitochondrial function and the associated neurodegeneration, specific inhibitors have been developed to investigate how a reduction in KGDHC activity alters brain function. Succinyl phosphonate (SP) and its monomethyl phosphonate ester effectively compete with α‐ketoglutarate in muscle and Escherichia coli KGDHC by interacting with thiamine diphosphate in the KGDHC active center (Biryukov et al, 1996). SP is selective for KGDHC and has minimal effects on other α‐keto acid‐dependent enzymes (Bunik et al, 2005).…”

“…Specific inhibitors can be used to evaluate the importance of certain enzymes in a metabolic pathway and their influence on the organism. As described above, some phosphonate analogues of α‐ketoglutarate have been shown to be specific inhibitors of the isolated KGDHC and of KGDHC activity in permeabilized cells (Biryukov et al, 1996; Bunik et al, 2005). To test further the potential of these analogues, it is imperative to perform studies on nonpermeabilized cells.…”