The inhibitory effects of lipoic compounds on mammalian pyruvate dehydrogenase complex and its catalytic components

To examine the stereospecific effects of lipoic compounds on pyruvate metab olism, the effects of R-lipoic acid (R-LA), S-lipoic acid (S-LA) and 1,2-di selenolane-3-pentanoic acid (Se-LA) on the activities of the mammalian pyru vate dehydrogenase complex (PDC) and its catalytic components were investig ated. Both S-LA and R-LA markedly inhibited PDC activity; whereas Se-LA dis played inhibition only at higher concentrations. Examination of the effects on the individual catalytic components indicated that Se-LA inhibited the pyruvate dehydrogenase component; whereas R-LA and S-LA inhibited the dihyd rolipoamide acetyltransferase component. The three lipoic compounds lowered dihydrolipoamide dehydrogrenase (E3) activity in the forward reaction by a bout 30 to 45%. The kinetic data of E3 showed that both R-LA and Se-LA are used as substrates by E3 for the reverse reaction. Decarboxylation of [1-C- 14]pyruvate via PDC by cultured HepG2 cells was not affected by R-LA, but m oderately decreased with S-LA and Se-LA. These findings indicate that (i) p urified PDC and its catalytic components are affected by lipoic compounds b ased on their stereoselectivity; and (ii) the oxidation of pyruvate by inta ct HepG2 cells is not inhibited by R-LA. The later finding with the intact cells is in support of therapeutic role of R-LA as an antioxidant. (C) 1999 Elsevier Science Inc.