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

Free Radic Biol Med. 1999 Mar;26(5-6):685-94. doi: 10.1016/s0891-5849(98)00243-3.

Abstract

To examine the stereospecific effects of lipoic compounds on pyruvate metabolism, the effects of R-lipoic acid (R-LA), S-lipoic acid (S-LA) and 1,2-diselenolane-3-pentanoic acid (Se-LA) on the activities of the mammalian pyruvate dehydrogenase complex (PDC) and its catalytic components were investigated. Both S-LA and R-LA markedly inhibited PDC activity; whereas Se-LA displayed 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 dihydrolipoamide acetyltransferase component. The three lipoic compounds lowered dihydrolipoamide dehydrogrenase (E3) activity in the forward reaction by about 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 [1-14C]pyruvate via PDC by cultured HepG2 cells was not affected by R-LA, but moderately decreased with S-LA and Se-LA. These findings indicate that (i) purified PDC and its catalytic components are affected by lipoic compounds based on their stereoselectivity; and (ii) the oxidation of pyruvate by intact 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyltransferases / antagonists & inhibitors
  • Animals
  • Antioxidants / pharmacology*
  • Dihydrolipoamide Dehydrogenase / antagonists & inhibitors
  • Dihydrolipoyllysine-Residue Acetyltransferase
  • Humans
  • Kinetics
  • Mammals
  • Myocardium / enzymology
  • Organoselenium Compounds / pharmacology*
  • Pentanoic Acids / pharmacology*
  • Pyruvate Dehydrogenase Complex / antagonists & inhibitors*
  • Recombinant Proteins / antagonists & inhibitors
  • Stereoisomerism
  • Swine
  • Thioctic Acid / analogs & derivatives
  • Thioctic Acid / pharmacology*
  • Tumor Cells, Cultured

Substances

  • 1,2-diselenolane-3-pentanoic acid
  • Antioxidants
  • Organoselenium Compounds
  • Pentanoic Acids
  • Pyruvate Dehydrogenase Complex
  • Recombinant Proteins
  • Thioctic Acid
  • dihydrolipoic acid
  • Dihydrolipoamide Dehydrogenase
  • Acetyltransferases
  • Dihydrolipoyllysine-Residue Acetyltransferase