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 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.
Hong
Y S
YS
Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 14214-3000, USA.
Jacobia
S J
SJ
Packer
L
L
Patel
M S
MS
D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D008058:Dihydrolipoamide Dehydrogenase / Q000037:antagonists & inhibitors; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D006801:Humans; D007700:Kinetics; D008322:Mammals; D009206:Myocardium / Q000201:enzymology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010421:Pentanoic Acids / Q000494:pharmacology*; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013552:Swine; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C109588:1,2-diselenolane-3-pentanoic acid; D000975:Antioxidants; D016566:Organoselenium Compounds; D010421:Pentanoic Acids; D011768:Pyruvate Dehydrogenase Complex; D011994:Recombinant Proteins; D008063:Thioctic Acid; C015144:dihydrolipoic acid; D008058:Dihydrolipoamide Dehydrogenase; D000123:Acetyltransferases; D051047:Dihydrolipoyllysine-Residue Acetyltransferase