INTERACTION OF ALPHA-LIPOIC ACID ENANTIOMERS AND HOMOLOGS WITH THE ENZYME COMPONENTS OF THE MAMMALIAN PYRUVATE-DEHYDROGENASE COMPLEX

Lipoic acid (alpha-lipoic acid, thioctic acid) is applied as a therape utic agent in various diseases accompanied by polyneuropathia such as diabetes mellitus. The stereoselectivity and specificity of lipoic aci d for the pyruvate dehydrogenase complex and its component enzymes fro m different sources has been studied. The dihydrolipoamide dehydrogena se component from pig heart has a clear preference for R-lipoic acid, a substrate which reacts 24 times faster than the S-enantiomer. Select ivity is more at the stage of the catalytic reaction than of binding. The Michaelis constants of both enantiomers are comparable (K-m = 3.7 and 5.5 mM for R- and S-lipoic acid, respectively) and the S-enantiome r inhibits the R-lipoic acid dependent reaction with an inhibition con stant similar to its Michaelis constant. When three lipoic acid homolo gues were tested, RS-1,2-dithiolane-3-caproic acid was one carbon atom longer than lipoic acid, while RS-bisnorlipoic acid and RS-tetranorli poic acid were two and four carbon atoms shorter, respectively. All ar e poor substrates but bind to and inhibit the enzyme with an affinity similar to that of S-lipoic acid. No essential differences with respec t to its reaction with lipoic acid enantiomers and homologues exist be tween free and complex-bound dihydrolipoamide dehydrogenase. Dihydroli poamide dehydrogenase from human renal carcinoma has a higher Michaeli s constant for R-lipoic acid (K-m = 18 mM) and does not accept the S-e nantiomer as a substrate. Both enantiomers of lipoic acid are inhibito rs of the overall reaction of the bovine pyruvate dehydrogenase comple x, but stimulate the respective enzyme complexes from rat as well as f rom Escherichia coli. The S-enantiomer is the stronger inhibitor, the R-enantiomer the better activator. The two enantiomers have no influen ce on the partial reaction of the bovine pyruvate dehydrogenase compon ent, but do inhibit this enzyme component from rat kidney. The implica tions of these results are discussed.