D,L-S-methyllipoic acid methyl ester, a kinetically viable model for S- protonated lipoic acid as the oxidizing agent in reductive acyl transfers catalyzed by the 2-oxoacid dehydrogenase multienzyme complexes

Ke Pan, Frank Jordan

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D,L-S(6,8)-Methyllipoic acid methyl ester triflate salt (D,L-S- methyllipoic acid methyl ester) was synthesized as a model for S-protonated lipoic acid, suggested to be the active form of lipoic acid in the reductive acylation catalyzed by the E1 and E2 enzymes of the 2-oxoacid dehydrogenase multienzyme complexes by a previous model [Chiu, C. C., Chung, A., Barletta, G., and Jordan, F. (1996) J. Am. Chem. Soc. 118, 11026-11029]. While in that earlier study lipoic acid could only trap only the enamine/C2α-carbanion intermediate in an intramolecular model, and with the assistance of a mercury compound to shift the equilibrium to the products, D,L-S-methyllipoic acid methyl ester could trap the enamine derived from 2-α-methoxybenzyl-3,4,5- trimethylthiazolium salt in an intermolecular reaction in the absence of a mercury compound, and with a rate constant of 6.6 x 104 M-1 s-1. A tetrahedral adduct at the C2α-position formed between the enamine and D,L- S-methyllipoic acid methyl ester was isolated and characterized. The reaction likely takes place by two-electron nucleophilic attack, since no evidence was found for C2α-linked homodimers, expected from a free-radical mechanism. The results suggest that, in the reductive acyl transfer, there is nucleophilic attack by the enamine at one of the sulfur atoms of the lipoic acid [probably at S8, according to Frey, P. A., Flournoy, D. S, Gruys, K., and Yang, Y. S. (1989) Ann. N.Y. Acad. Sci. 373, 21-35], while there is concomitant electrophilic catalysis by a proton juxtaposed at S6 via a general acid catalyst located on the E1 enzyme. Oxidation of the enamine derived from C2α-hydroxybenzyl-3,4,5-trimethylthiazolium salt by D,L-S-methyllipoic acid methyl ester was also deduced on the basis of the formation of 2- benzoylthiazolium ion as a major product; however, the tetrahedral intermediate could not be detected. Oxidation of the enamine by D,L-S- methyllipoic acid methyl ester can take place with either an ether or an alcohol at the C2α position of the enamine.

Original languageEnglish (US)
Pages (from-to)1357-1364
Number of pages8
Issue number5
StatePublished - Feb 3 1998


All Science Journal Classification (ASJC) codes

  • Biochemistry

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