Design of a conformationally restricted analogue of the antiepilepsy drug vigabatrin that directs its mechanism of inactivation of γ-aminobutyric acid aminotransferase

Sun Choi, Paola Storici, Tilman Schirmer, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The antiepilepsy drug vigabatrin (1, 4-aminohex-5-enoic acid, γ-vinylGABA) is known to be a mechanism-based inactivator of the pyridoxal phosphate (PLP)-dependent enzyme γ-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M.; Silverman, R. B. J. Am. Chem. Soc. 1991, 113, 9341-9349). The major pathway involves γ-proton removal, tautomerization into the PLP ring, followed by Michael addition of an active site lysine residue at the conjugated vinyl group to give a stable covalent adduct with the protein (Scheme 2, pathway a). The minor inactivation mechanism also involves γ-proton removal, but tautomerization occurs through the vinyl group, followed by an enamine rearrangement that leads to attachment of the inactivator to the PLP, which is bound to the protein (Scheme 2, pathway b). The cause for the two different inactivation pathways was hypothesized to be potential overlap of the incipient carbanion with the π-orbitals of both the PLP and the vinyl group. With use of the crystal structure data for GABA-AT recently reported (Storici, P.; Capitani, C.; De Biase, D.; Moser, M.; John, R. A.; Jansonius, J. N.; Schirmer, T. Biochemistry 1999, 38, 8628-8634) a computer model of vigabatrin bound to the PLP was constructed and energy minimized. This model indicated that the major Michael addition pathway could only occur if the vinyl group were allowed to rotate by 180°. A conformationally rigid analogue of vigabatrin, cis-3-aminocyclohex-4-ene-1-carboxylic acid (9), was designed to prevent bond rotation and block the Michael addition pathway. A detailed study of the mechanism of inactivation of GABA-AT by 9 revealed that it inactivates by a single mechanism, the enamine pathway.

Original languageEnglish (US)
Pages (from-to)1620-1624
Number of pages5
JournalJournal of the American Chemical Society
Volume124
Issue number8
DOIs
StatePublished - Feb 27 2002

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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