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Hymeglusin inhibition of bacterial hydroxymethylglutaryl‐ CoA synthase (mvaS)
Author(s) -
Miziorko Henry M,
Skaff D Andrew,
Ramyar Kasra X,
McWhorter William J,
Geisbrecht Brian V
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.964.3
Subject(s) - thioester , chemistry , adduct , stereochemistry , enterococcus faecalis , biochemistry , atp synthase , enzyme , organic chemistry , escherichia coli , gene
Hymeglusin (1233A; F244) is established as a specific beta lactone inhibitor of eukaryotic hydroxymethylglutaryl‐CoA synthase (HMGCS; Greenspan et al., PNAS (1987) 84: 7488–7492). Inhibition results from formation of a thioester adduct to the active site cysteine. Hymeglusin inhibition has primarily been studied for eukaryotic HMGCS, with little characterization of effects on prokaryotic mvaS. Hymeglusin blocks growth of Enterococcus faecalis. After inhibitor is removed from culture media, a growth curve inflection point at 3.1 hr is observed (versus 0.7 hr for uninhibited control). Upon hymeglusin inactivation of purified E. faecalis mvaS, the thioester adduct is more stable than measured for human HMGCS. Hydroxylamine cleaves the thioester adduct; substantial enzyme activity is restored at a rate that is 5‐fold faster for human HMGCS than for mvaS. Structural results explain these differences in enzyme‐inhibitor thioester adduct stability and/or solvent accessibility. The E. faecalis mvaS‐hymeglusin structure (1.95 Å) reveals virtually complete occlusion of bound inhibitor in a solvent inaccessible narrow tunnel. In contrast, eukaryotic (Brassica juncea) HMGCS (Pojer et al. (2006) PNAS 103:11491–11496) binds hymeglusin in a more solvent exposed cavity. NIH AI071028, AI090149; Marion‐Merrell‐Dow Fdn.