PMID- 22510038
OWN - NLM
STAT- MEDLINE
DCOM- 20120917
LR  - 20211021
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 51
IP  - 23
DP  - 2012 Jun 12
TI  - Biochemical and structural basis for inhibition of Enterococcus faecalis 
      hydroxymethylglutaryl-CoA synthase, mvaS, by hymeglusin.
PG  - 4713-22
LID - 10.1021/bi300037k [doi]
AB  - Hymeglusin (1233A, F244, L-659-699) is established as a specific beta-lactone 
      inhibitor of eukaryotic hydroxymethylglutaryl-CoA synthase (HMGCS). Inhibition 
      results from formation of a thioester adduct to the active site cysteine. In 
      contrast, the effects of hymeglusin on bacterial HMG-CoA synthase, mvaS, have 
      been minimally characterized. Hymeglusin blocks growth of Enterococcus faecalis. 
      After removal of the inhibitor from culture media, a growth curve inflection 
      point at 3.1 h is observed (vs 0.7 h for the uninhibited control). Upon 
      hymeglusin inactivation of purified E. faecalis mvaS, the thioester adduct is 
      more stable than that measured for human HMGCS. Hydroxylamine cleaves the 
      thioester adduct; substantial enzyme activity is restored at a rate that is 
      8-fold faster for human HMGCS than for mvaS. Structural results explain these 
      differences in enzyme-inhibitor thioester adduct stability and solvent 
      accessibility. The E. faecalis mvaS-hymeglusin cocrystal structure (1.95 A) 
      reveals virtually complete occlusion of the bound inhibitor in a narrow tunnel 
      that is largely sequestered from bulk solvent. In contrast, eukaryotic (Brassica 
      juncea) HMGCS binds hymeglusin in a more solvent-exposed cavity.
FAU - Skaff, D Andrew
AU  - Skaff DA
AD  - University of Missouri, Kansas City, MO, USA.
FAU - Ramyar, Kasra X
AU  - Ramyar KX
FAU - McWhorter, William J
AU  - McWhorter WJ
FAU - Barta, Michael L
AU  - Barta ML
FAU - Geisbrecht, Brian V
AU  - Geisbrecht BV
FAU - Miziorko, Henry M
AU  - Miziorko HM
LA  - eng
GR  - R01 AI071028/AI/NIAID NIH HHS/United States
GR  - R21 AI090149/AI/NIAID NIH HHS/United States
GR  - AI071028/AI/NIAID NIH HHS/United States
GR  - AI090149/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120525
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Fatty Acids, Unsaturated)
RN  - 0 (Lactones)
RN  - 29066-42-0 (antibiotic 1233A)
RN  - 2FP81O2L9Z (Hydroxylamine)
RN  - EC 2.3.3.10 (Hydroxymethylglutaryl-CoA Synthase)
SB  - IM
MH  - Cloning, Molecular
MH  - Crystallography, X-Ray
MH  - Enterococcus faecalis/*enzymology
MH  - Enzyme Inhibitors/chemistry/*pharmacology
MH  - Fatty Acids, Unsaturated/chemistry/*pharmacology
MH  - Gene Expression Regulation, Bacterial/physiology
MH  - Gene Expression Regulation, Enzymologic
MH  - Humans
MH  - Hydroxylamine/chemistry/pharmacology
MH  - Hydroxymethylglutaryl-CoA Synthase/*antagonists & inhibitors/genetics/metabolism
MH  - Kinetics
MH  - Lactones/chemistry/*pharmacology
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Protein Binding
MH  - X-Ray Diffraction
PMC - PMC3431454
MID - NIHMS372645
EDAT- 2012/04/19 06:00
MHDA- 2012/09/18 06:00
PMCR- 2013/06/12
CRDT- 2012/04/19 06:00
PHST- 2012/04/19 06:00 [entrez]
PHST- 2012/04/19 06:00 [pubmed]
PHST- 2012/09/18 06:00 [medline]
PHST- 2013/06/12 00:00 [pmc-release]
AID - 10.1021/bi300037k [doi]
PST - ppublish
SO  - Biochemistry. 2012 Jun 12;51(23):4713-22. doi: 10.1021/bi300037k. Epub 2012 May 
      25.