1x9e
From Proteopedia
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Crystal structure of HMG-CoA synthase from Enterococcus faecalis
Overview
Biosynthesis of the isoprenoid precursor, isopentenyl diphosphate, is a, critical function in all independently living organisms. There are two, major pathways for this synthesis, the non-mevalonate pathway found in, most eubacteria and the mevalonate pathway found in animal cells and a, number of pathogenic bacteria. An early step in this pathway is the, condensation of acetyl-CoA and acetoacetyl-CoA into HMG-CoA, catalyzed by, the enzyme HMG-CoA synthase. To explore the possibility of a small, molecule inhibitor of the enzyme functioning as a non-cell wall, antibiotic, the structure of HMG-CoA synthase from Enterococcus faecalis, (MVAS) was determined by selenomethionine MAD phasing to 2.4 A and the, enzyme complexed with its second substrate, acetoacetyl-CoA, to 1.9 A., These structures show that HMG-CoA synthase from Enterococcus is a member, of the family of thiolase fold enzymes and, while similar to the recently, published HMG-CoA synthase structures from Staphylococcus aureus, exhibit, significant differences in the structure of the C-terminal domain. The, acetoacetyl-CoA binary structure demonstrates reduced coenzyme A and, acetoacetate covalently bound to the active site cysteine through a, thioester bond. This is consistent with the kinetics of the reaction that, have shown acetoacetyl-CoA to be a potent inhibitor of the overall, reaction, and provides a starting point in the search for a small molecule, inhibitor.
About this Structure
1X9E is a Single protein structure of sequence from Enterococcus faecalis with SO4 as ligand. Active as Hydroxymethylglutaryl-CoA synthase, with EC number 2.3.3.10 Full crystallographic information is available from OCA.
Reference
X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA., Steussy CN, Vartia AA, Burgner JW 2nd, Sutherlin A, Rodwell VW, Stauffacher CV, Biochemistry. 2005 Nov 1;44(43):14256-67. PMID:16245942
Page seeded by OCA on Sun Nov 25 01:42:12 2007
