PDBsum entry 1x9e

Lyase

PDB id: 1x9e

Contents

Protein chains

383 a.a. *

Ligands

SO4 ×4

Waters ×170

* Residue conservation analysis

PDB id:

1x9e

Name:

Lyase

Title:

Crystal structure of hmg-coa synthase from enterococcus faecalis

Structure:

Hmg-coa synthase. Chain: a, b. Engineered: yes

Source:

Enterococcus faecalis. Organism_taxid: 1351. Gene: mvas. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

2.40Å R-factor: 0.235 R-free: 0.254

Authors:

C.N.Steussy,A.A.Vartia,J.W.Burgner Ii,A.Sutherlin,V.W.Rodwell, C.V.Stauffacher

Key ref:

C.N.Steussy et al. (2005). X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA. Biochemistry, 44, 14256-14267. PubMed id: 16245942 DOI: 10.1021/bi051487x

Date:

20-Aug-04 Release date: 01-Nov-05

Protein chains

Q9FD71  (HMGCS_ENTFL) -  Hydroxymethylglutaryl-CoA synthase from Enterococcus faecalis

Seq: 383 a.a.

Struc: 383 a.a.

Enzyme reactions

• Enzyme class: E.C.2.3.3.10 - hydroxymethylglutaryl-CoA synthase.
• Pathway: Mevalonate Biosynthesis
• Reaction: acetoacetyl-CoA + acetyl-CoA + H2O = (3S)-3-hydroxy-3-methylglutaryl-CoA + CoA + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/bi051487x

Biochemistry 44:14256-14267 (2005)

PubMed id: 16245942

X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA.

C.N.Steussy, A.A.Vartia, J.W.Burgner, A.Sutherlin, V.W.Rodwell, C.V.Stauffacher.

ABSTRACT

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.