Staphylococcus aureus 3-hydroxy-3-methylglutaryl-CoA synthase: crystal structure and mechanism.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, a member of the family of acyl-condensing enzymes, catalyzes the first committed step in the mevalonate pathway and is a potential target for novel antibiotics and cholesterol-lowering agents. The Staphylococcus aureus mvaS gene product (43.2 kDa) was overexpressed in Escherichia coli, purified to homogeneity, and shown biochemically to be an HMG-CoA synthase. The crystal structure of the full-length enzyme was determined at 2.0-A resolution, representing the first structure of an HMG-CoA synthase from any organism. HMG-CoA synthase forms a homodimer. The monomer, however, contains an important core structure of two similar alpha/beta motifs, a fold that is completely conserved among acyl-condensing enzymes. This common fold provides a scaffold for a catalytic triad made up of Cys, His, and Asn required by these enzymes. In addition, a crystal structure of HMG-CoA synthase with acetoacetyl-CoA was determined at 2.5-A resolution. Together, these structures provide the structural basis for an understanding of the mechanism of HMG-CoA synthase.
GlaxoSmithKline Pharmaceuticals, Computational, Analytical, and Structural Sciences, King of Prussia, Pennsylvania 19406, USA. Nino.2.Campobasso@gsk.com
Nino
N
Campobasso
Mehul
M
Patel
Imogen E
IE
Wilding
Howard
H
Kallender
Martin
M
Rosenberg
Michael N
MN
Gwynn
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001216:Asparagine / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D002784:Cholesterol / Q000378:metabolism; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D019281:Dimerization; D004926:Escherichia coli / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000737:chemistry* / Q000235:genetics; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000201:enzymology*
D006639:Histidine; D001216:Asparagine; D002784:Cholesterol; D006904:Hydroxymethylglutaryl-CoA Synthase; D003545:Cysteine