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Crystal structure and substrate specificity of the -ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus

GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA

(RECEIVED April 7, 2005; FINAL REVISION May 17, 2005; ACCEPTED May 18, 2005)

-Ketoacyl-ACP synthase III (FabH), an essential enzyme for bacterial viability, catalyzes the initiation of fatty acid elongation by condensing malonyl-ACP with acetyl-CoA. We have determined the crystal structure of FabH from Staphylococcus aureus, a Gram-positive human pathogen, to 2 Å resolution. Although the overall structure of S. aureus FabH is similar to that of Escherichia coli FabH, the primer binding pocket in S. aureus FabH is significantly larger than that present in E. coli FabH. The structural differences, which agree with kinetic parameters, provide explanation for the observed varying substrate specificity for E. coli and S. aureus FabH. The rank order of activity of S. aureus FabH with various acyl-CoA primers was as follows: isobutyryl->hexanoyl->butyryl->isovaleryl- >>acetyl-CoA. The availability of crystal structure may aid in designing potent, selective inhibitors of S. aureus FabH.

Keywords: Staphylococcus aureus; FabH; X-ray crystallography; kinetics; substrate specificity

Abbreviations: FAS, fatty acid synthase • ACP, acyl carrier protein • KAS, -ketoacyl-ACP synthase • CoA, coenzyme A • TLM, thiolactomycin • IPTG, isopropyl -D-thiogalactopyranoside • TCEP, Tris(2- carboxyethyl)-phosphine hydrochloride, CHAPS, 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonic acid • SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis • TCA, trichloracetic acid

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051501605.

Reprint requests to: Sanjay S. Khandekar, Gene Expression and Protein Biochemistry, Mail Code UE 0433, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA; e-mail: sanjay. khandekar{at}gsk.com; fax: (610) 270-7359.

¹ Present addresses: Pfizer Inc., Groton, CT 06340, USA;

² Shamrock Structures, Woodridge, IL 60517, USA.

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