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J. Biol. Chem., Vol. 278, Issue 43, 42352-42360, October 24, 2003

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Crystal Structure of Mycobacterium tuberculosis MenB, a Key Enzyme in Vitamin K₂ Biosynthesis^*

James J. Truglio, Karsten Theis, Yuguo Feng, Ramona Gajda, Carl Machutta, Peter J. Tonge¶, and Caroline Kisker||

From the Department of Pharmacological Sciences, Center for Structural Biology, State University of New York at Stony Brook, New York 11794-5115 and the Department of Chemistry, State University of New York at Stony Brook, New York 11794-3400

Bacterial enzymes of the menaquinone (Vitamin K₂) pathway are potential drug targets because they lack human homologs. MenB, 1,4-dihydroxy-2-naphthoyl-CoA synthase, the fourth enzyme in the biosynthetic pathway leading from chorismate to menaquinone, catalyzes the conversion of O-succinylbenzoyl-CoA (OSB-CoA) to 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA). Based on our interest in developing novel tuberculosis chemotherapeutics, we have solved the structures of MenB from Mycobacterium tuberculosis and its complex with acetoacetyl-coenzyme A at 1.8 and 2.3 Å resolution, respectively. Like other members of the crotonase superfamily, MenB folds as an (₃)₂ hexamer, but its fold is distinct in that the C terminus crosses the trimer-trimer interface, forming a flexible part of the active site within the opposing trimer. The highly conserved active site of MenB contains a deep pocket lined by Asp-192, Tyr-287, and hydrophobic residues. Mutagenesis shows that Asp-192 and Tyr-287 are essential for enzymatic catalysis. We postulate a catalytic mechanism in which MenB enables proton transfer within the substrate to yield an oxyanion as the initial step in catalysis. Knowledge of the active site geometry and characterization of the catalytic mechanism of MenB will aid in identifying new inhibitors for this potential drug target.

Received for publication, July 10, 2003 , and in revised form, August 6, 2003.

The atomic coordinates and structure factors (code 1Q52 and 1Q51) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This research was supported by DOE Grant (DE-FG02-01ER63073) and Pew Scholars Program in the Biomedical Sciences (to C. K.) as well as National Institutes of Health Grants GM58190 (to C. K.) and AI44639 (to P. J. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ An Alfred P. Sloan Research Fellow. To whom correspondence may be addressed. Tel.: 631-632-7907; Fax: 631-632-7960; E-mail: peter.tonge{at}sunysb.edu.

^|| To whom correspondence may be addressed. Tel.: 631-632-1465; Fax: 631-632-1555; E-mail: kisker{at}pharm.sunysb.edu.

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