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Identification of Phthiodiolone Ketoreductase, an Enzyme Required for Production of Mycobacterial Diacyl Phthiocerol Virulence Factors

Kenolisa C. Onwueme,^1, Cheryl J. Vos,^1, Juan Zurita,¹ Clifford E. Soll,² and Luis E. N. Quadri^1*

Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021,¹ Department of Chemistry, Hunter College, New York, New York 10021²

Received 29 January 2005/ Accepted 31 March 2005

Diacyl phthiocerol esters and their congeners are mycobacterial virulence factors. The biosynthesis of these complex lipids remains poorly understood. Insight into their biosynthesis will aid the development of rationally designed drugs that inhibit their production. In this study, we investigate a biosynthetic step required for diacyl (phenol)phthiocerol ester production, i.e., the reduction of the keto group of (phenol)phthiodiolones. We utilized comparative genomics to identify phthiodiolone ketoreductase gene candidates and provide a genetic analysis demonstrating gene function for two of these candidates. Moreover, we present data confirming the existence of a diacyl phthiotriol intermediate in diacyl phthiocerol biosynthesis. We also elucidate the mechanism underlying diacyl phthiocerol deficiency in some mycobacteria, such as Mycobacterium ulcerans and Mycobacterium kansasii. Overall, our findings shed additional light on the biosynthesis of an important group of mycobacterial lipids involved in virulence.

Supplemental material for this article may be found at http://jb.asm.org/.

Both authors contributed equally to this work.

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