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J. Biol. Chem., Vol. 280, Issue 1, 326-333, January 7, 2005

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Identification of the namH Gene, Encoding the Hydroxylase Responsible for the N-Glycolylation of the Mycobacterial Peptidoglycan^*

Jon B. Raymond, Sebabrata Mahapatra¶, Dean C. Crick¶, and Martin S. Pavelka, Jr.||

From the Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642 and the ^¶Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523

The peptidoglycan of most bacteria consists of a repeating disaccharide unit of -1,4-linked N-acetylmuramic acid and N-acetylglucosamine. However, the muramic acid moieties of the mycobacterial peptidoglycan are N-glycolylated, not N-acetylated. This is a rare modification seen only in the peptidoglycan of mycobacteria and five other closely related genera of bacteria. The N-glycolylation of sialic acids is a unique carbohydrate modification that has been studied extensively in eukaryotes. However, the significance of the N-glycolylation of bacterial peptidoglycan is unknown. The goal of this project was to identify the gene encoding the hydroxylase responsible for the N-glycolylation of the mycobacterial peptidoglycan. We developed a novel assay for the mycobacterial UDP-N-acetylmuramic acid hydroxylation reaction and demonstrated that Mycobacterium smegmatis has an enzyme activity that can convert UDP-N-acetylmuramic acid to UDP-N-glycolylmuramic acid. We identified the gene namH encoding the mycobacterial UDP-N-acetylmuramic acid hydroxylase by computer data base searching and motif comparisons with the eukaryotic enzymes responsible for the N-glycolyation of sialic acids. The namH gene is not essential for in vitro growth as we were successful in deleting the gene in M. smegmatis. The M. smegmatis mutant is devoid of UDP-N-acetylmuramic acid hydroxylase activity and synthesizes only N-acetylated muropeptide precursors. Furthermore, the mutant exhibits increased susceptibility to -lactam antibiotics and lysozyme. Our studies suggest that the N-glycolylation of mycobacterial peptidoglycan may play a role in lysozyme resistance or may contribute to the structural stability of the cell wall architecture.

Received for publication, September 24, 2004 , and in revised form, October 27, 2004.

^* This work was supported by NIAID, National Institutes of Health Grants AI47311 (to M. S. P.), AI049151 (to D. C. C.), and a Burroughs Wellcome Fund Career Award in the Biomedical Sciences (to M. S. P.). 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.

Supported by the Molecular Pathogenesis of Bacteria and Viruses National Institutes of Health Training Grant T32 AI07362.

^|| To whom correspondence should be addressed: University of Rochester Medical Center, Dept. of Microbiology and Immunology, 601 Elmwood Ave., Box 672. Rochester, NY 14642. Tel.: 585-275-4670; Fax: 585-473-9573; E-mail: martin_pavelka{at}urmc.rochester.edu.

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