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J. Biol. Chem., Vol. 280, Issue 7, 5651-5663, February 18, 2005

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Roles of Conserved Proline and Glycosyltransferase Motifs of EmbC in Biosynthesis of Lipoarabinomannan^*

Stefan Berg, James Starbuck, Jordi B. Torrelles, Varalakshmi D. Vissa, Dean C. Crick, Delphi Chatterjee, and Patrick J. Brennan¶

From the Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682

D-Arabinans, composed of D-arabinofuranose (D-Araf), dominate the structure of mycobacterial cell walls in two settings, as part of lipoarabinomannan (LAM) and arabinogalactan, each with markedly different structures and functions. Little is known of the complexity of their biosynthesis. -D-Arabinofuranosyl-1-monophosphoryldecaprenol is the only known sugar donor. EmbA, EmbB, and EmbC, products of the paralogous genes embA, embB, and embC, the sites of resistance to the anti-tuberculosis drug ethambutol (EMB), are the only known implicated enzymes. EmbA and -B apparently contribute to the synthesis of arabinogalactan, whereas EmbC is reserved for the synthesis of LAM. The Emb proteins show no overall similarity to any known proteins beyond Mycobacterium and related genera. However, functional motifs, equivalent to a proline-rich motif of several bacterial polysaccharide co-polymerases and a superfamily of glycosyltransferases, were found. Site-directed mutagenesis in glycosyltransferase superfamily C resulted in complete ablation of LAM synthesis. Point mutations in three amino acids of the proline motif of EmbC resulted in marked reduction of LAM-arabinan synthesis and accumulation of an unknown intermediate and of the known precursor lipomannan. Yet the pattern of the differently linked D-Araf units observed in wild type LAM-arabinan was largely retained in the proline motif mutants. The results allow for the presentation of a unique model of arabinan synthesis.

Received for publication, October 6, 2004 , and in revised form, November 10, 2004.

^* This work was supported in part by NIAID Grants AI18357 (to P. J. B.), AI49151 (to D. C. C.), and AI37139 (to D. C.) from the National Institutes of Health. 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 a postdoctoral fellowship from The Wenner-Gren Foundations, Sweden.

Present address: Dept. of Medicine, Division of Infectious Diseases, Center for Microbial Interface Biology, the Ohio State University, Columbus, OH 43210.

^¶ To whom correspondence should be addressed. Tel.: 970-491-6700; Fax: 970-491-1815; E-mail: Patrick.Brennan{at}colostate.edu.

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