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J. Biol. Chem., Vol. 278, Issue 29, 26497-26504, July 18, 2003

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Polymerization of Mycobacterial Arabinogalactan and Ligation to Peptidoglycan^*

Tetsuya Yagi , Sebabrata Mahapatra, Katarína Mikuová , Dean C. Crick and Patrick J. Brennan ¶

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

The cell wall of Mycobacterium spp. consists predominately of arabinogalactan chains linked at the reducing ends to peptidoglycan via a P-GlcNAc-(1–3)-Rha linkage unit (LU) and esterified to a variety of mycolic acids at the nonreducing ends. Several aspects of the biosynthesis of this complex have been defined, including the initial formation of the LU on a polyprenyl phosphate (Pol-P) molecule followed by the sequential addition of galactofuranosyl (Galf) units to generate Pol-P-P-LU-(Galf)_{1,2,3, etc.} and Pol-P-P-LU-galactan, catalyzed by a bifunctional galactosyltransferase (Rv3808c) capable of adding alternating 5- and 6-linked Galf units. By applying cell-free extracts of Mycobacterium smegmatis, containing cell wall and membrane fragments, and differential labeling with UDP-[¹⁴C]Galp and recombinant UDP-Galp mutase as the source of [¹⁴C]Galf for galactan biosynthesis and 5-P-[¹⁴C]ribosyl-P-P as a donor of [¹⁴C]Araf for arabinan synthesis, we now demonstrate sequential synthesis of the simpler Pol-P-P-LU-(Galf)_n glycolipid intermediates followed by the Pol-P-P-LU-arabinogalactan and, finally, ligation of the P-LU-arabinogalactan to peptidoglycan. This first time demonstration of in vitro ligation of newly synthesized P-LU-arabinogalactan to newly synthesized peptidoglycan is a necessary forerunner to defining the genetics and enzymology of cell wall polymer-peptidoglycan ligation in Mycobacterium spp. and examining this step as a target for new antibacterial drugs.

Received for publication, March 4, 2003 , and in revised form, April 28, 2003.

^* This work was supported by NIAID, National Institutes of Health, Grants AI-18357 and AI-46393 (to P. J. B.) and AI-49151 (to D. C. C.). 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 in part by the Japan Health Sciences Foundation. Present address: Dept. of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan.

Present address: Dept. of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina CH-1, Bratislava 842 15, Slovakia.

^¶ 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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