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J. Biol. Chem., Vol. 278, Issue 31, 28840-28848, August 1, 2003

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Identification of Genes Encoding Arabinosyltransferases (SCA) Mediating Developmental Modifications of Lipophosphoglycan Required for Sand Fly Transmission of Leishmania major^*

Deborah E. Dobson  , Brenda J. Mengeling ¶, Salvatore Cilmi ||, Suzanne Hickerson , Salvatore J. Turco ¶ and Stephen M. Beverley  ||

From the Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, the ^¶Department of Biochemistry, University of Kentucky Medical Center, Lexington, Kentucky 40536, and the ^||Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

At key steps in the infectious cycle pathogens must adhere to target cells, but at other times detachment is required for transmission. During sand fly infections by the protozoan parasite Leishmania major, binding of replicating promastigotes is mediated by galactosyl side chain (scGal) modifications of phosphoglycan repeats of the major surface adhesin, lipophosphoglycan (LPG). Release is mediated by arabinosyl (Ara) capping of LPG scGal residues upon differentiation to the infective metacyclic stage. We used intraspecific polymorphisms of LPG structure to develop a genetic strategy leading to the identification of two genes (SCA1/2) mediating scAra capping. These LPG side chain 1,2-arabinosyltransferases (scAraTs) exhibit canonical glycosyltransferase motifs, and their overexpression leads to elevated microsomal scAraT activity. Although the level of scAra caps is maximal in metacyclic parasites, scAraT activity is maximal in log phase cells. Because quantitative immunolocalization studies suggest this is not mediated by sequestration of SCA scAraTs away from the Golgi apparatus during log phase, regulation of activated Ara precursors may control LPG arabinosylation in vivo. The SCA genes define a new family of eukaryotic AraTs and represent novel developmentally regulated LPG-modifying activities identified in Leishmania.

Received for publication, March 18, 2003 , and in revised form, May 14, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY230143.

^* This work was supported by National Institutes of Health grants (to S. J. T. and S. M. B.). 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.

To whom correspondence should be addressed: Dept. of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8230, St. Louis, MO 63110. Tel.: 314-747-2631; Fax: 314-747-2634; E-mail: dedobson{at}borcim.wustl.edu.

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