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J. Biol. Chem., Vol. 282, Issue 19, 14006-14017, May 11, 2007

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Two Functionally Divergent UDP-Gal Nucleotide Sugar Transporters Participate in Phosphoglycan Synthesis in Leishmania major^*

Althea A. Capul, Tamara Barron, Deborah E. Dobson, Salvatore J. Turco, and Stephen M. Beverley¹

From the Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110 and the Department of Biochemistry, University of Kentucky Medical Center, Lexington, Kentucky 40536

In the protozoan parasite Leishmania, abundant surface and secreted molecules, such as lipophosphoglycan (LPG) and proteophosphoglycans (PPGs), contain extensive galactose in the form of phosphoglycans (PGs) based on (Gal-Man-PO₄) repeating units. PGs are synthesized in the parasite Golgi apparatus and require transport of cytoplasmic nucleotide sugar precursors to the Golgi lumen by nucleotide sugar transporters (NSTs). GDP-Man transport is mediated by the LPG2 gene product, and here we focused on transporters for UDP-Gal. Data base mining revealed 12 candidate NST genes in the L. major genome, including LPG2 as well as a candidate endoplasmic reticulum UDP-glucose transporter (HUT1L) and several pseudogenes. Gene knock-out studies established that two genes (LPG5A and LPG5B) encoded UDP-Gal NSTs. Although the single lpg5A^– and lpg5B^– mutants produced PGs, an lpg5A^–/5B^– double mutant was completely deficient. PG synthesis was restored in the lpg5A^–/5B^– mutant by heterologous expression of the human UDP-Gal transporter, and heterologous expression of LPG5A and LPG5B rescued the glycosylation defects of the mammalian Lec8 mutant, which is deficient in UDP-Gal uptake. Interestingly, the LPG5A and LPG5B functions overlap but are not equivalent, since the lpg5A^– mutant showed a partial defect in LPG but not PPG phosphoglycosylation, whereas the lpg5B^– mutant showed a partial defect in PPG but not LPG phosphoglycosylation. Identification of these key NSTs in Leishmania will facilitate the dissection of glycoconjugate synthesis and its role(s) in the parasite life cycle and further our understanding of NSTs generally.

Received for publication, November 27, 2006 , and in revised form, February 22, 2007.

^* This work was supported by National Institutes of Health Grant AI31078 (to S. M. B. and S. J. T.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1–S3 and Figs. S1–S4.

¹ To whom correspondence should be addressed: Dept. of Molecular Microbiology, 660 S. Euclid Ave., Box 8230, St. Louis, MO 63110. E-mail: beverley{at}borcim.wustl.edu.

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