Nature Structural & Molecular Biology11, 721 - 729 (2004)
Published online: 18 July 2004; | doi:10.1038/nsmb802
Identification, function and structure of the mycobacterial sulfotransferase that initiates sulfolipid-1 biosynthesis
Joseph D Mougous1, 4, Christopher J Petzold2, Ryan H Senaratne3, Dong H Lee2, 4, David L Akey1, Fiona L Lin2, 4, Sarah E Munchel1, Matthew R Pratt2, 4, Lee W Riley3, Julie A Leary2, James M Berger1
& Carolyn R Bertozzi1, 2, 4
1
Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
2
Department of Chemistry, University of California, Berkeley, California 94720, USA.
3
School of Public Health, University of California, Berkeley, California 94720, USA.
4
Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.
Correspondence should be addressed to Carolyn R Bertozzi crb@berkeley.edu
Sulfolipid-1 (SL-1) is an abundant sulfated glycolipid and potential virulence factor found in Mycobacterium tuberculosis. SL-1 consists of a trehalose-2-sulfate (T2S) disaccharide elaborated with four lipids. We identified and characterized a conserved mycobacterial sulfotransferase, Stf0, which generates the T2S moiety of SL-1. Biochemical studies demonstrated that the enzyme requires unmodified trehalose as substrate and is sensitive to small structural perturbations of the disaccharide. Disruption of stf0 in Mycobacterium smegmatis and M. tuberculosis resulted in the loss of T2S and SL-1 formation, respectively. The structure of Stf0 at a resolution of 2.6 Å reveals the molecular basis of trehalose recognition and a unique dimer configuration that encloses the substrate into a bipartite active site. These data provide strong evidence that Stf0 carries out the first committed step in the biosynthesis of SL-1 and establish a system for probing the role of SL-1 in M. tuberculosis infection.
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