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M204613200v1
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Papers In Press, published online ahead of print June 18, 2002
J. Biol. Chem, 10.1074/jbc.M204613200
Submitted on May 10, 2002
Revised on June 17, 2002
Accepted on June 18, 2002

5'-Adenosinephosphosulfate lies at a metabolic branchpoint in mycobacteria

Spencer J. Williams, Ryan H. Senaratne, Joseph D. Mougous, Lee W. Riley, and Carolyn R. Bertozzi

Chemistry and Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720

Corresponding Author: bertozzi{at}cchem.berkeley.edu

Bacterial sulfate assimilation pathways provide for activation of inorganic sulfur for the biosynthesis of cysteine and methionine, through either adenosine 5'-phosphosulfate (APS) or 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as intermediates. PAPS is also the substrate for sulfotransferases that produce sulfolipids, putative virulence factors, in Mycobacterium tuberculosis such as SL-1. In this report, genetic complementation using E. coli mutant strains deficient in APS kinase and PAPS reductase was used to define the M. tuberculosis and M. smegmatis CysH enzymes as APS reductases. Consequently, the sulfate assimilation pathway of M. tuberculosis proceeds from sulfate through APS, which is acted on by APS reductase in the first committed step towards cysteine and methionine. Thus, M. tuberculosis most likely produces PAPS for the sole use of this organism's sulfotransferases. Deletion of CysH from M. smegmatis afforded a cysteine and methionine auxotroph consistent with a metabolic branch-point centered on APS. In addition, we have redefined the substrate specificity of the B. subtilis CysH, formerly designated a PAPS reductase, as an APS reductase, based on its ability to complement a mutant E. coli strain deficient in APS kinase. Together, these studies show that two conserved sequence motifs, CCXXRKXXPL and SXGCXXCT, found in the C-termini of all APS reductases, but not in PAPS reductases, may be used to predict the substrate specificity of these enzymes. A functional domain of the M. tuberculosis CysC protein was cloned and expressed in E. coli, confirming the ability of this organism to make PAPS. The expression of recombinant M. tuberculosis APS kinase provides a means for the discovery of inhibitors of this enzyme and thus of the biosynthesis of SL-1.


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