JBC Transcription and Nuclear Factor Monoclonals

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Originally published In Press as doi:10.1074/jbc.M204613200 on June 18, 2002

J. Biol. Chem., Vol. 277, Issue 36, 32606-32615, September 6, 2002
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5'-Adenosinephosphosulfate Lies at a Metabolic Branch Point in Mycobacteria*

Spencer J. WilliamsDagger §, Ryan H. Senaratne, Joseph D. MougousDagger ||, Lee W. Riley, and Carolyn R. BertozziDagger **

From the Dagger  Howard Hughes Medical Institute and Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, California 94720 and the  School of Public Health, University of California, Berkeley, California 94720

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 Escherichia coli mutant strains deficient in APS kinase and PAPS reductase was used to define the M. tuberculosis and Mycobacterium 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 toward 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.

* This work was supported by National Institutes of Health (NIH) Grants GM59907 and AI51622. Sequencing of M. avium and M. smegmatis was accomplished with support from NIAID, NIH.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ A Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation.

|| Recipient of a Ford Foundation graduate Fellowship.

** To whom correspondence should be addressed. E-mail: bertozzi@cchem.berkeley.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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