| PapA1 and PapA2 are acyltransferases essential for the biosynthesis of the Mycobacterium tuberculosis virulence factor sulfolipid-1. | |
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MedLine Citation:
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PMID: 17592143 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mycobacterium tuberculosis produces numerous exotic lipids that have been implicated as virulence determinants. One such glycolipid, Sulfolipid-1 (SL-1), consists of a trehalose-2-sulfate (T2S) core acylated with four lipid moieties. A diacylated intermediate in SL-1 biosynthesis, SL(1278), has been shown to activate the adaptive immune response in human patients. Although several proteins involved in SL-1 biosynthesis have been identified, the enzymes that acylate the T2S core to form SL(1278) and SL-1, and the biosynthetic order of these acylation reactions, are unknown. Here we demonstrate that PapA2 and PapA1 are responsible for the sequential acylation of T2S to form SL(1278) and are essential for SL-1 biosynthesis. In vitro, recombinant PapA2 converts T2S to 2'-palmitoyl T2S, and PapA1 further elaborates this newly identified SL-1 intermediate to an analog of SL(1278). Disruption of papA2 and papA1 in M. tuberculosis confirmed their essential role in SL-1 biosynthesis and their order of action. Finally, the Delta papA2 and Delta papA1 mutants were screened for virulence defects in a mouse model of infection. The loss of SL-1 (and SL(1278)) did not appear to affect bacterial replication or trafficking, suggesting that the functions of SL-1 are specific to human infection. |
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Authors:
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Pawan Kumar; Michael W Schelle; Madhulika Jain; Fiona L Lin; Christopher J Petzold; Michael D Leavell; Julie A Leary; Jeffery S Cox; Carolyn R Bertozzi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-06-25 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 104 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2007 Jul |
Date Detail:
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Created Date: 2007-07-04 Completed Date: 2007-09-26 Revised Date: 2010-09-16 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 11221-6 Citation Subset: IM |
Affiliation:
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Department of Chemistry and Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acyltransferases
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genetics,
isolation & purification,
physiology* Animals Bacterial Proteins / biosynthesis, isolation & purification, physiology* Glycolipids / biosynthesis* Mice Multigene Family Mycobacterium tuberculosis / enzymology*, genetics, pathogenicity* Trehalose / analogs & derivatives, metabolism Tuberculosis / enzymology, microbiology Virulence Factors / biosynthesis* |
| Grant Support | |
ID/Acronym/Agency:
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AI51622/AI/NIAID NIH HHS; AI51667/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bacterial Proteins; 0/Glycolipids; 0/Virulence Factors; 53580-08-8/sulfolipid I; 91667-49-1/trehalose 2-sulfate; 99-20-7/Trehalose; EC 2.3.-/Acyltransferases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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