Tetrahydrolipstatin Inhibition, Functional Analyses, and Three-dimensional Structure of a Lipase Essential for Mycobacterial Viability

Crellin, Paul K., Vivian, Julian P., Scoble, Judith, Chow, Frances M., West, Nicholas P., Brammananth, Rajini, Proellocks, Nicholas I., Shahine, Adam, Le Nours, Jerome, Wilce, Matthew C. J., Britton, Warwick J., Coppel, Ross L., Rossjohn, Jamie and Beddoe, Travis (2010) Tetrahydrolipstatin Inhibition, Functional Analyses, and Three-dimensional Structure of a Lipase Essential for Mycobacterial Viability. Journal of Biological Chemistry, 285 39: 30050-30060. doi:10.1074/jbc.M110.150094

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Author Crellin, Paul K.
Vivian, Julian P.
Scoble, Judith
Chow, Frances M.
West, Nicholas P.
Brammananth, Rajini
Proellocks, Nicholas I.
Shahine, Adam
Le Nours, Jerome
Wilce, Matthew C. J.
Britton, Warwick J.
Coppel, Ross L.
Rossjohn, Jamie
Beddoe, Travis
Title Tetrahydrolipstatin Inhibition, Functional Analyses, and Three-dimensional Structure of a Lipase Essential for Mycobacterial Viability
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2010-09
Year available 2010
Sub-type Article (original research)
DOI 10.1074/jbc.M110.150094
Open Access Status File (Publisher version)
Volume 285
Issue 39
Start page 30050
End page 30060
Total pages 11
Place of publication Bethesda, MD United States
Publisher American Society for Biochemistry and Molecular Biology, Inc.
Collection year 2010
Language eng
Formatted abstract
The highly complex and unique mycobacterial cell wall is critical to the survival of Mycobacteria in host cells. However, the biosynthetic pathways responsible for its synthesis are, in general, incompletely characterized. Rv3802c from Mycobacterium tuberculosis is a partially characterized phospholipase/thioesterase encoded within a genetic cluster dedicated to the synthesis of core structures of the mycobacterial cell wall, including mycolic acids and arabinogalactan. Enzymatic assays performed with purified recombinant proteins Rv3802c and its close homologs from Mycobacterium smegmatis (MSMEG_6394) and Corynebacterium glutamicum (NCgl2775) show that they all have significant lipase activities that are inhibited by tetrahydrolipstatin, an anti-obesity drug that coincidently inhibits mycobacterial cell wall biosynthesis. The crystal structure of MSMEG_6394, solved to 2.9 Å resolution, revealed an α/β hydrolase fold and a catalytic triad typically present in esterases and lipases. Furthermore, we demonstrate direct evidence of gene essentiality in M. smegmatis and show the structural consequences of loss of MSMEG_6394 function on the cellular integrity of the organism. These findings, combined with the predicted essentiality of Rv3802c in M. tuberculosis, indicate that the Rv3802c family performs a fundamental and indispensable lipase-associated function in mycobacteria.
Keyword Bacterial genetics
Cell Surface Enzymes
Cell Wall
Pancreatic Lipase
Mycolic Acids
Tuberculosis
Identification
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
 
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Citation counts: TR Web of Science Citation Count  Cited 16 times in Thomson Reuters Web of Science Article | Citations
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