Tetrahydrolipstatin inhibition, functional analyses, and three-dimensional structure of a lipase essential for mycobacterial viability.

The Journal of Biological Chemistry
Paul K CrellinTravis Beddoe

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 o...Continue Reading

References

Nov 1, 1992·FEMS Microbiology Letters·C GuilhotC Martín
Jan 11, 1991·Methods in Enzymology·W R JacobsB R Bloom
Jan 1, 1995·Annual Review of Biochemistry·P J Brennan, H Nikaido
Jan 1, 1997·Methods in Enzymology·J D Schrag, M Cygler
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·D GhoshJ Eyzaguirre
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·T C Terwilliger, J Berendzen
May 13, 1999·Bioinformatics·P GouetF Métoz
May 20, 2000·Acta Crystallographica. Section D, Biological Crystallography·T HoltonJ C Sacchettini
Aug 10, 2000·The Journal of Biological Chemistry·K MikusováP J Brennan
Oct 9, 2002·Current Protein & Peptide Science·M Holmquist
Mar 27, 2003·Molecular Microbiology·Christopher M SassettiEric J Rubin
Dec 30, 2003·Proceedings of the National Academy of Sciences of the United States of America·Damien PortevinChristophe Guilhot
Dec 31, 2003·Methods in Enzymology·Thomas R Ioerger, James C Sacchettini
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jan 18, 2005·Clinical Microbiology Reviews·Kuni TakayamaGurdyal S Besra
Dec 22, 2005·Acta Crystallographica. Section D, Biological Crystallography·Philip Evans
Mar 10, 2007·Current Topics in Medicinal Chemistry·Patrick J Brennan, Dean C Crick
Jul 10, 2007·Nature Structural & Molecular Biology·Charles W PembleW Todd Lowther
Sep 12, 2007·Bioinformatics·M A LarkinD G Higgins
Feb 20, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nicholas P WestWarwick J Britton
Jun 27, 2009·Molecular Microbiology·Kimberly PayneGraham F Hatfull

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Citations

Mar 9, 2011·Chemical Communications : Chem Comm·Nicholas P WestRichard J Payne
Dec 24, 2011·The Journal of Biological Chemistry·Jessica C SeeligerCarolyn R Bertozzi
Oct 23, 2012·Journal of Molecular Graphics & Modelling·Parameswaran SaravananSanjukta Patra
Mar 21, 2013·Plant Physiology and Biochemistry : PPB·Isvett Josefina Flores-Sanchez, David Roger Gang
Aug 10, 2016·Antimicrobial Agents and Chemotherapy·Céline RensVéronique Fontaine
Jun 17, 2016·Microbiology and Molecular Biology Reviews : MMBR·Marietta Flores-DíazAntje Flieger
Sep 27, 2018·Future Microbiology·Nagender Rao RameshwaramSangita Mukhopadhyay
Oct 12, 2018·Drug Development Research·Erik M Larsen, R Jeremy Johnson
Dec 17, 2017·The Journal of Biological Chemistry·Christopher M GoinsDonald R Ronning
Oct 20, 2020·European Journal of Medicinal Chemistry·Jean-François CavalierStéphane Canaan

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