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Acceptor Substrate Discrimination in Phosphatidyl-myo-inositol Mannoside Synthesis

Batt, S.M and Jabeen, Talat and Mishra, Arun K. and Veerapen, Natacha and Krumbach, Karin and Eggeling, Lothar and Besra, Gurdyal S and Futterer, K. (2010) Acceptor Substrate Discrimination in Phosphatidyl-myo-inositol Mannoside Synthesis. The Journal of Biological Chemistry. ISSN 0021-9258

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URL of Published Version: http://www.jbc.org/content/285/48/37741

Identification Number/DOI: 10.1074/jbc.M110.165407

Long term survival of the pathogen Mycobacterium tuberculosis in humans is linked to the immunomodulatory potential of its complex cell wall glycolipids, which include the phosphatidylinositol mannoside (PIM) series as well as the related lipomannan and lipoarabinomannan glycoconjugates. PIM biosynthesis is initiated by a set of cytosolic α-mannosyltransferases, catalyzing glycosyl transfer from the activated saccharide donor GDP-α-d-mannopyranose to the acceptor phosphatidyl-myo-inositol (PI) in an ordered and regio-specific fashion. Herein, we report the crystal structure of mannosyltransferase Corynebacterium glutamicum PimB′ in complex with nucleotide to a resolution of 2.0 Å. PimB′ attaches mannosyl selectively to the 6-OH of the inositol moiety of PI. Two crystal forms and GDP- versus GDP-α-d-mannopyranose-bound complexes reveal flexibility of the nucleotide conformation as well as of the structural framework of the active site. Structural comparison, docking of the saccharide acceptor, and site-directed mutagenesis pin regio-selectivity to a conserved Asp residue in the N-terminal domain that forces presentation of the correct inositol hydroxyl to the saccharide donor.

Type of Work:Article
Date:15 September 2010 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Life & Environmental Sciences
Department:School of Biosciences
Subjects:QP Physiology
Institution:University of Birmingham
Copyright Holders:American Society for Biochemistry and Molecular Biology
ID Code:585
Refereed:YES
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