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Ppm1, a novel polyprenol monophosphomannose synthase from Mycobacterium tuberculosis

Lookup NU author(s): Dr Sudagar Gurcha, Dr Laurent Kremer, Professor Del Besra

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Abstract

Dolichol monophosphomannose (DPM) is an ever-present donor of mannose (Man) in various eukaryotic glycosylation processes. Intriguingly, the related polyprenol monophosphomannose (PPM) is involved in the biosynthesis of lipomannan and lipoarabinomanan, key bacterial factors termed modulins that are found in mycobacteria. Based on similarities to known DPM synthases, we have identified and characterized the PPM synthase of Mycobacterium tuberculosis, now termed Mt-Ppml. In the present study, we demonstrate that Mt-Ppml possesses an unusual two-domain architecture, by which the second domain is sufficient for PPM synthesis. However, when overexpressed separately in mycobacteria, domain 1 of Mt-Ppml appears to increase the synthesis of PPM. Interestingly, other mycobacteria such as M. smegmatis, M. avium and M. leprae produce two distinct proteins, which are similar to the two domains found in Mt-Ppml. Using an in vitro assay, we also demonstrate that Mt-Ppml transfers Man from GDP-Man to a structurally diverse range of lipid monophosphate acceptors. The identification of the PPM synthase as a key enzyme in lipoarabinomannan biosynthesis now provides an attractive candidate for gene disruption to generate mutants for subsequent immunological studies. PPM synthase can also be exploited as a target for specific inhibitors of M. tuberculosis.


Publication metadata

Author(s): Gurcha SS, Baulard AR, Kremer L, Locht C, Moody DB, Muhlecker W, Costello CE, Crick DC, Brennan PJ, Besra GS

Publication type: Article

Publication status: Published

Journal: Biochemical Journal

Year: 2002

Volume: 365

Issue: 2

Pages: 441-450

ISSN (print): 0264-6021

ISSN (electronic): 1470-8728

Publisher: Portland Press Ltd

URL: http://dx.doi.org/10.1042/BJ20020107

DOI: 10.1042/BJ20020107

PubMed id: 11931640


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Funding

Funder referenceFunder name
AI-38087NIAID NIH HHS
AI-49313NIAID NIH HHS
AI-18357NIAID NIH HHS
AR-01988NIAMS NIH HHS
R01 AI049313NIAID NIH HHS

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