Birch, Helen and Alderwick, Luke J. and Appelmelk, B. J. and Maaskant, J and Bhatt, Apoorva and Singh, Albel and Nigou, Jerome and Eggeling, Lothar and Geurtsen, J and Besra, Gurdyal S (2010) A truncated lipoglycan from mycobacteria with altered immunological properties. Proceedings of the National Academy of Sciences, 107 (6). p. 2634. ISSN 0027-8424
URL of Published Version: http://dx.doi.org/10.1073/pnas.0915082107
Identification Number/DOI: doi:10.1073/pnas.0915082107
Maintenance of cell-wall integrity in Mycobacterium tuberculosis is essential and is the target of several antitubercular drugs. For example, ethambutol targets arabinogalactan and lipoarabinomannan (LAM) biosynthesis through the inhibition of several arabinofuranosyltransferases. Apart from their role in cell-wall integrity, mycobacterial LAMs also exhibit important immunomodulatory activities. Here we report the isolation and detailed structural characterization of a unique LAM molecule derived from Mycobacterium smegmatis deficient in the arabinofuranosyltransferase AftC (AftC-LAM). This mutant LAM expresses a severely truncated arabinan domain completely devoid of 3,5-Araf–branching residues, revealing an intrinsic involvement of AftC in the biosynthesis of LAM. Furthermore, we found that ethambutol efficiently inhibits biosynthesis of the AftC-LAM arabinan core, unambiguously demonstrating the involvement of the arabinofuranosyltransferase EmbC in early stages of LAM-arabinan biosynthesis. Finally, we demonstrate that AftC-LAM exhibits an enhanced proinflammatory activity, which is due to its ability to activate Toll-like receptor 2 (TLR2). Overall, our efforts further describe the mechanism of action of an important antitubercular drug, ethambutol, and demonstrate a role for specific arabinofuranosyltransferases in LAM biosynthesis. In addition, the availability of sufficient amounts of chemically defined wild-type and isogenic truncated LAMs paves the way for further investigations of the structure–function relationship of TLR2 activation by mycobacterial lipoglycans.
|Type of Work:||Article|
|School/Faculty:||Colleges (2008 onwards) > College of Life & Environmental Sciences|
|Institution:||University of Birmingham|
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