Mycobacteria synthesize two unique intracellular α-(1-4)-linked polymethylated polysaccharides (PMPSs) of methylglucose (MGLP) or methylmannose (MMP) (1). PMPSs sequester long-chain fatty acyl-CoAs and stimulate fatty acid synthase I rate in vitro, raising the possibility of a similar role in vivo. MMPs have been identified in rapidly-growing mycobacteria (RGM) but not in slowly-growing mycobacteria (SGM) like M. tuberculosis, implying an essential role for MGLP in this pathogen and rendering the biosynthetic enzymes attractive drug targets. The genes for MGLP initiation, elongation and methylation have been identified (2, 3) alongside with the corresponding clusters implicated in MGLP biosynthesis. The newly discovered TreS-Mak-GlgE (trehalose synthase-maltokinase-maltosyltransferase) pathway proposed to divert trehalose to MGLP elongation implicated two additional clusters in the pathway (4). We have recently identified the phosphatase (GpgP) for the second step in MGLP biosynthesis (5) and a glucosylglycerate hydrolase (GgH) specific for the MGLP primer, raising the number of gene clusters involved in this pathway (6). GpgP was misannotated as a phosphoglycerate mutase and GgH is a member of GH63 family of glycoside hydrolases (7) The assignment of authentic functions to mycobacterial genes and the biochemical characterization of their products reported here shed additional light into the intricacy of MGLPs biogenesis/regulation and renew interest on these structures’ biological roles, placing us one step closer to devise new strategies to fight mycobacterial infections.
Acknowledgements:
NE lab is funded by FCT - Fundação para a Ciência e a Tecnologia (Grants PTDC/BIA-PRO/110523/2009, PTDC/BIA-BCM/112459/2009, PTDC/BIA-MIC/2779/2012), Portugal and by the Mizutani Foundation for Glycoscience, Japan. AM, SA, VM acknowledge FCT grants (SFRH/BD/74845/2010, SFRH/BPD/43321/2008 and SFRH/BPD/79531/2011).
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