期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：3
页码：835-844
DOI：10.1073/pnas.1813450116
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Mycobacteria are a wide group of organisms that includes strict pathogens, such as Mycobacterium tuberculosis , as well as environmental species known as nontuberculous mycobacteria (NTM), some of which—namely Mycobacterium aviumare important opportunistic pathogens. In addition to a distinctive cell envelope mediating critical interactions with the host immune system and largely responsible for their formidable resistance to antimicrobials, mycobacteria synthesize rare intracellular polymethylated polysaccharides implicated in the modulation of fatty acid metabolism, thus critical players in cell envelope assembly. These are the 6- O -methylglucose lipopolysaccharides (MGLP) ubiquitously detected across the Mycobacterium genus, and the 3- O -methylmannose polysaccharides (MMP) identified only in NTM. The polymethylated nature of these polysaccharides renders the intervening methyltransferases essential for their optimal function. Although the knowledge of MGLP biogenesis is greater than that of MMP biosynthesis, the methyltransferases of both pathways remain uncharacterized. Here, we report the identification and characterization of a unique S -adenosyl-l -methionine–dependent sugar 1- O -methyltransferase (MeT1) from Mycobacterium hassiacum that specifically blocks the 1-OH position of 3,3′-di- O -methyl-4α-mannobiose, a probable early precursor of MMP, which we chemically synthesized. The high-resolution 3D structure of MeT1 in complex with its exhausted cofactor, S -adenosyl-l -homocysteine, together with mutagenesis studies and molecular docking simulations, unveiled the enzyme’s reaction mechanism. The functional and structural properties of this unique sugar methyltransferase further our knowledge of MMP biosynthesis and provide important tools to dissect the role of MMP in NTM physiology and resilience.
关键词：Mycobacterium ; polymethylated polysaccharides ; sugar methyltransferase ; S -adenosyl- l -methionine ; 3D structure
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