6G80

Structure of Mycobacterium hassiacum MeT1 from orthorhombic crystals.

Summary for 6G80

• Entry DOI: 10.2210/pdb6g80/pdb
• Descriptor: Methyltransferase domain protein, S-ADENOSYL-L-HOMOCYSTEINE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: 3-o-methyltransferase, transferase
• Biological source: Mycobacterium hassiacum (strain DSM 44199 / CIP 105218 / JCM 12690 / 3849)
• Total number of polymer chains: 4
• Total formula weight: 103026.69

Authors

Pereira, P.J.B.,Ripoll-Rozada, J. (deposition date: 2018-04-06, release date: 2019-01-16, Last modification date: 2024-05-08)

Primary citation

Ripoll-Rozada, J.,Costa, M.,Manso, J.A.,Maranha, A.,Miranda, V.,Sequeira, A.,Ventura, M.R.,Macedo-Ribeiro, S.,Pereira, P.J.B.,Empadinhas, N.
Biosynthesis of mycobacterial methylmannose polysaccharides requires a unique 1-O-methyltransferase specific for 3-O-methylated mannosides.
Proc. Natl. Acad. Sci. U.S.A., 116:835-844, 2019

PubMed Abstract: Mycobacteria are a wide group of organisms that includes strict pathogens, such as , as well as environmental species known as nontuberculous mycobacteria (NTM), some of which-namely -are 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--methylglucose lipopolysaccharides (MGLP) ubiquitously detected across the genus, and the 3--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 -adenosyl-l-methionine-dependent sugar 1--methyltransferase (MeT1) from that specifically blocks the 1-OH position of 3,3'-di--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, -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.

PubMed: 30606802
DOI: 10.1073/pnas.1813450116

Experimental method

X-RAY DIFFRACTION (2.05 Å)