title: The structure of the Mycobacterium smegmatis trehalose synthase reveals an unusual active site configuration and acarbose-binding mode.
abstract: Trehalose synthase (TreS) catalyzes the reversible conversion of maltose into trehalose in mycobacteria as one of three biosynthetic pathways to this nonreducing disaccharide. Given the importance of trehalose to survival of mycobacteria, there has been considerable interest in understanding the enzymes involved in its production; indeed the structures of the key enzymes in the other two pathways have already been determined. Herein, we present the first structure of TreS from Mycobacterium smegmatis, thereby providing insights into the catalytic machinery involved in this intriguing intramolecular reaction. This structure, which is of interest both mechanistically and as a potential pharmaceutical target, reveals a narrow and enclosed active site pocket within which intramolecular substrate rearrangements can occur. We also present the structure of a complex of TreS with acarbose, revealing a hitherto unsuspected oligosaccharide-binding site within the C-terminal domain. This may well provide an anchor point for the association of TreS with glycogen, thereby enhancing its role in glycogen biosynthesis and degradation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, British Columbia, Canada.
authors.forename: Sami
authors.initials: S
authors.lastname: Caner
authors.forename: Nham
authors.initials: N
authors.lastname: Nguyen
authors.forename: Adeleke
authors.initials: A
authors.lastname: Aguda
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.forename: Yuan T
authors.initials: YT
authors.lastname: Pan
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers
authors.forename: Gary D
authors.initials: GD
authors.lastname: Brayer
mesh_terms: D020909:Acarbose / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000595:Amino Acid Sequence; D055162:Biocatalysis / Q000187:drug effects; D020134:Catalytic Domain / Q000187:drug effects; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000201:enzymology*; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D005964:Glucosyltransferases; C099692:trehalose synthase; D020909:Acarbose
keywords: GH13 glycoside hydrolase; drug design; enzyme inhibition; trehalose synthase; tuberculosis