title: Mechanism-based candidate inhibitors of uridine diphosphate galactopyranose mutase (UGM).
abstract: Uridine diphosphate-galactopyranose mutase (UGM), an enzyme found in many eukaryotic and prokaryotic human pathogens, catalyzes the interconversion of UDP-galactopyranose (UDP-Galp) and UDP-galactofuranose (UDP-Galf), the latter being used as the biosynthetic precursor of the galactofuranose polymer portion of the mycobacterium cell wall. We report here the synthesis of a sulfonium and selenonium ion with an appended polyhydroxylated side chain. These compounds were designed as transition state mimics of the UGM-catalyzed reaction, where the head groups carrying a permanent positive charge were designed to mimic both the shape and positive charge of the proposed galactopyranosyl cation-like transition state. An HPLC-based UGM inhibition assay indicated that the compounds inhibited about 25% of UGM activity at 500 µM concentration.
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Mahdavi-Amiri
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Silvia
authors.initials: S
authors.lastname: Borrelli
authors.affiliation: Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Slowski
authors.affiliation: Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
authors.forename: David A R
authors.initials: DA
authors.lastname: Sanders
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6. Electronic address: bpinto@sfu.ca.
authors.forename: B Mario
authors.initials: BM
authors.lastname: Pinto
mesh_terms: D055162:Biocatalysis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005690:Galactose / Q000031:analogs & derivatives* / Q000378:metabolism; D006900:Hydroxylation; D007535:Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D018036:Selenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013452:Sulfonium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018036:Selenium Compounds; D013452:Sulfonium Compounds; C104136:uridine diphosphate galactofuranose; D014530:Uridine Diphosphate; D007535:Isomerases; D005690:Galactose
keywords: Enzyme inhibitors; Mycobacterium tuberculosis; Synthesis; Transition-state analogues; UDP-galactopyranose mutase; UGM