title: Synthesis, evaluation, and mechanism of N,N,N-trimethyl-D-glucosamine-(1→4)-chitooligosaccharides as selective inhibitors of glycosyl hydrolase family 20 β-N-acetyl-D-hexosaminidases.
abstract: GH20 β-N-acetyl-D-hexosaminidases are enzymes involved in many vital processes. Inhibitors that specifically target GH20 enzymes in pests are of agricultural and economic importance. Structural comparison has revealed that the bacterial chitindegrading β-N-acetyl-D-hexosaminidases each have an extra +1 subsite in the active site; this structural difference could be exploited for the development of selective inhibitors. N,N,Ntrimethyl-D-glucosamine (TMG)-chitotriomycin, which contains three GlcNAc residues, is a natural selective inhibitor against bacterial and insect β-N-acetyl-D-hexosaminidases. However, our structural alignment analysis indicated that the two GlcNAc residues at the reducing end might be unnecessary. To prove this hypothesis, we designed and synthesized a series of TMG-chitotriomycin analogues containing one to four GlcNAc units. Inhibitory kinetics and molecular docking showed that TMG-(GlcNAc)(2), is as active as TMG-chitotriomycin [TMG-(GlcNAc)(3)]. The selective inhibition mechanism of TMG-chitotriomycin was also explained.
authors.affiliation: State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, 200032 Shanghai, P. R. China.
authors.forename: You
authors.initials: Y
authors.lastname: Yang
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Yang
authors.forename: Qingyue
authors.initials: Q
authors.lastname: Wu
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Biao
authors.initials: B
authors.lastname: Yu
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013402:Sugar Alcohols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D013402:Sugar Alcohols; C528826:TMG-chitotriomycin; D001619:beta-N-Acetylhexosaminidases