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Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design

Authors :
Hua Wang
N.A. Burgess-Brown
Katsiaryna Belaya
Sylvain F. Royer
Sadra Hamedzade
Andaleeb Sajid
S.R. Bushell
Shahid Mehmood
Ashley C. W. Pike
Takuya Machida
Wei Wei Liu
Carol V. Robinson
David Beeson
Wei-Min Liu
Y.Y. Dong
Mervyn J. Bibb
Benjamin G. Davis
David A. Widdick
Seung Seo Lee
Filip J. Wyszynski
Shubhashish M.M. Mukhopadhyay
Clifton E. Barry
Elisabeth P. Carpenter
Leela Shrestha
Ricardo Lucas
Helena I. Boshoff
Stephen A. Cochrane
A. Chu
Publication Year :
2018
Publisher :
Cold Spring Harbor Laboratory, 2018.

Abstract

SummaryProtein glycosylation is a widespread post-translational modification. The first committed step to the lipid-linked glycan used for this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and congenital disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use as antibiotics. However, little is known about the mechanism or the effects of disease-associated mutations in this essential enzyme. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (and thus cause disease) and allow design of non-toxic ‘lipid-altered’ tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed design of potent antibiotics forMycobacterium tuberculosis, enabling treatmentin vitro,in celluloandin vivothereby providing a promising new class of antimicrobial drug.HighlightsStructures of DPAGT1 with UDP-GlcNAc and tunicamycin reveal mechanisms of catalysisDPAGT1 mutants in patients with glycosylation disorders modulate DPAGT1 activityStructures, kinetics and biosynthesis reveal role of lipid in tunicamycinLipid-altered, tunicamycin analogues give non-toxic antibiotics against TB

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....276ba68a90e798d26899fbe7f2ff3797
Full Text :
https://doi.org/10.1101/291278