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Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design

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

Abstract

Protein 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 for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo thereby providing a promising new class of antimicrobial drug.

Details

ISSN :
15565068
Database :
OpenAIRE
Journal :
SSRN Electronic Journal
Accession number :
edsair.doi...........381599891351649a9034cb4c6cc5312b
Full Text :
https://doi.org/10.2139/ssrn.3188395