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

Yin Yao Dong, Hua Wang, Ashley C. W. Pike, Stephen A. Cochrane, Sadra Hamedzadeh, Filip Wyszynski, Simon Bushell, Sylvain F. Royer, David A. Widdick, Andaleeb Sajid, Helena I. Boshoff, Yumi Park, Ricardo Lucas, Wei-Min Liu, Seung Soo Lee, Takuya Machida, Leanne Minall, Shahid Mehmood, Katsiaryna Belaya, Wei-Wei LiuAmy Chu, Leela Shrestha, Shubhashish M. M. Mukhopadhyay, Claire Strain-Damerell, Rod Chalk, Nicola A. Burgess-Brown, Mervyn Bibb, Clifton Barry 3rd, Carol Robinson, David Beeson, Benjamin Davis, Elisabeth P. Carpenter

Research output: Contribution to journalArticle

18 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)1045-1058
Number of pages14
JournalCell
Volume175
DOIs
Publication statusPublished - 01 Nov 2018

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