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

Dong, Yin Yao; Wang, Hua; Pike, Ashley C W; Cochrane, Stephen A; Hamedzadeh, Sadra; Wyszynski, Filip J; Bushell, Simon R; Royer, Sylvain F; Widdick, David A; Sajid, Andaleeb; Boshoff, Helena I; Park, Yumi; Lucas, Ricardo; Liu, Wei-Min; Lee, Seung Seo; Machida, Takuya; Minall, Leanne; Mehmood, Shahid; Belaya, Katsiaryna; Liu, Wei-Wei; Chu, Amy; Shrestha, Leela; Mukhopadhyay, Shubhashish M M; Strain-Damerell, Claire; Chalk, Rod; Burgess-Brown, Nicola A; Bibb, Mervyn J; Barry Iii, Clifton E; Robinson, Carol V; Beeson, David; Davis, Benjamin G; Carpenter, Elisabeth P.
Cell; 175(4): 1045-1058.e16, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388443
Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. Missense DPAGT1 variants cause congenital myasthenic syndrome and 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. 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 (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.
Selo DaSilva