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

Dong, Y. Y. et al. (2018) Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design. Cell, 175(4), 1045-1058.e16. (doi: 10.1016/j.cell.2018.10.037) (PMID:30388443) (PMCID:PMC6218659)

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Abstract

Summary: 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. 2.7.8.15). 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.

Item Type:Articles
Additional Information:Y.Y.D., A.C.W.P., S.R.B., L.S., A.C., S.M.M.M., R.C., N.A.B.B. and E.P.C. are members of the SGC. The SGC is a registered charity (number 1097737) funded by AbbVie (United States), Bayer Pharma AG (Germany), Boehringer Ingelheim (Germany), the Canada Foundation for Innovation (Canada), Eshelman Institute for Innovation, Genome Canada (Canada), Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen (United States), Merck KGaA Darmstadt Germany, MSD (USA), Novartis Pharma AG (Switzerland), the Ontario Ministry of Economic Development and Innovation (Canada), Pfizer (United States), São Paulo Research Foundation-FAPESP (Brazil) and Takeda (Japan), as well as Wellcome (United Kingdom) [grant no: 106169/Z/14/Z]. B.G.D is funded by The Gates Foundation, BBSRC (United Kingdom), EPSRC (United Kingdom), Wellcome and Evotec Ltd. S.A.C is funded by the Wellcome [grant no: 110270/A/15/Z]. S.M. and C.V.R.: MRC (United Kingdom) programme grant MR/N020413/1. D.B.: MRC [grant no: MR/M006824], Wellcome Strategic Award [WT084655MA]. D.W., and M.J.B.: BBSRC [grant nos: BB/J006637/1, BB/J009725/1 and BB/J004561/1]. This work was funded, in part, by the Intramural Research Program of NIAID.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wang, Dr Hua
Authors: Dong, Y. Y., Wang, H., Pike, A. C.W., Cochrane, S. A., Hamedzadeh, S., Wyszynski, F. J., Bushell, S. R., Royer, S. F., Widdick, D. A., Sajid, A., Boshoff, H. I., Park, Y., Lucas, R., Liu, W.-m., Lee, S. S., Machida, T., Minall, L., Mehmood, S., Belaya, K., Liu, W.-W., Chu, A., Shrestha, L., Mukhopadhyay, S. M.M., Strain-Damerell, C., Chalk, R., Burgess-Brown, N. A., Bibb, M. J., Barry III, C. E., Robinson, C. V., Beeson, D., Davis, B. G., and Carpenter, E. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell
Publisher:Elsevier (Cell Press)
ISSN:0092-8674
ISSN (Online):1097-4172
Published Online:01 November 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell 175(4):1045-1058.e16
Publisher Policy:Reproduced under a Creative Commons License
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