Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.
Cell
; 175(4): 1045-1058.e16, 2018 11 01.
Article
in En
| MEDLINE
| ID: mdl-30388443
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
N-Acetylglucosaminyltransferases
/
Congenital Disorders of Glycosylation
/
Enzyme Inhibitors
/
Antibiotics, Antitubercular
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cell
Year:
2018
Document type:
Article
Affiliation country:
Reino Unido