|
type |
Journal Article |
authors |
Cui Z, Overbay J, Wang X, Liu X, Zhang Y, Bhardwaj M, Lemke A, Wiegmann D, Niro G, Thorson JS, Ducho C, Van Lanen SG |
title |
Pyridoxal-5'-phosphate-dependent Alkyl Transfer in Nucleoside Antibiotic Biosynthesis |
journal |
Nat Chem Biol |
Activity |
mur24 |
Family |
mur24 |
sel |
selected |
ui |
32483377 |
year |
(2020) |
pages |
in press |
| |
keywords |
doi: 10.1038/s41589-020-0548-3 |
abstract |
Several nucleoside antibiotics are structurally characterized by a 5″-amino-5″-deoxyribose (ADR) appended via a glycosidic bond to a high-carbon sugar nucleoside (5'S,6'S)-5'-C-glycyluridine (GlyU). GlyU is further modified with an N-alkylamine linker, the biosynthetic origin of which has yet to be established. By using a combination of feeding experiments with isotopically labeled precursors and characterization of recombinant proteins from multiple pathways, the biosynthetic mechanism for N-alkylamine installation for ADR-GlyU-containing nucleoside antibiotics has been uncovered. The data reveal S-adenosyl-L-methionine (AdoMet) as the direct precursor of the N-alkylamine, but, unlike conventional AdoMet- or decarboxylated AdoMet-dependent alkyltransferases, the reaction is catalyzed by a pyridoxal-5'-phosphate-dependent aminobutyryltransferase (ABTase) using a stepwise γ-replacement mechanism that couples γ-elimination of AdoMet with aza-γ-addition onto the disaccharide alkyl acceptor. In addition to using a conceptually different strategy for AdoMet-dependent alkylation, the newly discovered ABTases require a phosphorylated disaccharide alkyl acceptor, revealing a cryptic intermediate in the biosynthetic pathway.
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fulltext |
file.pdf (1,655,765 bytes) |
last changed |
2020/06/03 15:38 |
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