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Appl Microbiol Biotechnol. 2017 Jul;101(13):5291-5300. doi: 10.1007/s00253-017-8256-y. Epub 2017 Apr 20.

Engineered jadomycin analogues with altered sugar moieties revealing JadS as a substrate flexible O-glycosyltransferase.

Author information

1
State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
2
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
3
Departamento de BiologĂ­a Funcional e Instituto Universitario de OncologĂ­a del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006, Oviedo, Spain.
4
State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China. yangkq@im.ac.cn.

Abstract

Glycosyltransferases (GTs)-mediated glycodiversification studies have drawn significant attention recently, with the goal of generating bioactive compounds with improved pharmacological properties by diversifying the appended sugars. The key to achieving glycodiversification is to identify natural and/or engineered flexible GTs capable of acting upon a broad range of substrates. Here, we report the use of a combinatorial biosynthetic approach to probe the substrate flexibility of JadS, the GT in jadomycin biosynthesis, towards different non-native NDP-sugar substrates, enabling us to identify six jadomycin B analogues with different sugar moieties. Further structural engineering by precursor-directed biosynthesis allowed us to obtain 11 new jadomycin analogues. Our results for the first time show that JadS is a flexible O-GT that can utilize both L- and D- sugars as donor substrates, and tolerate structural changes at the C2, C4 and C6 positions of the sugar moiety. JadS may be further exploited to generate novel glycosylated jadomycin molecules in future glycodiversification studies.

KEYWORDS:

Cytotoxicity; Glycosylation; Glycosyltransferase; JadS; Jadomycin; Precursor-directed biosynthesis

PMID:
28429060
DOI:
10.1007/s00253-017-8256-y
[Indexed for MEDLINE]

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