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language
eng
Author
Ozaki, Taro
Asamizu, Shumpei
Ikeda, Haruo
Omura, Satoshi
Oku, Naoya
Igarashi, Yasuhiro
Tomoda, Hiroshi
Onaka, Hiroyasu
Description
Although gt100 thiopeptides have been discovered, the number of validated gene clusters involved in their biosynthesis is lagging. We use genome mining to identify a silent thiopeptide biosynthetic gene cluster responsible for biosynthesis of lactazoles. Lactazoles are structurally unique thiopeptides with a 32-membered macrocycle and a 2-oxazolyl-6-thiazolyl pyridine core. We demonstrate that lactazoles originate from the simplest cluster, containing only six unidirectional genes (lazA to lazF). We show that lazC is involved in the macrocyclization process, leading to central pyridine moiety formation. Substitution of the endogenous promoter with a strong promoter results in an approximately 30-fold increase in lactazole A production and mutagenesis of lazC precursor gene in production of two analogs. Lactazoles do not exhibit antimicrobial activity but may modulate signaling cascades triggered by bone morphogenetic protein. Our approach facilitates the production of a more diverse set of thiopeptide structures, increasing the semisynthetic repertoire for use in drug development.
Journal Title
Chemistry & biology
Volume
21
Issue
5
Start Page
679
End Page
688
ISSN
10745521
Published Date
2014-05-22
DOI
PubMed ID
NCID
AA11072585
Publisher
Elsevier
NII Type
Journal Article
Rights
Copyright © 2014 Elsevier Ltd. All rights reserved.
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Department of Agricultural and Forest Sciences, Faculty of Life and Environmental Science
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