Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution

被引：53

作者：

Awakawa, Takayoshi ^{[1
,2
]}

Fujioka, Takuma ^{[1
]}

Zhang, Lihan ^{[1
]}

Hoshino, Shotaro ^{[1
]}

Hu, Zhijuan ^{[1
]}

Hashimoto, Junko ^{[3
]}

Kozone, Ikuko ^{[3
]}

Ikeda, Haruo ^{[4
]}

Shin-Ya, Kazuo ^{[2
,5
]}

Liu, Wen ^{[6
]}

Abe, Ikuro ^{[1
,2
]}

机构：

[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan

[2] Univ Tokyo, Collaborat Res Inst Innovat Microbiol, Bunkyo Ku, Yayoi 1-1-1, Tokyo 1138657, Japan

[3] Japan Biol Informat Consortium, Koto Ku, 2-4-7 Aomi, Tokyo 1358073, Japan

[4] Kitasato Univ, Kitasato Inst Life Sci, Lab Microbial Engn, Kanagawa 2520373, Japan

[5] Natl Inst Adv Ind Sci & Technol, Koto Ku, 2-4-7 Aomi, Tokyo 1350064, Japan

[6] Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bio Organ & Nat Prod Chem, Lingling Rd 345, Shanghai 200032, Peoples R China

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

中国国家自然科学基金;

关键词：

NONRIBOSOMAL PEPTIDE SYNTHETASES; MODULAR POLYKETIDE SYNTHASES; ACYLTRANSFERASE DOMAIN; BIOSYNTHESIS; PATHWAY; DESIGN; DEPSIPEPTIDES; NEOANTIMYCIN; ANTIBIOTICS; RECOGNITION;

D O I：

10.1038/s41467-018-05877-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Reprogramming of the NRPS/PKS assembly line is an attractive method for the production of new bioactive molecules. However, it is usually hampered by the loss of intimate domain/module interactions required for the precise control of chain transfer and elongation reactions. In this study, we first establish heterologous expression systems of the unique antimycin-type cyclic depsipeptides: JBIR-06 (tri-lactone) and neoantimycin (tetra-lactone), and engineer their biosyntheses by taking advantage of bioinformatic analyses and evolutionary insights. As a result, we successfully accomplish three manipulations: (i) ring contraction of neoantimycin (from tetra-lactone to tri-lactone), (ii) ring expansion of JBIR-06 (from tri-lactone to tetra-lactone), and (iii) alkyl chain diversification of JBIR-06 by the incorporation of various alkylmalonyl-CoA extender units, to generate a set of unnatural derivatives in practical yields. This study presents a useful strategy for engineering NRPS-PKS module enzymes, based on nature's diversification of the domain and module organizations.

引用

页数：10

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