Acyltransferase Domain Exchange between Two Independent Type I Polyketide Synthases in the Same Producer Strain of Macrolide Antibiotics

Author:

Kudo Fumitaka1ORCID,Kishikawa Kosuke1,Tsuboi Kazuma1,Kido Takafusa1,Usui Takeo2ORCID,Hashimoto Junko3ORCID,Shin‐ya Kazuo4ORCID,Miyanaga Akimasa1ORCID,Eguchi Tadashi1ORCID

Affiliation:

1. Department of Chemistry Tokyo Institute of Technology 2-12-1 Meguro-ku, O-okayama Tokyo 152-8551 Japan

2. Graduate School of Life and Environmental Sciences University of Tsukuba 1-1-1 Tennodai Tsukuba 305-8572 Ibaraki Japan

3. Japan Biological Informatics Consortium (JBIC) 2-4-7 Aomi, Koto-ku Tokyo 135-0064 Japan

4. National Institute of Advanced Industrial Science and Technology 2-4-7 Aomi, Koto-ku Tokyo 135-0064 Japan

Abstract

AbstractStreptomyces graminofaciens A‐8890 produces two macrolide antibiotics, FD‐891 and virustomycin A, both of which show significant biological activity. In this study, we identified the virustomycin A biosynthetic gene cluster, which encodes type I polyketide synthases (PKSs), ethylmalonyl‐CoA biosynthetic enzymes, methoxymalony‐acyl carrier protein biosynthetic enzymes, and post‐PKS modification enzymes. Next, we demonstrated that the acyltransferase domain can be exchanged between the Vsm PKSs and the PKSs involved in FD‐891 biosynthesis (Gfs PKSs), without any supply problems of the unique extender units. We exchanged the malonyltransferase domain in the loading module of Gfs PKS with the ethylmalonyltransferase domain and the methoxymalonyltransferase domain of Vsm PKSs. Consequently, the expected two‐carbon‐elongated analog 26‐ethyl‐FD‐891 was successfully produced with a titer comparable to FD‐891 production by the wild type; however, exchange with the methoxymalonyltransferase domain did not produce any FD‐891 analogs. Furthermore, 26‐ethyl‐FD‐891 showed potent cytotoxic activity against HeLa cells, like natural FD‐891.

Funder

Ministry of Education, Culture, Sports, Science and Technology

Uehara Memorial Foundation

Publisher

Wiley

Subject

Organic Chemistry,Molecular Biology,Molecular Medicine,Biochemistry

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