One Polyketide Synthase, Two Distinct Products: Trans-Acting Enzyme-Controlled Product Divergence in Calbistrin Biosynthesis
Dr. Hui Tao
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
Search for more papers by this authorDr. Takahiro Mori
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo, 113-8657 Japan
PRESTO (Japan) Science and Technology Agency, Kawaguchi, Saitama, 332-0012 Japan
Search for more papers by this authorXingxing Wei
Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, China
Search for more papers by this authorCorresponding Author
Dr. Yudai Matsuda
Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, China
Search for more papers by this authorCorresponding Author
Prof. Dr. Ikuro Abe
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo, 113-8657 Japan
Search for more papers by this authorDr. Hui Tao
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
Search for more papers by this authorDr. Takahiro Mori
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo, 113-8657 Japan
PRESTO (Japan) Science and Technology Agency, Kawaguchi, Saitama, 332-0012 Japan
Search for more papers by this authorXingxing Wei
Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, China
Search for more papers by this authorCorresponding Author
Dr. Yudai Matsuda
Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, China
Search for more papers by this authorCorresponding Author
Prof. Dr. Ikuro Abe
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo, 113-8657 Japan
Search for more papers by this authorGraphical Abstract
Calbistrin biosynthesis involves an unusual dual-functional polyketide synthase CalA, which synthesizes both of the two structurally distinct moieties of calbistrins. The product divergence is intriguingly controlled by two trans-acting enzymes, a trans-acting enoylreductase CalK and a trans-acting C-methyltransferase CalH, to yield the decalin and polyene portions, respectively.
Abstract
Calbistrins are fungal polyketides consisting of the characteristic decalin and polyene moieties. Although the biosynthetic gene cluster of calbistrin A was recently identified, the pathway of calbistrin A biosynthesis has largely remained uninvestigated. Herein, we investigated the mechanism by which the backbone structures of calbistrins are formed, by heterologous and in vitro reconstitution of the biosynthesis and a structural biological study. Intriguingly, our analyses revealed that the decalin and polyene portions of calbistrins are synthesized by the single polyketide synthase (PKS) CalA, with the aid of the trans-acting enoylreductase CalK and the trans-acting C-methyltransferase CalH, respectively. We also determined that the esterification of the two polyketide parts is catalyzed by the acyltransferase CalD. Our study has uncovered a novel dual-functional PKS and thus broadened our understanding of how fungi synthesize diverse polyketide natural products.
Conflict of interest
The authors declare no conflict of interest.
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