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.
Angew Chem Int Ed Engl. 2021 Apr 12;60(16):8851-8858. doi: 10.1002/anie.202016525. Epub 2021 Mar 1.
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.
钙调蛋白是真菌聚酮化合物，由特征性的十氢化萘和多烯部分组成。尽管最近已经确定了钙调蛋白 A 的生物合成基因簇，但钙调蛋白 A 的生物合成途径在很大程度上仍未得到研究。在此，我们通过异源和体外重建生物合成以及结构生物学研究，研究了钙调蛋白骨架结构形成的机制。有趣的是，我们的分析表明，钙调蛋白的十氢化萘和多烯部分分别由单一聚酮合酶（PKS）CalA 通过反式作用烯酰还原酶 CalK 和反式作用 C-甲基转移酶 CalH 合成，我们还确定了两个聚酮部分的酯化反应由酰基转移酶 CalD 催化。我们的研究揭示了一种新型的双重功能 PKS，从而拓宽了我们对真菌如何合成不同聚酮天然产物的理解。
