Unexpected Role of a Short‐Chain Dehydrogenase/Reductase Family Protein in Type II Polyketide Biosynthesis. Issue 7 (20th December 2021)

• Record Type: Journal Article
• Authors: Gao, Yaojie; Zhao, Yuchun; Zhou, Jie; Yang, Maohua; Lin, Lin; Wang, Wenning; Tao, Meifeng; Deng, Zixin; Jiang, Ming
• Is Part Of: Angewandte Chemie international edition. Volume 61:Issue 7(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-20
• Subjects: biosynthesis -- cyclization -- polyketides -- SDR enzymes -- thioesterase; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202110445
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: We investigated the biosynthetic pathway of type II polyketide murayaquinone. The murayaquinone biosynthetic cluster contains genes for three putative short‐chain dehydrogenase/reductase family enzymes including MrqF and MrqH with known functions and MrqM with unclear function. We report the functional characterization of MrqM for its role in murayaquinone biosynthesis. Our gene deletion experiment and structural elucidation of the accumulated intermediates revealed that MrqM is related with the second polyketide ring cyclization, because the inactivation of mrqM resulted in the accumulation of an off‐pathway intermediate SEK43 and disrupted the second and third ring cyclization. Site‐directed mutagenesis studies showed that two conserved residues in MrqM and homologous proteins Y151 and K155 are essential for its activity. The previously proposed second/third ring cyclase, MrqD, might instead play another important role in the chain releasing step of the murayaquinone biosynthesis. Abstract : A short‐chain dehydrogenase/reductase family protein, MrqM, was revealed as a cyclase in the biosynthesis of murayaquinone by the in vivo genetic experiment, which is a new strategy used in type II polyketide cyclization. This finding not only broadens the functions of the short‐chain dehydrogenase/reductase family proteins, but also paves the way for future work in polyketide cyclization and engineering.