Polyketides are a group of microbial secondary metabolites biosynthesized by gigantic multienzymes termed polyketide synthases (PKSs). A large number of these complex molecules, such as erythromycins and avermectins serve as life-saving pharmaceuticals and agrochemicals, while others, such as aflatoxins and fumonisins act as mycotoxins that cause severe damages to human health and agriculture. Understanding the underlying mechanisms of polyketide biosynthesis may facilitate the drug discovery process or provide solutions to mycotoxin contamination.

Recently, Prof. Xu Yuquan’s team from Biotechnology Research Institute, CAAS, together with their collaborators has revealed the intrinsic and extrinsic programming rules of collaborating iterative PKSs that control the product chain length and release mode during fungal polyketide biosynthesis. By using subunit and domain exchanges, the researchers showed that the SAT domain of non-reducing PKS (nrPKS) can actively download premature intermediates from the highly-reducing PKS (hrPKS) partner and is thus part of the chain length metaprogram of the hrPKS. They also demonstrated that the TE domain works as a size-selective filter that actively gates intermediates based on their chain length, thus is also involved in the observable metaprogram of the hrPKS subunit. These results revealed additional, unexpected layers of programming complexities in fungal iterative PKS enzymes and may guide future fungal PKS engineering studies.

This work has been published in the Journal of American Chemical Society on August 24, 2020 (https://pubs.acs.org/doi/10.1021/jacs.0c07050). The whole project was supported by the National Key Research and Development Program of China (2018YFA0901800) and National Natural Science Foundation of China (21807110 and 31870076).

Figure. Metaprogram of Fungal Collaborating Iterative Polyketide Synthases

By Xu Yuquan (xuyuquan@caas.cn)