Streptomyceshas the largest repertoire of natural product biosynthetic gene clusters (BGCs), yet developing a universal engineering strategy for eachStreptomycesspecies is challenging. Given that someStreptomycesspecies have larger BGC repertoires than others, we proposed that a set of genes co-evolved with BGCs to support biosynthetic proficiency must exist in those strains, and that their identification may provide universal strategies to improve the productivity of other strains. We show here that genes co-evolved with natural product BGCs inStreptomycescan be identified by phylogenomics analysis. Among the 597 genes that co-evolved with polyketide BGCs, 11 genes in the ‘coenzyme’ category have been examined, including a gene cluster encoding for the cofactor pyrroloquinoline quinone. When the pqq gene cluster was engineered into 11Streptomycesstrains, it enhanced production of 16,385 metabolites, including 36 known natural products with up to 40-fold improvement and several activated silent gene clusters. This study provides an innovative engineering strategy for improving polyketide production and finding previously unidentified BGCs.

Xinran Wang, Ningxin Chen, Pablo Cruz-Morales, Biming Zhong, Yangming Zhang, Jian Wang, Yifan Xiao, Xinnan Fu, Yang Lin, Suneil Acharya, Zhibo Li, Huaxiang Deng, Yuhui Sun, Linquan Bai, Xiaoyu Tang, Jay D. Keasling & Xiaozhou Luo

Elucidation of genes enhancing natural

product biosynthesis through co-evolution analysis

Nature Metabolism(2024)

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