Evolution-guided high yield production of potent Gαq/11-signalling inhibitors FR900359 and YM-254890

Yiwen Zhou; Xinyi Zhao; Xingyu Zhao; Fei Zhang; Yunchuan Jia; Shuang Xia; Jianming Zhang; Yinhua Lu; Lei Li

doi:10.1016/j.ymben.2026.102497

Evolution-guided high yield production of potent Gα_q/11-signalling inhibitors FR900359 and YM-254890

Metab Eng. 2026 Sep:97:102497. doi: 10.1016/j.ymben.2026.102497. Epub 2026 Jun 29.

Authors

Yiwen Zhou¹, Xinyi Zhao¹, Xingyu Zhao², Fei Zhang², Yunchuan Jia³, Shuang Xia³, Jianming Zhang³, Yinhua Lu⁴, Lei Li⁵

Affiliations

¹ State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China; College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China.
² State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
³ Institute of Translational Medicine and National Facility for Translational Medicine (Shanghai), Shanghai Jiao Tong University, Shanghai, 200240, China.
⁴ College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China.
⁵ State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: lei.li@sjtu.edu.cn.

PMID: 42373013
DOI: 10.1016/j.ymben.2026.102497

Abstract

Heterotrimeric G proteins modulate a wide range of important intracellar effectors and play indispensable roles in diverse human physiological processes. The cyclic depsipeptides FR900359 and YM-254890 have emerged as potent and selective inhibitors for deconvoluting Gα_q/11-mediated signalling and targeted therapy of Gα_q/11-mutated tumors. Here we introduced an evolution-guided synthetic biology strategy to develop a set of robust heterologous microbial systems for high-yield producing FR900359 or YM-254890. First, following the uncultivable source (Candidatus Burkholderia crenata) of FR900359, Burkholderia gladioli Δgbn::attB was identified as an excellent, genetically tractable heterologous host. Second, inspired by high-GC-content feature of FR900359 or YM-254890 biosynthetic gene clusters (BGCs), the inter-genus, Streptomyces-derived superstrong promoter stnYp enabled FR900359 production to 101.7 mg/L in Δgbn::attB. Meanwhile, the stnYp-controlled YM-254890 BGC was de novo assembled due to the unavailability bottleneck of its native producer followed by efficiently heterologous production in Δgbn::attB. Finally, duplication of FR900359 or YM-254890 BGCs in our newly developed host Δgbn::2attB further increased their titers to 177.9 and 29.2 mg/L (the highest yields reported to date), respectively. Collectively, our study paved the way for the cost-efficient, sustainable microbial production of both FR900359 and YM-254890, significantly facilitating the biotechnological application and drug development of the two potent Gα_q/11-signalling inhibitors.

Keywords: Burkholderia gladioli; FR900359; Gene cluster amplification; Promoter engineering; YM-254890.

MeSH terms

Burkholderia* / genetics
Burkholderia* / metabolism
Depsipeptides* / biosynthesis
Depsipeptides* / genetics
GTP-Binding Protein alpha Subunits, Gq-G11* / antagonists & inhibitors
GTP-Binding Protein alpha Subunits, Gq-G11* / genetics
GTP-Binding Protein alpha Subunits, Gq-G11* / metabolism
Peptides, Cyclic* / biosynthesis
Peptides, Cyclic* / genetics
Signal Transduction* / drug effects
Streptomyces* / genetics
Streptomyces* / metabolism

Substances

YM-254890
FR900359
Depsipeptides
GTP-Binding Protein alpha Subunits, Gq-G11
Peptides, Cyclic