Uncovering the substrate promiscuity of mammalian PTGR2: insights into metabolic crosstalk

Abstract

Ene-reductases (ERs) catalyze the reduction of activated carbon–carbon double bonds, a key transformation in metabolism and biocatalysis. While microbial ERs are well characterized, higher-eukaryote ERs remain largely unexplored. Here, the mammalian NADPH-dependent ER PTGR2 was systematically characterized through whole-cell biotransformations, in vitro assays, and molecular docking, revealing a broad substrate scope and demonstrating that xenobiotics competitively inhibit the reduction of endogenous mediators. This work adds to the known diversity of ERs beyond microbial families and provides a chemical perspective on the crosstalk between xenobiotic metabolism and inflammatory regulation.