Exploring the role of flavin-dependent monooxygenases in the biosynthesis of aromatic compounds

Hydroxylated aromatic compounds exhibit exceptional biological activities. In the biosynthesis of these compounds, three types of hydroxylases are commonly employed: cytochrome P450 (CYP450), pterin-dependent monooxygenase (PDM), and flavin-dependent monooxygenase (FDM). Among these, FDM is a preferred choice due to its small molecular weight, stable expression in both prokaryotic and eukaryotic fermentation systems, and a relatively high concentration of necessary cofactors. However, the catalytic efficiency of many FDMs falls short of meeting the demands of large-scale production. Additionally, challenges arise from the limited availability of cofactors and compatibility issues among enzyme components. Recently, significant progress has been achieved in improving its catalytic efficiency, but have not yet detailed and informative viewed so far. Therefore, this review emphasizes the advancements in FDMs for the biosynthesis of hydroxylated aromatic compounds and presents a summary of three strategies aimed at enhancing their catalytic efficiency: (a) Developing efficient enzyme mutants through protein engineering; (b) enhancing the supply and rapid circulation of critical cofactors; (c) facilitating cofactors delivery for enhancing FDMs catalytic efficiency. Furthermore, the current challenges and further perspectives on improving catalytic efficiency of FDMs are also discussed.