Discovery of an ene-reductase for initiating flavone and flavonol catabolism in gut bacteria

Gaohua Yang,Sen Hong,Yuwei Sun,Peng Zhang,Weihong Jiang,Yang Gu,Yong Wang,Pengjie Yang

doi:10.1038/s41467-021-20974-2

Abstract

Gut microbial transformations of flavonoids, an enormous class of polyphenolic compounds abundant in plant-based diets, are closely associated with human health. However, the enzymes that initiate the gut microbial metabolism of flavones and flavonols, the two most abundant groups of flavonoids, as well as their underlying molecular mechanisms of action remain unclear. Here, we discovered a flavone reductase (FLR) from the gut bacterium, Flavonifractor plautii ATCC 49531 (originally assigned as Clostridium orbiscindens DSM 6740), which specifically catalyses the hydrogenation of the C2–C3 double bond of flavones/flavonols and initiates their metabolism as a key step. Crystal structure analysis revealed the molecular basis for the distinct catalytic property of FLR. Notably, FLR and its widespread homologues represent a class of ene-reductases that has not been previously identified. Genetic and biochemical analyses further indicated the importance of FLR in gut microbial consumption of dietary and medicinal flavonoids, providing broader insight into gut microbial xenobiotic transformations and possible guidance for personalized nutrition and medicine.

Highlights

Gut microbial transformations of flavonoids, an enormous class of polyphenolic compounds abundant in plant-based diets, are closely associated with human health
Considering the high structural similarity between isoflavones and flavones, we first hypothesized that the reported isoflavone reductase (IFR), which is capable of reducing the C2–C3 double bond of isoflavones (Supplementary Fig. 1a), has catalytic activity towards flavones
These results strongly suggest that IFRs are incapable of hydrogenation of the flavone C2–C3 double bond and the enzyme initiating flavone catabolism may be highly specific and distinct from the known reductases involved in flavonoid metabolism

Summary

Introduction

Gut microbial transformations of flavonoids, an enormous class of polyphenolic compounds abundant in plant-based diets, are closely associated with human health. The enzymes that initiate the gut microbial metabolism of flavones and flavonols, the two most abundant groups of flavonoids, as well as their underlying molecular mechanisms of action remain unclear. Flavonoids are the most abundant polyphenols in plants[6] According to their chemical structure, flavonoids may be roughly categorized into the following subclasses: flavones, flavanols, flavanones, flavonols, isoflavones, anthocyanins, and chalcones[7]. These compounds possess a great diversity of medicinal activities against diseases, such as cancer, inflammation, cardiovascular diseases[8,9,10], and the recently erupted novel coronavirus pneumonia[11]. No existing reductase is reported to have the catalytic activity towards this reaction, and it is unclear whether this essential transformation step involves a distinct class of reductases

Methods

Results

Conclusion