A Chalcone Synthase-Like Bacterial Protein Catalyzes Heterocyclic C-Ring Cleavage of Naringenin to Alter Bioactivity Against Nuclear Receptors in Colonic Epithelial Cells

Gülşan, Ebru Ece; Nowshad, Farrhin; Leigh, Meredith  Davis; Crott, Jimmy W.; Park, Hyejin; Martin, Greg; Safe, Stephen; Chapkin, Robert S.; Jayaraman, Arul; Lee, Kyongbum

doi:10.2139/ssrn.4236793

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“…Therefore, we set this number as the cutoff value for predictions. Chalcone synthase is classified a transferase enzyme, but we previously found that it can catalyze the C-ring cleavage of naringenin through promiscuous enzymatic action (Gülşan et al, 2022 ). This was correctly predicted by the tool developed in this work (Table 1 ).…”

Section: Figurementioning

confidence: 52%

“…We proposed a pathway of O-deglycosylation of tilianin to acacetin, aglycone version of tilianin, demethylation of acacetin to apigenin, hydrogenation of apigenin to naringenin and ring cleavage reaction of naringenin to 3-(4-hydroxyphenyl) propionic acid. Naringenin ring cleavage was heavily investigated in a recent study by Gülşan et al (Gülşan et al, 2022 ), hence, we excluded this reaction from our analysis. We started our predictions with educated guesses.…”

Section: Prediction Of Promiscuous Enzyme Activity Of Flavonoid Metab...mentioning

confidence: 99%

“…KCTC 0041BP that can catalyze the methylation of quercetin, luteolin, myricetin, quercetin 3-O-β-Dglucoside and fisetin (Darsandhari et al, 2018 ) by cloning and heterologously expressing the enzyme in E. coli. We recently used in silico predictions and in vitro experiments to show that a chalcone synthase-like bacterial polyketide synthase can catalyze the cleavage of naringenin's Cring (Gülşan et al, 2022 ). In plants, flavanone ring cleavage is catalyzed by chalcone isomerases (Braune et al, 2016 ), which suggests that the polyketide synthase's ability to cleave the C-ring of naringenin reflects a promiscuous activity.…”

Section: Introductionmentioning

confidence: 99%

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A Chemical Reaction Similarity-Based Prediction Algorithm Identifies the Multiple Taxa Required to Catalyze an Entire Metabolic Pathway of Dietary Flavonoids

Gulsan,

Nowshad,

Yamaguchi

et al. 2023

Preprint

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Flavonoids are polyphenolic phytochemicals abundant in plant-based, health-promoting foods. They are only partially absorbed in the small intestine, and gut microbiota plays a significant role in their metabolism. As flavonoids are not natural substrates of gut bacterial enzymes, reactions of flavonoid metabolism have been attributed to the ability of general classes of enzymes to metabolize non-natural substrates. To systematically characterize this promiscuous enzyme activity, we developed a prediction tool that is based on chemical reaction similarity. The tool takes a list of enzymes or organisms to match microbial enzymes with their non-native flavonoid substrates and orphan reactions. We successfully predicted the promiscuous activity of known flavonoid-metabolizing bacterial and plant enzymes. Next, we used this tool to identify the multiple taxa required to catalyze an entire metabolic pathway of dietary flavonoids. Tilianin is a flavonoid-O-glycoside having biological and pharmacological activities, including neuroprotection. Using our prediction tool, we defined a novel bacterial pathway of tilianin metabolism that includes O-deglycosylation to acacetin, demethylation of acacetin to apigenin, and hydrogenation of apigenin to naringenin. We predicted and confirmed using in vitro experiments and LC-MS techniques that Bifidobacterium longum subsp. animalis, Blautia coccoides and Flavonifractor plautii can catalyze this pathway. Prospectively, the prediction-validation methodology developed in this work could be used to systematically characterize gut microbial metabolism of dietary flavonoids and other phytochemicals. The bioactivities of flavonoids and their metabolic products can vary widely. We used an in vitro rat neuronal model to show that tilianin metabolites exhibit protective effect against H2O2 through reactive oxygen species (Delepine et al.) scavenging activity and thus, improve cell viability, while the parent compound, tilianin, was ineffective. These results are important to understand the gut microbiota-dependent physiological effects of dietary flavonoids.

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Section: Figurementioning

confidence: 52%

Section: Prediction Of Promiscuous Enzyme Activity Of Flavonoid Metab...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Chemical Reaction Similarity-Based Prediction Algorithm Identifies the Multiple Taxa Required to Catalyze an Entire Metabolic Pathway of Dietary Flavonoids

Gulsan,

Nowshad,

Yamaguchi

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

A Chalcone Synthase-Like Bacterial Protein Catalyzes Heterocyclic C-Ring Cleavage of Naringenin to Alter Bioactivity Against Nuclear Receptors in Colonic Epithelial Cells

Cited by 1 publication

References 0 publications

A Chemical Reaction Similarity-Based Prediction Algorithm Identifies the Multiple Taxa Required to Catalyze an Entire Metabolic Pathway of Dietary Flavonoids

A Chemical Reaction Similarity-Based Prediction Algorithm Identifies the Multiple Taxa Required to Catalyze an Entire Metabolic Pathway of Dietary Flavonoids

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