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Flavin-Containing Monooxygenases Are Conserved Regulators of Stress Resistance and Metabolism.

ABSTRACT: Flavin-Containing Monooxygenases are conserved xenobiotic-detoxifying enzymes. Recent studies have revealed endogenous functions of FMOs in regulating longevity in Caenorhabditis elegans and in regulating aspects of metabolism in mice. To explore the cellular mechanisms of FMO's endogenous function, here we demonstrate that all five functional mammalian FMOs may play similar endogenous roles to improve resistance to a wide range of toxic stresses in both kidney and liver cells. We further find that stress-activated c-Jun N-terminal kinase activity is enhanced in FMO-overexpressing cells, which may lead to increased survival under stress. Furthermore, FMO expression modulates cellular metabolic activity as measured by mitochondrial respiration, glycolysis, and metabolomics analyses. FMO expression augments mitochondrial respiration and significantly changes central carbon metabolism, including amino acid and energy metabolism pathways. Together, our findings demonstrate an important endogenous role for the FMO family in regulation of cellular stress resistance and major cellular metabolic activities including central carbon metabolism.

SUBMITTER: Huang S

PROVIDER: S-EPMC7907451 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Flavin-Containing Monooxygenases Are Conserved Regulators of Stress Resistance and Metabolism.

Huang Shijiao S Howington Marshall B MB Dobry Craig J CJ Evans Charles R CR Leiser Scott F SF

Frontiers in cell and developmental biology 20210212

Flavin-Containing Monooxygenases are conserved xenobiotic-detoxifying enzymes. Recent studies have revealed endogenous functions of FMOs in regulating longevity in <i>Caenorhabditis elegans</i> and in regulating aspects of metabolism in mice. To explore the cellular mechanisms of FMO's endogenous function, here we demonstrate that all five functional mammalian FMOs may play similar endogenous roles to improve resistance to a wide range of toxic stresses in both kidney and liver cells. We further ...[more]

PMID: 33644069

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Project description:Enzymatic processing of fish by-products for recovery of peptides (hydrolysates) is a promising technology to reach food grade ingredients of high nutritional quality. Despite this, their bitter taste and "fish" odor block implementation in food products and limit their economic potential. Trimethylamine (TMA) is a known contributor to malodor in fish. Current strategies to mask or remove the odor either are not effective or give rise to undesirable side effects. As an alternative approach to remediate TMA, we propose a novel enzymatic strategy to convert TMA into the odorless trimethylamine N-oxide (TMAO) using TMA monooxygenases (Tmms). We identified a diverse set of bacterial Tmms using a sequence similarity network. Purified, recombinant enzymes were assessed for their biocatalytic capacity by monitoring NADPH consumption and TMAO generation. Selected Tmms were subjected to biochemical characterization and investigated for their ability to oxidize TMA in an industry-relevant substrate. From the 45 bacterial Tmm candidates investigated, eight enzymes from four different taxa were selected for their high activity toward TMA. The three most active enzymes were shown to vary in temperature optimum, with the highest being 45°C. Enzymatic activity dropped at high temperatures, likely due to structural unfolding. The enzymes were all active from pH 6.0 to 8.5, with functional stability being lowest around the optimal pH. All three Tmms, given sufficient NADPH cofactor, were found to generate TMAO in the TMA-rich salmon protein hydrolysate. The Tmms serve as unique starting points for engineering and should be useful for guiding process development for marine biorefineries.IMPORTANCE Enzyme-based conversion of marine biomass to high-quality peptide ingredients leaves a distinct smell of "fish" caused by the presence of trimethylamine, which limits their economic potential. We suggest an enzymatic solution for converting trimethylamine to the odorless trimethylamine N-oxide as a novel strategy to improve the smell quality of marine protein hydrolysates. Following a systematic investigation of 45 putative bacterial trimethylamine monooxygenases from several phyla, we expand the repertoire of known active trimethylamine monooxygenases. As a proof-of-concept, we demonstrate that three of these enzymes oxidized trimethylamine in an industry-relevant salmon protein hydrolysate. Our results add new oxidoreductases to the industrial biocatalytic toolbox and provide a new point of departure for enzyme process developments in marine biorefineries.

Dataset Information

Flavin-Containing Monooxygenases Are Conserved Regulators of Stress Resistance and Metabolism.

Publications

Flavin-Containing Monooxygenases Are Conserved Regulators of Stress Resistance and Metabolism.

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