Flavin-containing monooxygenases: new structures from old proteins

Phillips, Ian; Shephard, Elizabeth A.

doi:10.1038/s41594-019-0356-1

Cited by 5 publications

(3 citation statements)

References 19 publications

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“…Introduction NADPH-dependent flavin-containing monooxygenases are a family of enzymes that catalyze the oxidation of a wide range of nitrogen-containing compounds and metabolize drugs (Eswaramoorthy et al, 2006;Phillips and Shephard, 2020). Based on the cDNA sequence, FMOs were classified into five subfamilies (FMO1 to 5) (Lawton et al, 1994;Lattard et al, 2003).…”

Section: Graphical Abstractmentioning

confidence: 99%

Spontaneously hypertensive rats exhibit increased liver flavin monooxygenase expression and elevated plasma TMAO levels compared to normotensive and Ang II-dependent hypertensive rats

Gawryś-Kopczyńska,

Szudzik,

Samborowska

et al. 2024

Front. Physiol.

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Background: Flavin monooxygenases (FMOs) are enzymes responsible for the oxidation of a broad spectrum of exogenous and endogenous amines. There is increasing evidence that trimethylamine (TMA), a compound produced by gut bacteria and also recognized as an industrial pollutant, contributes to cardiovascular diseases. FMOs convert TMA into trimethylamine oxide (TMAO), which is an emerging marker of cardiovascular risk. This study hypothesized that blood pressure phenotypes in rats might be associated with variations in the expression of FMOs.Methods: The expression of FMO1, FMO3, and FMO5 was evaluated in the kidneys, liver, lungs, small intestine, and large intestine of normotensive male Wistar-Kyoto rats (WKY) and two distinct hypertensive rat models: spontaneously hypertensive rats (SHRs) and WKY rats with angiotensin II-induced hypertension (WKY-ANG). Plasma concentrations of TMA and TMAO were measured at baseline and after intravenous administration of TMA using liquid chromatography-mass spectrometry (LC-MS).Results: We found that the expression of FMOs in WKY, SHR, and WKY-ANG rats was in the descending order of FMO3 > FMO1 >> FMO5. The highest expression of FMOs was observed in the liver. Notably, SHRs exhibited a significantly elevated expression of FMO3 in the liver compared to WKY and WKY-ANG rats. Additionally, the plasma TMAO/TMA ratio was significantly higher in SHRs than in WKY rats.Conclusion: SHRs demonstrate enhanced expression of FMO3 and a higher plasma TMAO/TMA ratio. The variability in the expression of FMOs and the metabolism of amines might contribute to the hypertensive phenotype observed in SHRs.

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Section: Graphical Abstractmentioning

confidence: 99%

Spontaneously hypertensive rats exhibit increased liver flavin monooxygenase expression and elevated plasma TMAO levels compared to normotensive and Ang II-dependent hypertensive rats

Gawryś-Kopczyńska,

Szudzik,

Samborowska

et al. 2024

Front. Physiol.

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“…The FMO gene family comprises 11 genes; FMO1, FMO2, FMO3, FMO4. and FMO5 are functional genes, and the remaining family members are pseudogenes ( 17 ). It has been established that FMOs are expressed in many cancers and are associated with the development and prognosis.…”

Section: Introductionmentioning

confidence: 99%

FMO family may serve as novel marker and potential therapeutic target for the peritoneal metastasis in gastric cancer

et al. 2023

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ObjectiveTo explore the relationship between flavin-containing monooxygenases (FMOs) and peritoneal metastasis (PM) in gastric cancer (GC).Materials and methodsTIMER 2.0 was used to perform pan-cancer analysis and assess the correlation between the expression of FMOs and cancers. A dataset from The Cancer Genome Atlas (TCGA) was used to analyze the correlation between FMOs and clinicopathological features of GC. PM is well established as the most common mode of metastasis in GC. To further analyze the correlation between FMOs and PM of GC, a dataset was obtained from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database. The results were validated by immunohistochemistry. The relationship between FMOs and PM of GC was explored, and a novel PM risk signature was constructed by least absolute shrinkage and selection operator (LASSO) regression analysis. The regression model’s validity was tested by multisampling. A nomogram was established based on the model for predicting PM in GC patients. The mechanism of FMOs in GC patients presenting with PM was assessed by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses in TCGA and GEO datasets. Finally, the potential relationship between FMOs and immunotherapy was analyzed.ResultsThe pan-cancer analysis in TCGA and GEO datasets showed that FMO1 was upregulated, while FMO2 and FMO4 were downregulated in GC. Moreover, FMO1 and FMO2 correlated positively with the T and N stage of GC in the TCGA dataset. FMO1 and FMO2 expression was a risk factor for GC (hazard ratio: 1.112 and 1.185). The overexpression of FMO1 was significantly correlated with worse disease-free-survival (DFS) and overall survival (OS). However, no relationship was found between FMO2 expression in GC and DFS and OS. PM was highly prevalent among GC patients and typically associated with a worse prognosis. FMO1 was highly expressed in GC with PM. FMO1 and FMO2 were positively correlated with PM in GC. We identified a 12-gene panel for predicting the PM risk signature by LASSO (Area Under Curve (AUC) = 0.948, 95%CI: 0.896–1.000). A 10-gene panel for PM prediction was identified (AUC = 0.932, 95%CI: 0.874–0.990), comprising FMO1 and FMO2. To establish a model for clinical application, a 7-gene panel was established (AUC = 0.927, 95% CI: 0.877–0.977) and successfully validated by multisampling. (AUC = 0.892, 95% CI: 0.878–0.906). GO and KEGG analyses suggest that FMO1 and FMO2 regulate the extracellular matrix and cell adhesion. FMO1 and FMO2 were positively correlated with the immune score of GC, and their expression was associated with the infiltration of immune cells.ConclusionPM in GC is strongly correlated with FMOs. Overall, FMO1 and FMO2 have huge prospects for application as novel diagnostic and therapeutic targets.

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“…22 FMOs from vertebrates are slightly different, because they are membrane-bound enzymes 114 . This makes them, for their isolation, dependent on detergents to render them water-soluble.…”

Section: Flavin-containing Monooxygenases (Fmos)mentioning

confidence: 99%

Exploiting cofactor-dependent oxidoreductases by enzyme discovery, engineering and reconstruction

Yang

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Enzymes, also known as biocatalysts, are proteins which catalyze chemical reactions. Enzymes typically use functional groups from the side chains of their amino acid residues to perform catalysis. However, the functional groups derived from the 20 canonical amino acids cannot support the diversity of catalysis required by nature.Therefore, some enzymes utilize non-proteinaceous molecules and/or metal ions to broaden their catalytic scope. These protein ligands are called cofactors. Some of these cofactors have been suggested to originate as remnants of ancient ribozymes, whose active core was retained during evolution. Among all enzymes, oxidoreductases account for a considerable proportion (about one third) and most of them require dedicated redox cofactors. They participate in many crucial steps in metabolism and cover a huge range of reaction types. Except for a crucial role in nature, research in the last decades has revealed that these enzymes have enormous potential in industrial application for the production of many high-valued products.General introduction to cofactors and cofactor-dependent redox enzymes 9 Ⅰ. CofactorsCofactors: definitions Cofactors are non-protein molecules or metal ions that are required for the proper functioning of certain enzymes. In general, cofactors are classified into two main groups: inorganic and organic cofactors. Sometimes cofactors are also referred to as coenzymes or prosthetic groups. Because of the ambiguity in terminology 1 in literature, here in this thesis, we adopt the definition described by Lehninger (Principles of Biochemistry, 8 th edition) 2 . Therefore, cofactors are defined as either inorganic ions, or organic/metalloorganic molecules that are required for enzyme activity; coenzymes contain all cofactors excluding the inorganic ones; and prosthetic groups are either metal ions or organic non-protein molecules that tightly bound to a protein and essential to its activity. Inorganic cofactors include metal ions such as iron and copper. These ions often act as electron carriers or participate in redox reactions during enzymatic reactions 3 . Organic cofactors, or coenzymes, are more complex organic molecules that can be further divided into two groups: vitamin derived or not. For example, some of the best-known cofactors, pyridoxal phosphate, coenzyme A, flavins and nicotinamides, are derivatives of vitamin B 5 , B 6 , B 2 and B 3 respectively. Organic cofactors often act as carriers of electrons or functional groups 3 (Table 1). Moreover, cofactors can also provide structural stability to the enzyme 4 . 34 22.

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Flavin-containing monooxygenases: new structures from old proteins

Cited by 5 publications

References 19 publications

Spontaneously hypertensive rats exhibit increased liver flavin monooxygenase expression and elevated plasma TMAO levels compared to normotensive and Ang II-dependent hypertensive rats

Spontaneously hypertensive rats exhibit increased liver flavin monooxygenase expression and elevated plasma TMAO levels compared to normotensive and Ang II-dependent hypertensive rats

FMO family may serve as novel marker and potential therapeutic target for the peritoneal metastasis in gastric cancer

Exploiting cofactor-dependent oxidoreductases by enzyme discovery, engineering and reconstruction

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