Molecular Cloning and Kinetic Characterization of a Flavin-Containing Monooxygenase fromSaccharomyces cerevisiae

Suh, Jung Keun; Poulsen, Lawrence L.; Ziegler, Daniel M.; Robertus, Jon D.

doi:10.1006/abbi.1996.0557

Cited by 43 publications

(50 citation statements)

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“…FMO from S. pombe is 30% identical to the FMO of Saccharomyces cerevisiae that catalyzes oxidation of biological thiols to maintain the endoplasmic reticulum redox buffer ratio for correct folding of disulfide-bonded proteins (Fig. 8, which is published as supporting information on the PNAS web site) (9,13). The characteristic sequence motifs, (i) FAD binding domain (GXGXXG), (ii) NADPH binding domain (GXGXXG), and (iii) FMO identifying sequence (FXGXXX-HXXXY͞F), are conserved across FMOs (14).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of action of a flavin-containing monooxygenase

Eswaramoorthy

Bonanno

Burley³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

172

170

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Elimination of nonnutritional and insoluble compounds is a critical task for any living organism. Flavin-containing monooxygenases (FMOs) attach an oxygen atom to the insoluble nucleophilic compounds to increase solubility and thereby increase excretion. Here we analyze the functional mechanism of FMO from Schizosaccharomyces pombe using the crystal structures of the wild type and protein–cofactor and protein–substrate complexes. The structure of the wild-type FMO revealed that the prosthetic group FAD is an integral part of the protein. FMO needs NADPH as a cofactor in addition to the prosthetic group for its catalytic activity. Structures of the protein–cofactor and protein–substrate complexes provide insights into mechanism of action. We propose that FMOs exist in the cell as a complex with a reduced form of the prosthetic group and NADPH cofactor, readying them to act on substrates. The 4α-hydroperoxyflavin form of the prosthetic group represents a transient intermediate of the monooxygenation process. The oxygenated and reduced forms of the prosthetic group help stabilize interactions with cofactor and substrate alternately to permit continuous enzyme turnover.

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Section: Discussionmentioning

confidence: 99%

Mechanism of action of a flavin-containing monooxygenase

Eswaramoorthy

Bonanno

Burley³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

172

170

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“…dation of biological thiols such as glutathione, cysteine, and cysteamine (45), thus maintaining the optimal redox environment at the cytosolic surface of the ER (39). The production of these oxidizing equivalents is essential for a proper folding of disulfide containing proteins at the ER; yeast FMO is vital to the yeast response to reductive stress (46).…”

Section: Discussionmentioning

confidence: 99%

Evolutionary recruitment of a flavin-dependent monooxygenase for the detoxification of host plant-acquired pyrrolizidine alkaloids in the alkaloid-defended arctiid mothTyriajacobaeae

Naumann

Hartmann

Ober

2002

Proc. Natl. Acad. Sci. U.S.A.

116

109

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Larvae of Tyria jacobaeae feed solely upon the pyrrolizidine alkaloidcontaining plant Senecio jacobaea. Ingested pyrrolizidine alkaloids (PAs), which are toxic to unspecialized insects and vertebrates, are efficiently N-oxidized in the hemolymph of T. jacobaeae by senecionine N-oxygenase (SNO), a flavin-dependent monooxygenase (FMO) with a high substrate specificity for PAs. Peptide microsequences obtained from purified T. jacobaeae SNO were used to clone the corresponding cDNA, which was expressed in active form in Escherichia coli. T. jacobaeae SNO possesses a signal peptide characteristic of extracellular proteins, and it belongs to a large family of mainly FMO-like sequences of mostly unknown function, including two predicted Drosophila melanogaster gene products. The data indicate that the gene for T. jacobaeae SNO, highly specific for toxic pyrrolizidine alkaloids, was recruited from a preexisting insect-specific FMO gene family of hitherto unknown function. The enzyme allows the larvae to feed on PA-containing plants and to accumulate predation-deterrent PAs in the hemolymph.N-oxidation ͉ alkaloid sequestering insects ͉ insect adaptation ͉ chemical defense ͉ gene recruitment

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“…Neutral zwitterions are likely to be poor substrates (6), but the lone Saccharomyces cerevisiae FMO (yFMO1) can oxygenate free cysteine (20). FMOs' charge selectivity is the proposed mechanism by which they preferentially act on xenobiotics, as charged compounds cannot easily enter cells through the plasma membrane (6).…”

Section: Substratesmentioning

confidence: 99%

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

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Edited by F. Peter GuengerichFlavin-containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well-conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.

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Molecular Cloning and Kinetic Characterization of a Flavin-Containing Monooxygenase fromSaccharomyces cerevisiae

Cited by 43 publications

References 0 publications

Mechanism of action of a flavin-containing monooxygenase

Mechanism of action of a flavin-containing monooxygenase

Evolutionary recruitment of a flavin-dependent monooxygenase for the detoxification of host plant-acquired pyrrolizidine alkaloids in the alkaloid-defended arctiid mothTyriajacobaeae

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

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