Biocatalytic Characterization of Human FMO5: Unearthing Baeyer–Villiger Reactions in Humans

Fiorentini, Filippo; Geier, Martina; Binda, Claudia; Winkler, Margit; Faber, Kurt; Hall, Mélanie; Mattevi, Andrea

doi:10.1021/acschembio.5b01016

Cited by 60 publications

(76 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The rate-limiting step of FMOs is thought to be the release of either H 2 O or NADP ϩ . The significance of FMOs' reaction kinetics, reactive oxygen species leakage, and effects on cellular NAD(P)H is not known (7,8).…”

Section: Catalytic Cyclementioning

confidence: 99%

“…Pig FMO1 has a K m from 0.3 to 10 M in vitro for several organic selenium-containing xenobiotics (6), and both hFMO1 and hFMO3 are capable of catalyzing the formation of pyruvate from selenocysteine (12), consistent with a role in endogenous selenium metabolism. Mammalian FMO5 does not metabolize typical FMO substrates, and may act more like a BVMO (8,13).…”

Section: Substratesmentioning

confidence: 99%

See 1 more Smart Citation

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

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.

show abstract

Section: Catalytic Cyclementioning

confidence: 99%

Section: Substratesmentioning

confidence: 99%

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

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In addition, kinetic and mechanistic studies on FMOs and BVMOs have revealed that these flavoprotein monooxygenases also share a common catalytic mechanism. This is also reflected in the type of oxygenations reactions that are catalyzed by members of both monooxygenase groups: they overlap and include N-oxygenations, sulfoxidations, and Baeyer-Villiger oxidations (Fiorentini et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Microbial Flavoprotein Monooxygenases as Mimics of Mammalian Flavin-Containing Monooxygenases for the Enantioselective Preparation of Drug Metabolites

Gül

Krzek

Permentier

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Mammalian flavin-containing monooxygenases, which are difficult to obtain and study, play a major role in detoxifying various xenobiotics. To provide alternative biocatalytic tools to generate flavin-containing monooxygenases (FMO)-derived drug metabolites, a collection of microbial flavoprotein monooxygenases, sequence-related to human FMOs, was tested for their ability to oxidize a set of xenobiotic compounds. For all tested xenobiotics [nicotine, lidocaine, 3-(methylthio)aniline, albendazole, and fenbendazole], one or more monooxygenases were identified capable of converting the target compound. Chiral liquid chromatography with tandem mass spectrometry analyses of the conversions of 3-(methylthio) aniline, albendazole, and fenbendazole revealed that the respective sulfoxides are formed in good to excellent enantiomeric excess (e.e.) by several of the tested monooxygenases. Intriguingly, depending on the chosen microbial monooxygenase, either the (R)-or (S)-sulfoxide was formed. For example, when using a monooxygenase from Rhodococcus jostii the (S)-sulfoxide of albendazole (ricobendazole) was obtained with a 95% e.e. whereas a fungal monooxygenase yielded the respective (R)-sulfoxide in 57% e.e. For nicotine and lidocaine, monooxygenases could be identified that convert the amines into their respective N-oxides. This study shows that recombinantly expressed microbial monooxygenases represent a valuable toolbox of mammalian FMO mimics that can be exploited for the production of FMO-associated xenobiotic metabolites.

show abstract

“…The enzyme is thought to have a deeper binding pocket than either FMO1 or FMO3, based on the data collected from long-chain hydrocarbons with terminal tertiary amines (Cashman, 2008). Recently, Fiorentini et al (2016) examined the catalytic properties of FMO5 as a BV mono-oxygenase. They took a set of cyclic and noncyclic ketones and aldehydes and performed in vitro experiments with hFMO5.…”

Section: Flavin-containing Monooxygenasementioning

confidence: 99%

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, γ-Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

Pw¹,

Zhang²,

Js³

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

The significant roles that cytochrome P450 (P450) and UDPglucuronosyl transferase (UGT) enzymes play in drug discovery cannot be ignored, and these enzyme systems are commonly examined during drug optimization using liver microsomes or hepatocytes. At the same time, other drug-metabolizing enzymes have a role in the metabolism of drugs and can lead to challenges in drug optimization that could be mitigated if the contributions of these enzymes were better understood. We present examples (mostly from Genentech) of five different non-P450 and non-UGT enzymes that contribute to the metabolic clearance or bioactivation of drugs and drug candidates. Aldehyde oxidase mediates a unique amide hydrolysis of ,7-tetrahydro-1-benzothiophene-2-carboxamide), leading to high clearance of the drug. Likewise, the rodent-specific ribose conjugation by ADP-ribosyltransferase leads to high clearance of an interleukin-2-inducible T-cell kinase inhibitor. Metabolic reactions by flavin-containing monooxygenases (FMO) are easily mistaken for P450-mediated metabolism such as oxidative defluorination of 4-fluoro-N-methylaniline by FMO. Gamma-glutamyl transpeptidase is involved in the initial hydrolysis of glutathione metabolites, leading to formation of proximate toxins and nephrotoxicity, as is observed with cisplatin in the clinic, or renal toxicity, as is observed with efavirenz in rodents. Finally, cathepsin B is a lysosomal enzyme that is highly expressed in human tumors and has been targeted to release potent cytotoxins, as in the case of brentuximab vedotin. These examples of non-P450-and non-UGT-mediated metabolism show that a more complete understanding of drug metabolizing enzymes allows for better insight into the fate of drugs and improved design strategies of molecules in drug discovery.

show abstract

Biocatalytic Characterization of Human FMO5: Unearthing Baeyer–Villiger Reactions in Humans

Cited by 60 publications

References 52 publications

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

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

Microbial Flavoprotein Monooxygenases as Mimics of Mammalian Flavin-Containing Monooxygenases for the Enantioselective Preparation of Drug Metabolites

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, γ-Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

Contact Info

Product

Resources

About