Endogenous Roles of Mammalian Flavin-Containing Monooxygenases

Phillips, Ian; Shephard, Elizabeth A.

doi:10.3390/catal9121001

Cited by 11 publications

(12 citation statements)

References 122 publications

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“…The mechanism of oxygenation of nucleophilic groups catalyzed by FMO enzymes is presented in the context of the following three steps (Phillips and Shephard 2019 ; Siddens et al 2014 ; Ziegler 1988 ) (Fig. 4 ): (1) NADPH binds to the enzyme and reduces FAD to FADH 2 (a rapid reaction).…”

Section: Resultsmentioning

confidence: 99%

Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

Rendić¹,

Crouch

Guengerich

2022

Arch Toxicol

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This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e., drugs, “general chemicals,” natural products, and physiological compounds) are discussed. We identified a higher fraction of bioactivation reactions for FMO enzymes compared to other enzymes, predominately involving drugs and general chemicals. With MAO enzymes, physiological compounds predominate as substrates, and some products lead to unwanted side effects or illness. AOX and XOR enzymes are molybdenum hydroxylases that catalyze the oxidation of various heteroaromatic rings and aldehydes and the reduction of a number of different functional groups. While neither of these two enzymes contributes substantially to the metabolism of currently marketed drugs, AOX has become a frequently encountered route of metabolism among drug discovery programs in the past 10–15 years. XOR has even less of a role in the metabolism of clinical drugs and preclinical drug candidates than AOX, likely due to narrower substrate specificity.

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Section: Resultsmentioning

confidence: 99%

Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

Rendić¹,

Crouch

Guengerich

2022

Arch Toxicol

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“…This enzyme binds noncovalently one molecule of FAD and is reduced by NADPH before exerting its catalysis [1][2][3]. Human FMO3 catalyzes the monooxygenation of nucleophilic heteroatom containing chemicals (drugs, pesticides, and xenobiotics) [4][5][6] through an unusual mechanism of activation of molecular oxygen via a stable FAD intermediate in the absence of the bound substrate. This mechanism accounts for the broad substrate range as well as uncoupling of this enzyme [7,8] i.e., the wastage of electrons without oxygenation of the substrate leading to the formation of reactive oxygen species (ROS) such as the superoxide radical and hydrogen peroxide.…”

Section: Introductionmentioning

confidence: 99%

N- and S-oxygenation activity of truncated human flavin-containing monooxygenase 3 and its common polymorphic variants

Bortolussi

Catucci

Gilardi

et al. 2021

Archives of Biochemistry and Biophysics

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Human flavin-containing monooxygenase 3 (FMO3) is a membrane-bound, phase I drug metabolizing enzyme. It is highly polymorphic with some of its variants demonstrating differences in rates of turnover of its substrates: xenobiotics including drugs as well as dietary compounds. In order to measure its in vitro activity and compare any differences between the wild type enzyme and its polymorphic variants, we undertook a systematic study using different engineered proteins, heterologously expressed in bacteria, purified and catalytically characterized with 3 different substrates. These included the full-length as well as the more soluble C-terminal truncated versions of the common polymorphic variants (E158K, V257M and E308G) of FMO3 in addition to the fulllength and truncated wild-type proteins. In vitro activity assays were performed with benzydamine, tamoxifen and sulindac sulfide, whose products were measured by HPLC. Differences in catalytic properties between the wild-type FMO3 and its common polymorphic variants were similar to those observed with the truncated, more soluble versions of the enzymes. Interestingly, the truncated enzymes were better catalysts than the full-length proteins. The data obtained point to the feasibility of using the more soluble forms of this enzyme for in vitro drug assays as well as future biotechnological applications possibly in high throughput systems such as bioelectrochemical platforms and biosensors.

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“…Phase I drug metabolism involves monooxygenase enzymes that are able to split the two atoms of molecular oxygen with insertion of one of them in a stable, often unreactive, carbon atom or a heteroatom (sulphur or nitrogen) of the substrate (drug) with concomitant production of a water molecule [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Human flavin-containing monooxygenase 1 and its long-sought hydroperoxyflavin intermediate

Cheropkina

Catucci

Marucco

et al. 2021

Biochemical Pharmacology

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Out of the five isoforms of human flavin-containing monooxygenase (hFMO), FMO1 and FMO3 are the most relevant to Phase I drug metabolism. They are involved in the oxygenation of xenobiotics including drugs and pesticides using NADPH and FAD as cofactors. Majority of the characterization of these enzymes has involved hFMO3, where intermediates of its catalytic cycle have been described. On the other hand, research efforts have so far failed in capturing the same key intermediate that is responsible for the monooxygenation activity of hFMO1. In this work we demonstrate spectrophotometrically the formation of a highly stable C4ahydroperoxyflavin intermediate of hFMO1 upon reduction by NADPH and in the presence of O2. The measured half-life of this flavin intermediate revealed it to be stable and not fully reoxidized even after 30 minutes at 15 °C in the absence of substrate, the highest stability ever observed for a human FMO. In addition, the uncoupling reactions of hFMO1 show that this enzyme is <1% uncoupled in the presence of substrate, forming small amounts of H2O2 with no observable superoxide as confirmed by EPR spin trapping experiments. This behaviour is different from hFMO3, that is shown to form both H2O2 and superoxide anion radical as a result of ~50% uncoupling. These data are consistent with the higher stability of the hFMO1 intermediate in comparison to hFMO3. Taken together, these data demonstrate the different behaviours of these two closely related enzymes with consequences for drug metabolism as well as possible toxicity due to reactive oxygen species.

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Endogenous Roles of Mammalian Flavin-Containing Monooxygenases

Cited by 11 publications

References 122 publications

Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

N- and S-oxygenation activity of truncated human flavin-containing monooxygenase 3 and its common polymorphic variants

Human flavin-containing monooxygenase 1 and its long-sought hydroperoxyflavin intermediate

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