Reactions of the 4a-hydroperoxide of liver microsomal flavin-containing monooxygenase with nucleophilic and electrophilic substrates.

Jones, Kenneth C.; Ballou, David P.

doi:10.1016/s0021-9258(17)35823-4

Cited by 79 publications

(27 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, while with few exceptions, the chemical reaction is acid catalyzed, thus entailing a protonated peroxide, the catalytic flavin species requires a deprotonated peroxy group . While quickly decaying in solution, some BVMOs stabilize this reactive species for several minutes in the absence of a substrate, before its decomposition forms hydrogen peroxide in the “uncoupling” side reaction known to occur in all monooxygenases. − The exact factors flavoenzymes exert to influence the longevity of both the protonated and unprotonated peroxyflavin are largely unknown, despite reported lifetimes ranging from milliseconds in some oxidases to several minutes or even hours in FMOs , and luciferases . In BVMOs and other class B monooxygenases, NADP + was, however, found to be critical for intermediate stabilization, as a manifold increased peroxyflavin decay was observed in the absence of the cofactor. ,, Crystal structures and quantum mechanics calculations indicate that the NADP + amide oxygen establishes a crucial hydrogen bond to the hydrogen of the flavin’s N5 (Scheme ).…”

Section: Mechanism Of the Baeyer–villiger Reactionmentioning

confidence: 99%

Baeyer–Villiger Monooxygenases: Tunable Oxidative Biocatalysts

et al. 2019

View full text Add to dashboard Cite

Pollution, accidents, and misinformation have earned the pharmaceutical and chemical industry a poor public reputation, despite their undisputable importance to society. Biotechnological advances hold the promise to enable a future of drastically reduced environmental impact and rigorously more efficient production routes at the same time. This is exemplified in the Baeyer–Villiger reaction, which offers a simple synthetic route to oxidize ketones to esters, but application is hampered by the requirement of hazardous and dangerous reagents. As an attractive alternative, flavin-containing Baeyer–Villiger monooxygenases (BVMOs) have been investigated for their potential as biocatalysts for a long time, and many variants have been characterized. After a general look at the state of biotechnology, we here summarize the literature on biochemical characterizations, mechanistic and structural investigations, as well as enzyme engineering efforts in BVMOs. With a focus on recent developments, we critically outline the advances toward tuning these enzymes suitable for industrial applications.

show abstract

Section: Mechanism Of the Baeyer–villiger Reactionmentioning

confidence: 99%

Baeyer–Villiger Monooxygenases: Tunable Oxidative Biocatalysts

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Initially, we found inspiration from nature in the way of flavin monooxygenases. This family of flavoenzymes houses a conserved flavin cofactor which is able to transform aromatic boronic acids to aromatic alcohols harnessing molecular O 2 . As photocatalysts, flavin cofactors have also been shown to act as single-electron photo-oxidants or reductants in deaerated water under visible light irradiation.…”

mentioning

confidence: 99%

General Access to C-Centered Radicals: Combining a Bioinspired Photocatalyst with Boronic Acids in Aqueous Media

2020

View full text Add to dashboard Cite

Carbon-centered radicals are indispensable building blocks for modern synthetic chemistry. In recent years, visible light photoredox catalysis has become a promising avenue to access C-centered radicals from a broad array of latent functional groups, including boronic acids. Herein, we present an aqueous protocol wherein water features a starring role to help transform aliphatic, aromatic, and heteroaromatic boronic acids to C-centered radicals with a bioinspired flavin photocatalyst. These radicals are used to deliver a diverse pool of alkylated products, including three pharmaceutically relevant compounds, via open-shell conjugate addition to disparate Michael acceptors. The mechanism of the reaction is investigated by computational studies, deuterium labeling, radical-trapping experiments, and spectroscopic analysis.

show abstract

“…Many drugs possessing nucleophilic heteroatoms in their structure are substrates of these enzymes (Phillips and Shephard 2017 ; Sawada and Yokosawa 1991 ; Yamazaki et al 2014 ; Cashman, 2000 ) (Table 3 ), as well as general chemicals (Table 4 ) and natural products and physiological compounds (Table 5 ). Additional substrates are iodides and boron-containing compounds (Jones and Ballou 1986 ). Drug oxidations are the most studied group of reactions with human FMOs (Tables 3 , 4 , 5 ), followed by general chemicals and physiological compounds.…”

Section: Resultsmentioning

confidence: 99%

“…Substances with a sulfur atom can be oxygenated with FMO enzymes to form electrophilic intermediates (e.g., thiols, thioamide, 2-mercaptoimidazole, thiocarbamate, thiocarbamide metabolites). Such electrophilic metabolites can bind to cellular proteins and inactivate enzymes in the endoplasmic reticulum, e.g., P450s (Başaran and Can Eke 2017 ; Jones and Ballou 1986 ).…”

Section: Examples Of Reactions Resulting In the Formation Of Toxic Me...mentioning

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

View full text Add to dashboard Cite

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.

show abstract

Reactions of the 4a-hydroperoxide of liver microsomal flavin-containing monooxygenase with nucleophilic and electrophilic substrates.

Cited by 79 publications

References 21 publications

Baeyer–Villiger Monooxygenases: Tunable Oxidative Biocatalysts

Baeyer–Villiger Monooxygenases: Tunable Oxidative Biocatalysts

General Access to C-Centered Radicals: Combining a Bioinspired Photocatalyst with Boronic Acids in Aqueous Media

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

Contact Info

Product

Resources

About