Control of catalysis in flavin-dependent monooxygenases

Palfey, Bruce A.; McDonald, Claudia A.

doi:10.1016/j.abb.2009.11.028

Cited by 162 publications

(253 citation statements)

References 67 publications

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“…4). The product analysis data also imply that the reaction of H120K is bifurcated; in addition to the regular hydroxylation pathway, a fraction of C4a-hydroperoxy-FMN (ϳ20%) generates H 2 O 2 and oxidized FMN (k 6 , Fig. 4).…”

Section: Versusmentioning

confidence: 88%

“…For the PHBH reaction, both the phenolic and phenolate forms of the substrate (pOHB) can bind to the enzyme, depending on the pH of the solution. However, once bound to the enzyme, the pK a of pOHB decreases to 7.4, ϳ1.9 units below the regular pK a of pOHB in solution (pK a ϭ 9.3) (6,9,40). The deprotonation of pOHB is necessary for facilitating the hydroxylation process because the hydroxylation rate constant increases ϳ6-fold with a rise in pH according to a pK a of 7.1 (9, 13).…”

Section: ⅐Hpamentioning

confidence: 99%

“…For the S146 variants, the rate constants of hydroxylation were 2.6 Ϯ 0.1 s Ϫ1 for S146A and 0.35 Ϯ 0.05 s Ϫ1 for S146C. The rate constants of H 2 O 2 elimination from the uncoupling pathway (k 6 , Fig. 5) were 1.3 Ϯ 0.1 s Ϫ1 for S146A and 0.17 Ϯ 0.05 s Ϫ1 for S146C.…”

mentioning

confidence: 99%

“…Oxygenation occurs via an oxygen atom transfer from C4a-hydroperoxy flavin to an organic substrate, resulting in the formation of a C4a-hydroxy flavin intermediate and an oxygenated product. The C4a-hydroxy flavin dehydrates at the last step of the reaction to form the final species, oxidized flavin (2)(3)(4)6). All steps for the reactions of singleprotein component flavin-dependent monooxygenases occur within the same polypeptide, whereas for the two-protein component type the flavin reduction occurs on a reductase component and the oxygenation occurs on an oxygenase component (4 -8).…”

mentioning

confidence: 99%

“…The best understood oxygenation reaction is the hydroxylation of aromatic compounds catalyzed by a single-component flavoenzyme, p-hydroxybenzoate (pOHB) 5 hydroxylase (PHBH) (4,6,9). Studies of PHBH and 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) monooxygenase (MHPCO) reactions showed that hydroxylation occurs via an electrophilic aromatic hydroxylation mechanism in which an aromatic substrate acts as a nucleophile and a terminal -OH group of C4a-hydroperoxy flavin acts as an electrophile (9 -12).…”

mentioning

confidence: 99%

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Interactions with the Substrate Phenolic Group Are Essential for Hydroxylation by the Oxygenase Component of p-Hydroxyphenylacetate 3-Hydroxylase

Tongsook

Sucharitakul

Thotsaporn

et al. 2011

Journal of Biological Chemistry

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plex, which in turn promotes oxygen atom transfer via an electrophilic aromatic substitution mechanism. Analysis of Ser-146 variants revealed that this residue is necessary for but not directly engaged in hydroxylation. Product formation in S146A is pH-independent and constant at ϳ70% over a pH range of 6 -10, whereas product formation for S146C decreased from ϳ65% at pH 6.0 to 27% at pH 10.0. These data indicate that the ionization of Cys-146 in the S146C variant has an adverse effect on hydroxylation, possibly by perturbing formation of the His ␦؉ ⅐HPA ␦؊ complex needed for hydroxylation.Incorporation of single oxygen atoms into organic compounds (monooxygenation) by hydroxylation or epoxidation is an important biological process for aerobic organisms. The monooxygenation reaction is generally catalyzed by cytochrome P450, metalloenzymes, pterin-dependent and flavindependent monooxygenases (1). Flavin-dependent monooxygenases are involved in a wide variety of biological processes (2, 3). These enzymes catalyze the monooxygenation of many aromatic and aliphatic compounds (3).Based on the number of proteins required for catalysis, flavin-dependent monooxygenases can be classified into singleprotein component and two-protein component types (2-5). Besides an organic substrate, both types of enzymes require NAD(P)H and oxygen as co-substrates. The initial part of the reaction is the reduction of an enzyme-bound flavin by NAD(P)H to generate reduced flavin followed by the reaction of reduced flavin with oxygen to form the C4a-(hydro)peroxy flavin, a key intermediate that is required for oxygenation of an organic substrate. Oxygenation occurs via an oxygen atom transfer from C4a-hydroperoxy flavin to an organic substrate, resulting in the formation of a C4a-hydroxy flavin intermediate and an oxygenated product. The C4a-hydroxy flavin dehydrates at the last step of the reaction to form the final species, oxidized flavin (2-4, 6). All steps for the reactions of singleprotein component flavin-dependent monooxygenases occur within the same polypeptide, whereas for the two-protein component type the flavin reduction occurs on a reductase component and the oxygenation occurs on an oxygenase component (4 -8). The mechanism by which the reduced flavin is transferred involves simple diffusion or protein-protein contacts (5,8). Although single-component flavin-dependent monooxygenases have been studied for more than 40 years, two-component flavin-dependent monooxygenases have only received significant attention during the past decade after recent discoveries of their involvement in a wide variety of reactions (2, 5).The mechanism by which the oxygen atom transfer occurs in flavin-dependent monooxygenases is well understood for only a few enzymatic systems. The best understood oxygenation reaction is the hydroxylation of aromatic compounds catalyzed *

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Section: Versusmentioning

confidence: 88%

Section: ⅐Hpamentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Interactions with the Substrate Phenolic Group Are Essential for Hydroxylation by the Oxygenase Component of p-Hydroxyphenylacetate 3-Hydroxylase

Tongsook

Sucharitakul

Thotsaporn

et al. 2011

Journal of Biological Chemistry

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The Recent Developments of Enzymatic Oxidation

Wedde

Biermann

Choi

et al. 2019

Green Oxidation in Organic Synthesis

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Flavoprotein Monooxygenases and Halogenases

Paul

Guarneri

Berkel

2021

Flavin‐Based Catalysis

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Article 25fa states that the author of a short scientific work funded either wholly or partially by Dutch public funds is entitled to make that work publicly available for no consideration following a reasonable period of time after the work was first published, provided that clear reference is made to the source of the first publication of the work.This publication is distributed under The Association of Universities in the Netherlands (VSNU) 'Article 25fa implementation' project. In this project research outputs of researchers employed by Dutch Universities that comply with the legal requirements of Article 25fa of the Dutch Copyright Act are distributed online and free of cost or other barriers in institutional repositories. Research outputs are distributed six months after their first online publication in the original published version and with proper attribution to the source of the original publication.

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Control of catalysis in flavin-dependent monooxygenases

Cited by 162 publications

References 67 publications

Interactions with the Substrate Phenolic Group Are Essential for Hydroxylation by the Oxygenase Component of p-Hydroxyphenylacetate 3-Hydroxylase

Interactions with the Substrate Phenolic Group Are Essential for Hydroxylation by the Oxygenase Component of p-Hydroxyphenylacetate 3-Hydroxylase

The Recent Developments of Enzymatic Oxidation

Flavoprotein Monooxygenases and Halogenases

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