Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes

Montellano, Paul R. Ortiz de

doi:10.1021/cr9002193

Cited by 1,021 publications

(769 citation statements)

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“…The cytochromes P450 are widespread throughout nature and catalyze monoxygenation reactions of organic substrates as a means to detoxify the biosystem, but also have functions related to the biosynthesis of compounds [1][2][3][4][5][6][7][8]. They bind and utilize molecular oxygen on a heme center and transfer one of its oxygen atoms to a substrate, whereas the other oxygen atom leaves the process as a water molecule [9].…”

Section: Introductionmentioning

confidence: 99%

Arene activation by a nonheme iron(III)–hydroperoxo complex: pathways leading to phenol and ketone products

2016

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Iron(III)-hydroperoxo complexes are found in various nonheme iron enzymes as catalytic cycle intermediates; however, little is known on their catalytic properties. Recent work of Banse and coworkers on a biomimetic nonheme iron(III)-hydroperoxo complex provided evidence of its involvement in reactivity with arenes. This contrasts the behavior of heme iron(III)-hydroperoxo complexes that are known to be sluggish oxidants. In order to gain insight into the reaction mechanism of the biomimetic iron(III)-hydroperoxo complex with arenes we performed a computational (density functional theory) study. The calculations show that iron(III)-hydroperoxo reacts with substrates via low free energies of activation that should be accessible at room temperature. Moreover, dominant ketone reaction product is observed as primary products rather than the thermodynamically more stable phenols. These product distributions are analyzed and the calculations show that charge interaction between the iron(III)-hydroxo group and the substrate in the intermediate state pushes the transferring proton to the metacarbon atom of substrate and guides the selectivity of ketone formation. These studies show that the relative ratio of ketone versus phenol as primary products can be affected by external interactions of the oxidant with substrate. Moreover, iron(III)-hydroperoxo complexes are shown to selectively give ketone products, whereas iron(IV)-oxo complexes will react with arenes to form phenols instead.

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Section: Introductionmentioning

confidence: 99%

Arene activation by a nonheme iron(III)–hydroperoxo complex: pathways leading to phenol and ketone products

2016

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“…The widely distributed heme-thiolate monooxygenases, such as cytochrome P450 (CYP), serve similar roles in catalyzing C−H hydroxylation reaction. CYP enzymes also participate in the primary pathways for oxidative steroid and prostaglandin biosynthesis as well as phase I drug metabolism (8)(9)(10)(11)(12). For example, 20 isoforms of CYP with significant physiological functions exist in Mycobacterium tuberculosis, making them potential drug targets (13).…”

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confidence: 99%

“…Decades of research have created a rich tapestry that has intertwined structural, spectroscopic, mechanistic, computational, genetic, metabolic, and chemical modeling approaches toward a deep understanding of such an important oxygenation system (9,(14)(15)(16)(17). The central paradigm of CYP oxygen activation is recognized to involve the formation of ferryl intermediates, Fe IV =O.…”

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confidence: 99%

Heme-thiolate ferryl of aromatic peroxygenase is basic and reactive

Wang

Ullrich

Hofrichter

et al. 2015

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

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A kinetic and spectroscopic characterization of the ferryl intermediate (APO-II) from APO, the heme-thiolate peroxygenase from Agrocybe aegerita, is described. APO-II was generated by reaction of the ferric enzyme with metachloroperoxybenzoic acid in the presence of nitroxyl radicals and detected with the use of rapidmixing stopped-flow UV-visible (UV-vis) spectroscopy. The nitroxyl radicals served as selective reductants of APO-I, reacting only slowly with APO-II. APO-II displayed a split Soret UV-vis spectrum (370 nm and 428 nm) characteristic of thiolate ligation. Rapid-mixing, pHjump spectrophotometry revealed a basic pK a of 10.0 for the Fe IV −O−H of APO-II, indicating that APO-II is protonated under typical turnover conditions. Kinetic characterization showed that APO-II is unusually reactive toward a panel of benzylic C−H and phenolic substrates, with second-order rate constants for C−H and O−H bond scission in the range of 10-10 7 M −1 ·s −1 . Our results demonstrate the important role of the axial cysteine ligand in increasing the proton affinity of the ferryl oxygen of APO intermediates, thus providing additional driving force for C−H and O−H bond scission.

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“…Prosthetic groups, such as flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) derived from riboflavin, serve as electron transfer centers. P450s activate molecular oxygen and catalyze unique onestep C-H bond oxidations by the insertion of one oxygen atom into the substrate while the other forms water [14,15]. They can catalyze diverse reactions ( Figure 2) and the nature of these reactions and the corresponding substrates does not appear to depend on the sequence of the P450 or its evolutionary proximity to other P450s [1].…”

Section: Reactions Catalyzed By Cytochrome P450 Monooxygenasesmentioning

confidence: 99%

Strategies for the construction of insect P450 fusion enzymes

Talmann

Wiesner

Vilcinskas

2017

Zeitschrift Für Naturforschung C

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Cytochrome P450 monooxygenases (P450s) are ubiquitous enzymes with a broad substrate spectrum. Insect P450s are known to catalyze reactions such as the detoxification of insecticides and the synthesis of hydrocarbons, which makes them useful for many industrial processes. Unfortunately, it is difficult to utilize P450s effectively because they must be paired with cytochrome P450 reductases (CPRs) to facilitate electron transfer from reduced nicotinamide adenine dinucleotide phosphate (NADPH). Furthermore, eukaryotic P450s and CPRs are membrane-anchored proteins, which means they are insoluble and therefore difficult to purify when expressed in their native state. Both challenges can be addressed by creating fusion proteins that combine the P450 and CPR functions while eliminating membrane anchors, allowing the production and purification of soluble multifunctional polypeptides suitable for industrial applications. Here we discuss several strategies for the construction of fusion enzymes combining insect P450 with CPRs.

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Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes

Cited by 1,021 publications

References 159 publications

Arene activation by a nonheme iron(III)–hydroperoxo complex: pathways leading to phenol and ketone products

Arene activation by a nonheme iron(III)–hydroperoxo complex: pathways leading to phenol and ketone products

Heme-thiolate ferryl of aromatic peroxygenase is basic and reactive

Strategies for the construction of insect P450 fusion enzymes

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