Structure and Chemistry of Cytochrome P450

Denisov, Ilia G.; Makris, Thomas M.; Sligar, Stephen G.; Schlichting, Ilme

doi:10.1002/chin.200537282

Cited by 221 publications

(380 citation statements)

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“…After protonation, the so-called "compound 0" is formed which releases H 2 O after further protonation via heterolytic cleavage of the O-O bond. The resulting reactive oxidative species "compound I" (ferryl oxido: Fe 4+ =O, one electron delocalized in the porphyrin) enables a variety of radical oxidation reactions, including hydroxylation [54,55].…”

Section: Mechanistic Considerationsmentioning

confidence: 99%

“…Uncoupling can occur through three pathways: (i) via autoxidation of the ferric superoxo radical accompanied with superoxide radical anion formation (autoxidation shunt), (ii) by losing H 2 O 2 from compound 0 (peroxide shunt) and (iii) deoxygenation of compound I, producing H 2 O (oxidase shunt). All uncoupling reactions release the enzyme in the high spin state and thereby destroy reduction equivalents [54]. For a handful of P450 that can utilize H 2 O 2 in a peroxygenase reactionmode, the mechanism is short-cut by a reversal of the peroxide shunt.…”

Section: Mechanistic Considerationsmentioning

confidence: 99%

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Regioselective Biocatalytic Hydroxylation of Fatty Acids by Cytochrome P450s

2017

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Section: Mechanistic Considerationsmentioning

confidence: 99%

Section: Mechanistic Considerationsmentioning

confidence: 99%

Regioselective Biocatalytic Hydroxylation of Fatty Acids by Cytochrome P450s

2017

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“…Due to their central role in drug metabolism and involvement in steroid biosynthesis, cytochromes P450 are one of the most intensively investigated metalloenzymes (2). There are nearly 4000 identified P450 genes and structures for 20 unique P450s on deposit in the RCSB PDB.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Complexes Formed by Cytochrome P450_c_am with Cytochrome b₅ and Putidaredoxin, Two Effectors of Camphor Hydroxylase Activity

Rui

Pochapsky

2006

Biochemistry

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Structural perturbations in cytochrome P450 cam (CYP101) induced by the soluble fragment of rate cytochrome b 5 , a non-physiological effector of CYP101, were investigated by NMR spectroscopy and compared with the perturbations induced by the physiological reductant and effector, putidaredoxin (Pdx). Chemical shifts of perdeuterated [U-15 The results are in accord with our previous suggestion that the observed perturbations are related to effector activity and support the proposal that the primary role of the effector is to populate the active conformation of CYP101 to prevent uncoupling [Pochapsky et al. Biochemistry 42, 5649-5656 (2003)]. A titratable perturbation is observed at the 1 H resonance of the 8-CH 3 of CYP101-bound camphor upon addition of cytochrome b 5 , a phenomenon also associated with the formation of CYP101·Pdx complex albeit with larger perturbations [Wei et al., J. Am. Chem. Soc. 127, 6974-6 976 (2005)]. The effector activity of the particular rat cytochrome b 5 construct used for NMR studies was confirmed by monitoring the enzymatic turnover to yield 5-exo-hydroxy camphor using gas chromatography/mass spectrometry. Finally, the common features of the perturbations observed in the NMR spectra of the two complexes are discussed and their relevance to effector activity considered.

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“…Rather than finalizing the reaction through rapid oxygen rebound, alkene synthesis proceeds through the formation of a reaction cycle intermediate with kinetics, optical properties, and reactivity indicative of an Fe 4+ −OH species, compound II. The direct observation of this intermediate, normally fleeting in hydroxylases, provides a rationale for the carbon−carbon scission reaction catalyzed by OleT. oxygen activation | metal−oxo | cytochrome P450 | hydrocarbon | compound II C ytochrome P450 (CYP) enzymes catalyze an extraordinary breadth of physiologically important oxidations for xenobiotic detoxification and specialized biosynthetic pathways (1,2). The metabolic diversity of CYP enzymes originates from a sophisticated interplay of substrate molecular recognition with precise tuning of metal oxygen species formed at the enzyme active site.…”

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confidence: 99%

Catalytic strategy for carbon−carbon bond scission by the cytochrome P450 OleT

Grant

Mitchell

Makris

2016

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

102

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OleT is a cytochrome P450 that catalyzes the hydrogen peroxidedependent metabolism of C n chain-length fatty acids to synthesize C n-1 1-alkenes. The decarboxylation reaction provides a route for the production of drop-in hydrocarbon fuels from a renewable and abundant natural resource. This transformation is highly unusual for a P450, which typically uses an Fe 4+ −oxo intermediate known as compound I for the insertion of oxygen into organic substrates. OleT, previously shown to form compound I, catalyzes a different reaction. A large substrate kinetic isotope effect (≥8) for OleT compound I decay confirms that, like monooxygenation, alkene formation is initiated by substrate C−H bond abstraction. Rather than finalizing the reaction through rapid oxygen rebound, alkene synthesis proceeds through the formation of a reaction cycle intermediate with kinetics, optical properties, and reactivity indicative of an Fe 4+ −OH species, compound II. The direct observation of this intermediate, normally fleeting in hydroxylases, provides a rationale for the carbon−carbon scission reaction catalyzed by OleT.C ytochrome P450 (CYP) enzymes catalyze an extraordinary breadth of physiologically important oxidations for xenobiotic detoxification and specialized biosynthetic pathways (1, 2). The metabolic diversity of CYP enzymes originates from a sophisticated interplay of substrate molecular recognition with precise tuning of metal oxygen species formed at the enzyme active site. CYPs use a thiolate-ligated heme iron cofactor to activate molecular oxygen and produce short-lived ferric superoxo (3-5), ferric (hydro)peroxo (6-8), and ferryl (9, 10) intermediates. Coordinated efforts over several decades have resulted in isolation of each intermediate, including recent characterization of the principal oxidant thought to be responsible for the vast majority of P450 oxidations, the Fe 4+ −oxo pi−cation radical species commonly referred to as compound I (or P450-I) (10).The archetypal P450 hydroxylation involves C−H bond abstraction by P450-I and ensuing rapid oxygen insertion through a recombination process termed "oxygen rebound" (11, 12). The hydrogen abstraction/rebound mechanism describes the strategy used for most P450 transformations, and is thought to describe catalysis by numerous metal-dependent oxygenases and synthetic bio-inspired metal−oxo complexes (e.g., refs. 13-17). Despite the ubiquity of this mechanism, in some metalloenzymes, a metal−oxo species is formed that is not ultimately destined for incorporation into a substrate. Some characterized examples include the nonheme dinuclear iron ribonucleotide reductase (RNR R2) (18,19) and mononuclear iron halogenase SyrB2 (20-22). The mechanisms for RNR and SyrB2 highlight the importance of quaternary structural elements, an extensive 35-Å proton-coupled electron transfer pathway in RNR (23), and extremely subtle (subangstrom) substrate positional tuning (SyrB2) (21,22), to enable efficient circumvention from the monooxygenation reaction coordinate.P450-I has also been link...

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Structure and Chemistry of Cytochrome P450

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 221 publications

References 1 publication

Regioselective Biocatalytic Hydroxylation of Fatty Acids by Cytochrome P450s

Regioselective Biocatalytic Hydroxylation of Fatty Acids by Cytochrome P450s

Comparison of the Complexes Formed by Cytochrome P450_c_am with Cytochrome b₅ and Putidaredoxin, Two Effectors of Camphor Hydroxylase Activity

Catalytic strategy for carbon−carbon bond scission by the cytochrome P450 OleT

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Structure and Chemistry of Cytochrome P450

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 221 publications

References 1 publication

Regioselective Biocatalytic Hydroxylation of Fatty Acids by Cytochrome P450s

Regioselective Biocatalytic Hydroxylation of Fatty Acids by Cytochrome P450s

Comparison of the Complexes Formed by Cytochrome P450cam with Cytochrome b5 and Putidaredoxin, Two Effectors of Camphor Hydroxylase Activity

Catalytic strategy for carbon−carbon bond scission by the cytochrome P450 OleT

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Comparison of the Complexes Formed by Cytochrome P450_c_am with Cytochrome b₅ and Putidaredoxin, Two Effectors of Camphor Hydroxylase Activity