A new spectral intermediate associated with cytochrome P-450 function in liver microsomes

Estabrook, Ronald W.; Hildebrandt, Alfred G.; Baron, Jeffrey; Netter, K.J.; Leibman, Kenneth C.

doi:10.1016/0006-291x(71)90372-x

Cited by 239 publications

(53 citation statements)

References 2 publications

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“…Under anaerobic conditions two electrons are transferred from NADPH to the P-450,,-substrate complex via the reductase, one to the iron atom and the other to an unidentified acceptor (10,11). Molecular oxygen is bound to the ferrocytochrome to form a ternary complex, as shown by Estabrook et al (12) with liver microsomal suspensions and by Gunsalus et al (13) and by Ishimura et al (14) with bacterial cytochrome P-450. We have recently confirmed the formation of the oxyferro complex in steady-state experiments with purified P-45%M.…”

mentioning

confidence: 92%

Studies on hydroperoxide-dependent substrate hydroxylation by purified liver microsomal cytochrome P-450

Nordblom

White

Coon

1976

Archives of Biochemistry and Biophysics

349

110

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Highly purified liver microsomal cytochrome P-450 catalyzes the hydroperoxide-dependent hydroxylation of a variety of substrates in the absence of NADPH, NADPHcytochrome P-450 reductase, and molecular oxygen. The addition of phosphatidylcholine is necessary for maximal activity. The absence of flavoproteins and cytochrome b, from the cytochromeP-450 preparations rules out the involvement of other known microsomal electron carriers. The ferrous form of cytochrome P-450 is not involved in peroxidedependent hydroxylation reactions, as indicated by the lack of inhibition by carbon monoxide. With cumene hydroperoxide present, a variety of substrates is attacked, including N-methylaniline, N,N-dimethylaniline, cyclohexane, benzphetamine, and aminopyrine.With benzphetamine as the substrate, cumene hydroperoxide may be replaced by other peroxides, including hydrogen peroxide, or by peracids or sodium chlorite. A study of the stoichiometry indicated that equimolar amounts ofN-methylaniline, formaldehyde, and cumyl alcohol (o,o-dimethylbenzyl alcohol) are formed in the reaction of N,N-dimethylaniline with cumene hydroperoxide. Since H,180 is incorporated only slightly into cyclohexanol in the reaction of cyclohexane with cumene hydroperoxide, it appears that the oxygen atom in cyclohexanol is derived primarily from the peroxide. The data obtained are in accord with a peroxidase-like mechanism for the action of cytochrome P-450.The mixed function oxidase of liver microsomal membranes is capable of hydroxylating or otherwise metabolizing fatty acids and steroids as well as a variety of foreign compounds, including drugs, insecticides, alkanes, anesthetics, and carcinogens. This enzyme system was resolved into three components, P-450LM ,3 NADPHcytochrome P-450 reductase, and phosphatidylcholine (3-61, and more recently our

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mentioning

confidence: 92%

Studies on hydroperoxide-dependent substrate hydroxylation by purified liver microsomal cytochrome P-450

Nordblom

White

Coon

1976

Archives of Biochemistry and Biophysics

349

110

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“…The most thoroughly studied function is in membrane biosynthesis where it provides reducing equivalents to a fatty acid desaturase located in the endoplasmic reticulum of liver cells (Oshino, Imai & Sato, 1971;Holloway & Katz, 1972). A second function is to act as a reductant for mammalian cytochrome P450, also in liver cells (Estabrook, Hildebrandt, Baron, Netter & Leibman, 1971;Enoch & Strittmatter, 1979). In both these functional roles cytochrome b5 is an integral membrane protein and accepts electrons from a specific NADH-linked cytochrome b5 reductase (Rogers & Strittmatter, 1975), also membrane bound.…”

Section: Introductionmentioning

confidence: 99%

Refinement and structural analysis of bovine cytochrome b5 at 1.5 Å Resolution

Durley¹,

Mathews²

1996

Acta Cryst D

146

198

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The structure of bovine liver cytochrome bs, a soluble 93-residue proteolytic fragment of a 16 kDa. membranebound hemoprotein, initially solved at 2.0A resolution, has been refined at 1.5/~ using data collected on a diffractometer. Refinement to 2.0/~ resolution used the Hendrickson-Konnert procedure PROLSQ and was then extended to 1.5 ~ resolution using the program PROFFT. Only residues 3-87 could be identified in the model and these residues together with 93 water molecules gave an agreement factor of R = 0.161 for data in the resolution range 1.5-5/~,. The structure was finally refined using the program X-PLOR, which enabled alternate conformers to be modelled for several surface side chains. Residues 1 and 2 at the amino terminus of the protein and residue 88 near the carboxyl terminus could be identified from these electron-density maps. However the remaining disordered carboxy-terminal residues could not successfully be included in the model. A total of 117 solvent molecules were included in the final refinement to give R =0.164 for the data between 1.5 and 10/~.

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“…The demonstration that such a release of oxidizing species can occur from cytochrome PgsO would give decisive evidence of its oxygenated intermediate, as has been postulated by Eastabrook [7] .…”

Section: Introductionmentioning

confidence: 69%

Low temperature studies of microsomal cytochrome P₄₅₀. Release of oxidizing species

1974

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A new spectral intermediate associated with cytochrome P-450 function in liver microsomes

Cited by 239 publications

References 2 publications

Studies on hydroperoxide-dependent substrate hydroxylation by purified liver microsomal cytochrome P-450

Studies on hydroperoxide-dependent substrate hydroxylation by purified liver microsomal cytochrome P-450

Refinement and structural analysis of bovine cytochrome b5 at 1.5 Å Resolution

Low temperature studies of microsomal cytochrome P₄₅₀. Release of oxidizing species

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A new spectral intermediate associated with cytochrome P-450 function in liver microsomes

Cited by 239 publications

References 2 publications

Studies on hydroperoxide-dependent substrate hydroxylation by purified liver microsomal cytochrome P-450

Studies on hydroperoxide-dependent substrate hydroxylation by purified liver microsomal cytochrome P-450

Refinement and structural analysis of bovine cytochrome b5 at 1.5 Å Resolution

Low temperature studies of microsomal cytochrome P450. Release of oxidizing species

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Low temperature studies of microsomal cytochrome P₄₅₀. Release of oxidizing species