Cytochrome by hydroxylation

Similar to some other antioxidants, pyrrolopyrimidines do not contain active free radical scavenging groups such as phenolic or thiolic substituents. At present, at least two different mechanisms of their antioxidant activity have been proposed [307], It was suggested that pyrrolopyrimidines, which are electron donating compounds, can be oxidized by hydroxyl or peroxyl radicals or hydroxylated by cytochrome P-450 forming phenolic metabolite... 

Newcomb M, Letadic MH, Putt DA, et al. An incredibly fast apparent oxygen rebound rate-constant for hydrocarbon hydroxylation by cytochrome-P-450 enzymes. J Am Chem Soc 1995 117(11) 3312—3313. 

Ogliaro F, Harris N, Cohen S, et al. A model rebound mechanism of hydroxylation by cytochrome P450 stepwise and effectively concerted pathways, and their reactivity patterns. J Am Chem Soc 2000 122(37) 8977-8989. 

Groves JT, Subramanian DV. Hydroxylation by cytochrome-P-450 and metalloporphyrin models—evidence for allylic rearrangement. J Am Chem Soc 1984 106(7) 2177-2181. 

F. Ogliaro, N. Harris, S. Cohen, M. Filatov, S. R de Visser, and S. Shaik, A Model Rebound Mechanism of Hydroxylation by Cytochrome P450. Stepwise and Effectively Concerted Pathways, and Their Reactivity Patterns, J. Am. Chem. Soc. 2000,122, 8977. Calculations explain puzzling aspects of cytochrome P450 hydroxylation reactions in terms of two, different, reactive spin states of the enzyme. 

It is now generally understood that the mechanism of hydroxylation by cytochrome P-450 proceeds by two successive one-electron reduction steps of the heme center, transforming dioxygen into a peroxide species bonded to iron (Scheme l).73,78 Well-defined steps (25) - (31) involve (a) the formation of a high-spin Fein-enzyme-substrate complex (26) (b) one-electron reduction of (26) to a high-spin ferrocytochrome (27) (c) addition of dioxygen to form a superoxo-Fe111 complex (28) and (d) one-electron reduction of the superoxo complex to a peroxide complex (29). 

D KIE associated with alkane hydroxylation by cytochromes P-450 and intermolec-ular D KIE in the alkane hydroxylations catalysed by manganese and iron porphyrin complexes... 

Hesse LM, He P, Krishnaswamy S, Hao Q, Hogan K, von Moltke LL, Greenblatt DJ, Court MH. Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics 2004 14 225-238. 

Yamazaki H, Guo Z, Persmark M, et al. Burfuralol hydroxylation by cytochrome P450 2D6 and 1A2 enzymes in human liver microsomes. Mol Pharmacol 1994 ... 

S. Shaik, S. Cohen, S. P. de Visser, P. K. Sharma, D. Kumar, S. Kozuch, F. Ogliaro, D. Danovich, Eur. J. Inorg. Chem. 207 (2004). The Rebound Controversy An Overview and Theoretical Modeling of the Robound Step in C—H Hydroxylation by Cytochrome P450. 

Table III. Isotope Effects for Cyclohexene Hydroxylation by Cytochrome P 450LM2...

Bathelt CM, L Ridder, AJ Mulholland, JN Harvey (2003) Aromatic hydroxylation by cytochrome P450 Model calculations of mechanism and substituent effects. J. Am. Chem. Soc. 125 (49) 15004-15005... 

Ortiz de Montellano PR. Hydrocarbon hydroxylation by cytochrome P450 enzymes. Chem Rev. 2009 110 932-48. 

Filatov, M., Harris, N., and Shaik, S. (1999) On the "rebound" mechanism of alkane hydroxylation by cytochrome P450 electronic structure of the intermediate and the electron transfer character in the rebound step. Angew. Chem., Int. Ed. 38, 3510-3512. 

Groves, J.T. and Subramanian, D.V. (1984) Hydroxylation by cytochrome P450 and metaloporphyrin models. Evidence for allylic reaction, /. Am. Chem. Soc. 106,2177-2181. 

Hydroxylation Hydroxylation can occur with an aliphatic or aromatic carbon atom. DDT and the carbamate insecticide carbaryl are known to be hydroxylated by cytochrome P450 monooxygenases as shown in Figures 8.3 and 8.4. Microsomal hydroxylation usually results in detoxification. 

W. Ando and Y. Moro-oka, Role of Oxygen in Chemistry and Biochemistry , Elsevier, Amsterdam, 1988. Includes chapters on (a) Cation-Radical Chain Catalyzed Oxygenation of Alkenes, by S. F. Nelsen, et al. (b) Photooxygenation of Organic Compounds via Thieir Radical Ions, by K. Mizono and Y. Otsuji (c) Triphenylpyrylium Sensitized Oxygenations, by K. Tokumaru a al. (d) Catalytic Oxidation of Metiiylarenes to Benzaldehydes, by R. A. Shddon and N. de Heij (e) Oxidation of Arylamines with Horseradish Peroxidase, 1 Fujimori et al. (f) Arene Hydroxylation by Cytochrome P-4S0, by M. Tsuda et al., and marry others. 

The biosynthesis of the ergot alkaloids involves condensation of dimethyl-allyl pyrophosphate (derived from mevalonic acid) with tryptophan. Closure of the C- and D-rings of the alkaloid involves specific hydroxylations by cytochrome P450-dependent oxidases and rearrangements. Further modifications involve N-methylation in the presence of S-adenosyl methionine and/or condensation with amino acids and peptides. Coupling of lysergyl CoA with certain peptides forms the peptide alkaloids which are the most bioactive of the ergot alkaloids. 

Steroids Are Hydroxylated by Cytochrome P450 Monooxygenases That Utilize NADPH and O2... 

Hay-Kraus, B.L. Greenblatt, D.J. Venkatakrishnan, K. Court, M.H. Evidence for propofol hydroxylation by cytochrome P4502B11 in canine liver microsomes bre and gender differences. Xenobiotica 2000, 30, 575-588. 

Shaik and co-workers have carried out a number studies using density functional theory based quantum chemical and QM/MM techniques to examine various aspects of the mechanism of alkane hydroxylation by cytochrome P450.178 181 These studies included, for example, calculation of the potential energy surface for the so-called rebound mechanism with methane as a substrate for two spin states, the high spin (HS) quartet state and low spin (LS) doublet state. In the rebound mechanism, Compound I initially abstracts a... 

Research on aromatic hydroxylation by cytochrome P450 provides an example of how quantum chemical calculations on small models can help in developing structure-reactivity relationships. Hydroxylation of C-H bonds is a particularly important class of reaction in drug metabolism,185 which can activate pro-drugs, or affect the bioavailability of pharmaceuticals. For the reliable prediction of pharmaceutical metabolism and toxicology (ADME/ TOX) properties, a key aim is the development of structure-activity relationships to predict conversions of drugs. Earlier work has shown that structure-activity relationships based on the structures and properties of substrates alone are of limited utility. There is a need for more detailed models, which can include effects of the reaction mechanism and specificity of different cytochrome P450 isozymes. 

Huang M-T, Johnson EF, Muller-Eberhard U, Koop DR, Coon MJ, Conney AH. 1981. Specificity in the activation and inhibition by flavonoids of benzo-[a]pyrene hydroxylation by cytochrome P-450 isozymes from rabbit liver microsomes. J. Biol. Chem. 256 10897-901... 

Bathelt CM, Ridder L, Mulholland AJ, Harvey JN. Mechanism and structure-reactivity relationships for aromatic hydroxylation by cytochrome P450. Org Biomol Chem 2004 2 2998-3005. 

LT Burka, TM Plucinski, TL MacDonald. Mechanisms of hydroxylation by cytochrome P-450 metabolism of monohalobenzenes by phenobarbital induced microsomes. Proc Natl Acad Sci USA 80 6680-6684, 1983. 

RP ffanzlik, GO Shearer. Secondary isotope effects on olefin hydroxylation by cytochrome P-450. Biochem Pharmacol 27 1441—1444, 1978. 

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