Journal articles: 'Oxidation with P450 enzymes'

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Cryle, Max J., Jeanette E. Stok, and James J. De Voss. "Reactions Catalyzed by Bacterial Cytochromes P450." Australian Journal of Chemistry 56, no. 8 (2003): 749. http://dx.doi.org/10.1071/ch03040.

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The cytochromes P450 are a large family of oxidative haemoproteins that are responsible for a wide variety of oxidative transformations in a variety of organisms. This review focuses upon the reactions catalyzed specifically by bacterial enzymes, which includes aliphatic hydroxylation, alkene epoxidation, aromatic hydroxylation, oxidative phenolic coupling, heteroatom oxidation and dealkylation, and multiple oxidations including C–C bond cleavage. The potential for the practical application of the oxidizing power of these enzymes is briefly discussed.

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Fasan, Rudi. "Tuning P450 Enzymes as Oxidation Catalysts." ACS Catalysis 2, no. 4 (March 20, 2012): 647–66. http://dx.doi.org/10.1021/cs300001x.

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Frank, Daniel J., Yarrow Madrona, and Paul R. Ortiz de Montellano. "Cholesterol Ester Oxidation by Mycobacterial Cytochrome P450." Journal of Biological Chemistry 289, no. 44 (September 10, 2014): 30417–25. http://dx.doi.org/10.1074/jbc.m114.602771.

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Mycobacteria share a common cholesterol degradation pathway initiated by oxidation of the alkyl side chain by enzymes of cytochrome P450 (CYP) families 125 and 142. Structural and sequence comparisons of the two enzyme families revealed two insertions into the N-terminal region of the CYP125 family (residues 58–67 and 100–109 in the CYP125A1 sequence) that could potentially sterically block the oxidation of the longer cholesterol ester molecules. Catalytic assays revealed that only CYP142 enzymes are able to oxidize cholesteryl propionate, and although CYP125 enzymes could oxidize cholesteryl sulfate, they were much less efficient at doing so than the CYP142 enzymes. The crystal structure of CYP142A2 in complex with cholesteryl sulfate revealed a substrate tightly fit into a smaller active site than was previously observed for the complex of CYP125A1 with 4-cholesten-3-one. We propose that the larger CYP125 active site allows for multiple binding modes of cholesteryl sulfate, the majority of which trigger the P450 catalytic cycle, but in an uncoupled mode rather than one that oxidizes the sterol. In contrast, the more unhindered and compact CYP142 structure enables enzymes of this family to readily oxidize cholesteryl esters, thus providing an additional source of carbon for mycobacterial growth.

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Mirzaei, Saber, Avat Arman Taherpour, and Shahryar Mohamadi. "Mechanistic study of allopurinol oxidation using aldehyde oxidase, xanthine oxidase and cytochrome P450 enzymes." RSC Advances 6, no. 111 (2016): 109672–80. http://dx.doi.org/10.1039/c6ra19197e.

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The oxidation reaction of allopurinol to its active metabolite (oxypurinol) is investigated using the AO and P450 enzymes. To the contrary of AO (and XO), the P450 enzyme can metabolize the allopurinol with a not self-inhibitory mechanism.

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McLean, Kirsty J., Marcus Hans, and Andrew W. Munro. "Cholesterol, an essential molecule: diverse roles involving cytochrome P450 enzymes." Biochemical Society Transactions 40, no. 3 (May 22, 2012): 587–93. http://dx.doi.org/10.1042/bst20120077.

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Cholesterol is an essential molecule for eukaryotic life and is an important precursor for a wide range of physiological processes. Biosynthesis and homoeostasis of cholesterol are complex mechanisms that are tightly regulated and interlinked with activities of a number of cytochrome P450 enzymes. These P450s play central critical roles in cholesterol metabolism. Key roles include a rate-limiting reaction in the synthesis of cholesterol itself, and in the oxidative transformations of cholesterol into steroid hormones and bile acids. However, microbial P450s also have important roles that impinge directly on human cholesterol synthesis and oxidation. Recent data reveal that Mycobacterium tuberculosis (which infects more than one-third of the world's human population) uses P450s to initiate breakdown of host cholesterol as an energy source. Microbial P450s also catalyse industrially important transformations in the synthesis of cholesterol-lowering statin drugs, with clear benefits to humans. The present article reviews the various roles of P450s in human cholesterol metabolism, from endogenous P450s through to microbial oxidases that enable catabolism of human cholesterol, or facilitate production of statins that regulate cholesterol production with positive outcomes in cardiovascular disease.

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Gillam, Elizabeth M. J., Lisa M. Notley, Hongliang Cai, James J. De Voss, and F. Peter Guengerich. "Oxidation of Indole by Cytochrome P450 Enzymes†." Biochemistry 39, no. 45 (November 2000): 13817–24. http://dx.doi.org/10.1021/bi001229u.

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Harken, Lauritz, and Shu-Ming Li. "Modifications of diketopiperazines assembled by cyclodipeptide synthases with cytochrome P450 enzymes." Applied Microbiology and Biotechnology 105, no. 6 (February 24, 2021): 2277–85. http://dx.doi.org/10.1007/s00253-021-11178-1.

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Abstract2,5-Diketopiperazines are the smallest cyclic peptides comprising two amino acids connected via two peptide bonds. They can be biosynthesized in nature by two different enzyme families, either by nonribosomal peptide synthetases or by cyclodipeptide synthases. Due to the stable scaffold of the diketopiperazine ring, they can serve as precursors for further modifications by different tailoring enzymes, such as methyltransferases, prenyltransferases, oxidoreductases like cyclodipeptide oxidases, 2-oxoglutarate-dependent monooxygenases and cytochrome P450 enzymes, leading to the formation of intriguing secondary metabolites. Among them, cyclodipeptide synthase-associated P450s attracted recently significant attention, since they are able to catalyse a broader variety of astonishing reactions than just oxidation by insertion of an oxygen. The P450-catalysed reactions include hydroxylation at a tertiary carbon, aromatisation of the diketopiperazine ring, intramolecular and intermolecular carbon-carbon and carbon-nitrogen bond formation of cyclodipeptides and nucleobase transfer reactions. Elucidation of the crystal structures of three P450s as cyclodipeptide dimerases provides a structural basis for understanding the reaction mechanism and generating new enzymes by protein engineering. This review summarises recent publications on cyclodipeptide modifications by P450s.Key Points• Intriguing reactions catalysed by cyclodipeptide synthase-associated cytochrome P450s• Homo- and heterodimerisation of diketopiperazines• Coupling of guanine and hypoxanthine with diketopiperazines Graphical abstract

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Uehara, Shotaro, Toru Oshio, Kazuyuki Nakanishi, Etsuko Tomioka, Miyu Suzuki, Takashi Inoue, Yasuhiro Uno, Erika Sasaki, and Hiroshi Yamazaki. "Survey of Drug Oxidation Activities in Hepatic and Intestinal Microsomes of Individual Common Marmosets, a New Nonhuman Primate Animal Model." Current Drug Metabolism 20, no. 2 (April 30, 2019): 103–13. http://dx.doi.org/10.2174/1389200219666181003143312.

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Background: Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450 (P450) enzymes is now available that supports the use of this primate species as an animal model for drug development. Here, we collect and provide an overview of information on the activities of common marmoset hepatic and intestinal microsomes with respect to 28 typical human P450 probe oxidations. Results: Marmoset P450 2D6/8-dependent R-metoprolol O-demethylation activities in hepatic microsomes were significantly correlated with those of midazolam 1′- and 4-hydroxylations, testosterone 6β-hydroxylation, and progesterone 6β-hydroxylation, which are probe reactions for marmoset P450 3A4/5/90. In marmosets, the oxidation activities of hepatic microsomes and intestinal microsomes were roughly comparable for midazolam and terfenadine. Overall, multiple forms of marmoset P450 enzymes in livers and intestines had generally similar substrate recognition functionalities to those of human and/or cynomolgus monkey P450 enzymes. Conclusion: The marmoset could be a model animal for humans with respect to the first-pass extraction of terfenadine and related substrates. These findings provide a foundation for understanding individual pharmacokinetic and toxicological results in nonhuman primates as preclinical models and will help to further support understanding of the molecular mechanisms of human P450 function.

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Murphy, Sharon E., Vytautas Raulinaitis, and Kathryn M. Brown. "NICOTINE 5′-OXIDATION AND METHYL OXIDATION BY P450 2A ENZYMES." Drug Metabolism and Disposition 33, no. 8 (April 28, 2005): 1166–73. http://dx.doi.org/10.1124/dmd.105.004549.

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Correia, Maria Almira, Sheila Sadeghi, and Eduardo Mundo-Paredes. "CYTOCHROME P450 UBIQUITINATION: Branding for the Proteolytic Slaughter?" Annual Review of Pharmacology and Toxicology 45, no. 1 (September 22, 2005): 439–64. http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100127.

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The hepatic cytochromes P450 (P450s) are monotopic endoplasmic reticulum (ER)-anchored hemoproteins engaged in the enzymatic oxidation of a wide variety of endo- and xenobiotics. In the course of these reactions, the enzymes generate reactive O2 species and/or reactive metabolic products that can attack the P450 heme and/or protein moiety and structurally and functionally damage the enzyme. The in vivo conformational unraveling of such a structurally damaged P450 signals its rapid removal via the cellular sanitation system responsible for the proteolytic disposal of structurally aberrant, abnormal, and/or otherwise malformed proteins. A key player in this process is the ubiquitin (Ub)-dependent 26S proteasome system. Accordingly, the structurally deformed P450 protein is first branded for recognition and proteolytic removal by the 26S proteasome with an enzymatically incorporated polyUb tag. P450s of the 3A subfamily such as the major human liver enzyme CYP3A4 are notorious targets for this process, and they represent excellent prototypes for the understanding of integral ER protein ubiquitination. Not all the participants in hepatic CYP3A ubiquitination and subsequent proteolytic degradation have been identified. The following discussion thus addresses the various known and plausible events and/or cellular participants involved in this multienzymatic P450 ubiquitination cascade, on the basis of our current knowledge of other eukaryotic models. In addition, because the detection of ubiquitinated P450s is technically challenging, the critical importance of appropriate methodology is also discussed.

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Svobodová, Martina, Helena Dračínská, Markéta Martínková, Jiří Hudeček, Petr Hodek, Eva Frei, and Marie Stiborová. "Oxidation of carcinogenic 2-nitroanisole by rat cytochromes P450 - similarity between human and rat enzymes." Interdisciplinary Toxicology 1, no. 2 (September 1, 2008): 182–85. http://dx.doi.org/10.2478/v10102-010-0035-x.

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Oxidation of carcinogenic 2-nitroanisole by rat cytochromes P450 - similarity between human and rat enzymes2-Nitroanisole (2-NA) is an important industrial pollutant and a potent carcinogen for rodents. Understanding which cytochrome P450 (CYP) enzymes are involved in its metabolism are important to assess an individual's susceptibility to this environmental carcinogen. The aim of this study was to evaluate the efficiency of rat hepatic CYPs to oxidize 2-NA, to examine the metabolites formed during such an oxidation, and to compare such efficiencies of rat CYPs with those of human. 2-NA is oxidized by rat hepatic microsomes to 2-nitrophenol (2-NP) as the major metabolite, and to 2,6-dihydroxynitrobenzene (2,6-DNB) and 2,5-dihydroxynitrobenzene (2,5-DNB) as the minor products. All these metabolites are suggested as detoxication products. Using hepatic microsomes of rats pre-treated with specific CYP inducers and microsomes from Baculovirus transfected insect cells expressing recombinant rat and human CYP enzymes we found that rat recombinant CYP2E1, 2D2, 2B2, 2C6 and 1A1, as well as orthologous human CYP enzymes are the most efficient enzymes metabolizing 2-NA. However, human CYP1A1 oxidize 2-NA with a higher efficiency than the enzyme of rats. The results show the participation of orthologous CYPs in 2-NA oxidation by both species and underline the suitability of rat species as a model to evaluate human susceptibility to 2-NA.

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Chapman, Stephen K., Simon Daff, and Tobias W. B. Ost. "Haem-thiolate redox enzymes: cytochrome P450 BM3 versus nitric oxide synthase: Power versus control." Biochemist 25, no. 4 (August 1, 2003): 20–23. http://dx.doi.org/10.1042/bio02504020.

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More than one-third of all enzymes catalyse the oxidation or reduction of a substrate and are therefore classed as oxidoreductases or redox enzymes. The, often complex, redox chemistry involved here is made possible by surprisingly few redox-active cofactors. Of these, flavin nucleotides (FAD and FMN) and haem groups are arguably the most significant. The P450 cytochromes (P450s) and nitric oxide synthases (NOSs) represent a very large and immensely important group of enzymes, which utilize both of these cofactors.

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Hosea, Natilie A., and F. Peter Guengerich. "Oxidation of Nonionic Detergents by Cytochrome P450 Enzymes." Archives of Biochemistry and Biophysics 353, no. 2 (May 1998): 365–73. http://dx.doi.org/10.1006/abbi.1998.0659.

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Kobayashi, Yuichiro, Kenji Kohara, Yusuke Kiuchi, Hiroki Onoda, Osami Shoji, and Hiroyasu Yamaguchi. "Control of microenvironment around enzymes by hydrogels." Chemical Communications 56, no. 49 (2020): 6723–26. http://dx.doi.org/10.1039/d0cc01332c.

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Guengerich, F. Peter, Clayton J. Wilkey, and Thanh T. N. Phan. "Human cytochrome P450 enzymes bind drugs and other substrates mainly through conformational-selection modes." Journal of Biological Chemistry 294, no. 28 (May 30, 2019): 10928–41. http://dx.doi.org/10.1074/jbc.ra119.009305.

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Cytochrome P450 (P450) enzymes are major catalysts involved in the oxidations of most drugs, steroids, carcinogens, fat-soluble vitamins, and natural products. The binding of substrates to some of the 57 human P450s and other mammalian P450s is more complex than a two-state system and has been proposed to involve mechanisms such as multiple ligand occupancy, induced-fit, and conformational-selection. Here, we used kinetic analysis of binding with multiple concentrations of substrates and computational modeling of these data to discern possible binding modes of several human P450s. We observed that P450 2D6 binds its ligand rolapitant in a mechanism involving conformational-selection. P450 4A11 bound the substrate lauric acid via conformational-selection, as did P450 2C8 with palmitic acid. Binding of the steroid progesterone to P450 21A2 was also best described by a conformational-selection model. Hexyl isonicotinate binding to P450 2E1 could be described by either a conformational-selection or an induced-fit model. Simulation of the binding of the ligands midazolam, bromocriptine, testosterone, and ketoconazole to P450 3A4 was consistent with an induced-fit or a conformational-selection model, but the concentration dependence of binding rates for varying both P450 3A4 and midazolam concentrations revealed discordance in the parameters, indicative of conformational-selection. Binding of the P450s 2C8, 2D6, 3A4, 4A11, and 21A2 was best described by conformational-selection, and P450 2E1 appeared to fit either mode. These findings highlight the complexity of human P450-substrate interactions and that conformational-selection is a dominant feature of many of these interactions.

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Hunter, Arwen L., Rani P. Cruz, Bo M. Cheyne, Bruce M. McManus, and David J. Granville. "Cytochrome p450 enzymes and cardiovascular disease." Canadian Journal of Physiology and Pharmacology 82, no. 12 (December 1, 2004): 1053–60. http://dx.doi.org/10.1139/y04-118.

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The cytochrome p450 (CYP) superfamily is responsible for the oxidation, peroxidation, and (or) reduction of vitamins, steroids, xenobiotics, and the majority of cardiovascular drugs in an oxygen- and NADPH-dependent manner. Although hepatic CYP have been studied extensively, the role of CYP in cardiovascular physiology and disease is poorly understood. Increasing evidence suggests that these enzymes play an important role in the pathogenesis of a number of cardiovascular diseases. The current review summarizes the understanding as to the role that dysregulated CYP expression and (or) activity may play in the onset and progression of cardiovascular disease.Key words: Cytochrome p450, heart, endothelial cell, ischemia, atherosclerosis, reactive oxygen species.

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Bořek-Dohalská, Lucie, Ivan Gut, Pavel Souček, Zdeněk Roth, and Petr Hodek. "Cytochromes P450 Involved in Cyclophosphamide, Paclitaxel and Docetaxel Metabolism in Rats." Collection of Czechoslovak Chemical Communications 65, no. 7 (2000): 1183–90. http://dx.doi.org/10.1135/cccc20001183.

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We investigated involvement of cytochromes P450 (CYPs) of rat liver microsomes in metabolism of two anticancer drugs, paclitaxel (PCT) and docetaxel (DTX), by an indirect method. This method is based on the presumption that the compound competitively inhibiting oxidation of the CYP-selective substrate should also be a substrate for the CYP enzyme. The validity of this approach was confirmed using the model drug, cyclophosphamide (CPA). Indeed, CPA competitively inhibited oxidation of substrates specific for CYP2B1 and CYP3A1/2, enzymes previously reported to be capable of metabolizing CPA. Using this method, we identified CYP enzymes participating in PCT and DTX metabolism. The CYP2D1/2/3 and CYP3A1/2 are enzymes oxidizing PCT while CYP3A1/2 and CYP2E1 are responsible for metabolism of DTX. Here, we report a suitable method serving for easy and fast estimation of CYP enzymes involved in drug metabolism.

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Eschenfeldt, William H., Yeyan Zhang, Hend Samaha, Lucy Stols, L. Dudley Eirich, C. Ronald Wilson, and Mark I. Donnelly. "Transformation of Fatty Acids Catalyzed by Cytochrome P450 Monooxygenase Enzymes of Candida tropicalis." Applied and Environmental Microbiology 69, no. 10 (October 2003): 5992–99. http://dx.doi.org/10.1128/aem.69.10.5992-5999.2003.

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ABSTRACT Candida tropicalis ATCC 20336 can grow on fatty acids or alkanes as its sole source of carbon and energy, but strains blocked in β-oxidation convert these substrates to long-chain α,ω-dicarboxylic acids (diacids), compounds of potential commercial value (Picataggio et al., Biotechnology 10:894-898, 1992). The initial step in the formation of these diacids, which is thought to be rate limiting, is ω-hydroxylation by a cytochrome P450 (CYP) monooxygenase. C. tropicalis ATCC 20336 contains a family of CYP genes, and when ATCC 20336 or its derivatives are exposed to oleic acid (C18:1), two cytochrome P450s, CYP52A13 and CYP52A17, are consistently strongly induced (Craft et al., this issue). To determine the relative activity of each of these enzymes and their contribution to diacid formation, both cytochrome P450s were expressed separately in insect cells in conjunction with the C. tropicalis cytochrome P450 reductase (NCP). Microsomes prepared from these cells were analyzed for their ability to oxidize fatty acids. CYP52A13 preferentially oxidized oleic acid and other unsaturated acids to ω-hydroxy acids. CYP52A17 also oxidized oleic acid efficiently but converted shorter, saturated fatty acids such as myristic acid (C14:0) much more effectively. Both enzymes, in particular CYP52A17, also oxidized ω-hydroxy fatty acids, ultimately generating the α,ω-diacid. Consideration of these different specificities and selectivities will help determine which enzymes to amplify in strains blocked for β-oxidation to enhance the production of dicarboxylic acids. The activity spectrum also identified other potential oxidation targets for commercial development.

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Munro, Andrew W., Kirsty J. McLean, Job L. Grant, and Thomas M. Makris. "Structure and function of the cytochrome P450 peroxygenase enzymes." Biochemical Society Transactions 46, no. 1 (February 6, 2018): 183–96. http://dx.doi.org/10.1042/bst20170218.

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The cytochromes P450 (P450s or CYPs) constitute a large heme enzyme superfamily, members of which catalyze the oxidative transformation of a wide range of organic substrates, and whose functions are crucial to xenobiotic metabolism and steroid transformation in humans and other organisms. The P450 peroxygenases are a subgroup of the P450s that have evolved in microbes to catalyze the oxidative metabolism of fatty acids, using hydrogen peroxide as an oxidant rather than NAD(P)H-driven redox partner systems typical of the vast majority of other characterized P450 enzymes. Early members of the peroxygenase (CYP152) family were shown to catalyze hydroxylation at the α and β carbons of medium-to-long-chain fatty acids. However, more recent studies on other CYP152 family P450s revealed the ability to oxidatively decarboxylate fatty acids, generating terminal alkenes with potential applications as drop-in biofuels. Other research has revealed their capacity to decarboxylate and to desaturate hydroxylated fatty acids to form novel products. Structural data have revealed a common active site motif for the binding of the substrate carboxylate group in the peroxygenases, and mechanistic and transient kinetic analyses have demonstrated the formation of reactive iron-oxo species (compounds I and II) that are ultimately responsible for hydroxylation and decarboxylation of fatty acids, respectively. This short review will focus on the biochemical properties of the P450 peroxygenases and on their biotechnological applications with respect to production of volatile alkenes as biofuels, as well as other fine chemicals.

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Li, Zhong, Yuanyuan Jiang, F. Peter Guengerich, Li Ma, Shengying Li, and Wei Zhang. "Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications." Journal of Biological Chemistry 295, no. 3 (December 6, 2019): 833–49. http://dx.doi.org/10.1074/jbc.rev119.008758.

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Cytochrome P450 enzymes (P450s) are broadly distributed among living organisms and play crucial roles in natural product biosynthesis, degradation of xenobiotics, steroid biosynthesis, and drug metabolism. P450s are considered as the most versatile biocatalysts in nature because of the vast variety of substrate structures and the types of reactions they catalyze. In particular, P450s can catalyze regio- and stereoselective oxidations of nonactivated C–H bonds in complex organic molecules under mild conditions, making P450s useful biocatalysts in the production of commodity pharmaceuticals, fine or bulk chemicals, bioremediation agents, flavors, and fragrances. Major efforts have been made in engineering improved P450 systems that overcome the inherent limitations of the native enzymes. In this review, we focus on recent progress of different strategies, including protein engineering, redox-partner engineering, substrate engineering, electron source engineering, and P450-mediated metabolic engineering, in efforts to more efficiently produce pharmaceuticals and other chemicals. We also discuss future opportunities for engineering and applications of the P450 systems.

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Meunier, Bernard, Samuël P. de Visser, and Sason Shaik. "Mechanism of Oxidation Reactions Catalyzed by Cytochrome P450 Enzymes." Chemical Reviews 104, no. 9 (September 2004): 3947–80. http://dx.doi.org/10.1021/cr020443g.

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Zhang, Jianhua, Yvan Pelletier, and Claudia Goyer. "Identification of potential detoxification enzyme genes in Leptinotarsa decemlineata (Say) and study of their expression in insects reared on different plants." Canadian Journal of Plant Science 88, no. 4 (July 1, 2008): 621–29. http://dx.doi.org/10.4141/cjps07001.

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Insects have evolved remarkable abilities to metabolize plant allelochemicals colonizing host plants otherwise toxic to them. These abilities largely rely on detoxification enzymes such as cytochromes P450 (P450), glutathione S-transferases (GST) and esterases. To identify the potential detoxification enzyme genes in Leptinotarsa decemlineata (Say), 44 expressed sequence tags (ESTs) including the ESTs of 38 P450, three GSTs and three esterases were generated using a degenerate rapid amplification of cDNA ends (RACE). The putative P450s were placed into 10 subfamilies representing five families. The gene expression was studied using a low-density reverse Northern array. The results showed that CYP4BN13v1 was up-regulated after the beetles transferred from potato to tomato, pepper or eggplant. The expression of CYP4Q11 was up-regulated in the beetles transferred to eggplants. In contrast, the expression of CYP9Z14v1 and CYP4BN13v1 was down-regulated after the beetles transferred to eggplant or flowering tobacco, respectively. This indicates that only a few P450 genes from the insect were induced or suppressed by different rearing plants. Although the function of these P450 enzymes in the metabolism of allelochemicals was not determined here, the result implies that the insect may use different oxidative metabolic pathways when they feed on different host plants. Key words: Cytochrome P450, glutathione S-transferase, esterase, gene expression, host plant

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Cribb, Alastair E., M. Joy Knight, Dagny Dryer, Judy Guernsey, Kimberly Hender, Marvin Tesch, and Tarek M. Saleh. "Role of Polymorphic Human Cytochrome P450 Enzymes in Estrone Oxidation." Cancer Epidemiology Biomarkers & Prevention 15, no. 3 (March 2006): 551–58. http://dx.doi.org/10.1158/1055-9965.epi-05-0801.

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Shimada, Tsutomu, Shigeo Takenaka, Norie Murayama, Hiroshi Yamazaki, Joo-Hwan Kim, Donghak Kim, Francis K. Yoshimoto, F. Peter Guengerich, and Masayuki Komori. "Oxidation of Acenaphthene and Acenaphthylene by Human Cytochrome P450 Enzymes." Chemical Research in Toxicology 28, no. 2 (February 2, 2015): 268–78. http://dx.doi.org/10.1021/tx500505y.

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Cao, Ngoc Tan, Ngoc Anh Nguyen, Thien-Kim Le, Gun Su Cha, Ki Deok Park, and Chul-Ho Yun. "Regioselective Hydroxylation of Oleanolic Acid Catalyzed by Human CYP3A4 to Produce Hederagenenin, a Chiral Metabolite." Catalysts 11, no. 2 (February 17, 2021): 267. http://dx.doi.org/10.3390/catal11020267.

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Oleanolic acid (OA) is a pentacyclic triterpenoid widely found in plants and foods as an aglycone of triterpenoid saponins or as a free acid. OA exhibits beneficial activities for humans, including antitumor, antivirus, and hepatoprotection properties without apparent toxicity. The metabolites produced by the cytochrome P450 (P450) enzymes are critical for the evaluation of the efficacy and safety of drugs. In this study, the potential metabolites of OA were investigated by P450-catalyzed oxidation reactions. Among the various tested human P450s, only human CYP3A4 was active for the hydroxylation of OA. The major metabolite was characterized by a set of analyses using HPLC, LC–MS, and NMR. It was found to be 4-epi-hederagenenin, a chiral product, by regioselective hydroxylation of the methyl group at the C-23 position. These results indicated that CYP3A4 can hydroxylate an OA substrate to make 4-epi-hederagenenin. Possible drug–food interactions are discussed.

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Jóźwik, Ilona K., Martin Litzenburger, Yogan Khatri, Alexander Schifrin, Marco Girhard, Vlada Urlacher, Andy-Mark W. H. Thunnissen, and Rita Bernhardt. "Structural insights into oxidation of medium-chain fatty acids and flavanone by myxobacterial cytochrome P450 CYP267B1." Biochemical Journal 475, no. 17 (September 11, 2018): 2801–17. http://dx.doi.org/10.1042/bcj20180402.

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Oxidative biocatalytic reactions performed by cytochrome P450 enzymes (P450s) are of high interest for the chemical and pharmaceutical industries. CYP267B1 is a P450 enzyme from myxobacterium Sorangium cellulosum So ce56 displaying a broad substrate scope. In this work, a search for new substrates was performed, combined with product characterization and a structural analysis of substrate-bound complexes using X-ray crystallography and computational docking. The results demonstrate the ability of CYP267B1 to perform in-chain hydroxylations of medium-chain saturated fatty acids (decanoic acid, dodecanoic acid and tetradecanoic acid) and a regioselective hydroxylation of flavanone. The fatty acids are mono-hydroxylated at different in-chain positions, with decanoic acid displaying the highest regioselectivity towards ω-3 hydroxylation. Flavanone is preferably oxidized to 3-hydroxyflavanone. High-resolution crystal structures of CYP267B1 revealed a very spacious active site pocket, similarly to other P450s capable of converting macrocyclic compounds. The pocket becomes more constricted near to the heme and is closed off from solvent by residues of the F and G helices and the B–C loop. The crystal structure of the tetradecanoic acid-bound complex displays the fatty acid bound near to the heme, but in a nonproductive conformation. Molecular docking allowed modeling of the productive binding modes for the four investigated fatty acids and flavanone, as well as of two substrates identified in a previous study (diclofenac and ibuprofen), explaining the observed product profiles. The obtained structures of CYP267B1 thus serve as a valuable prediction tool for substrate hydroxylations by this highly versatile enzyme and will encourage future selectivity changes by rational protein engineering.

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Kakimoto, Kensaku, Norie Murayama, Shigeo Takenaka, Haruna Nagayoshi, Young-Ran Lim, Vitchan Kim, Donghak Kim, et al. "Cytochrome P450 2A6 and other human P450 enzymes in the oxidation of flavone and flavanone." Xenobiotica 49, no. 2 (January 29, 2018): 131–42. http://dx.doi.org/10.1080/00498254.2018.1426133.

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Mizerovská, Jana, Helena Dračínská, Volker Arlt, Jiří Hudeček, Petr Hodek, Heinz Schmeiser, Eva Frei, and Marie Stiborová. "Rat cytochromes P450 oxidize 3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone." Interdisciplinary Toxicology 1, no. 2 (September 1, 2008): 150–54. http://dx.doi.org/10.2478/v10102-010-0031-1.

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Rat cytochromes P450 oxidize 3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone3-Aminobenzanthrone (3-ABA) is a human metabolite of carcinogenic 3-nitrobenzanthrone (3-NBA), which occurs in diesel exhaust and air pollution. Understanding which cytochrome P450 (CYP) enzymes are involved in metabolic activation and/or detoxication of this toxicant is important in the assessment of an individual's susceptibility to this substance. The aim of this study was to evaluate the efficiency of rat hepatic CYPs to oxidize 3-ABA and to examine the metabolites formed during such an oxidation. The metabolites formed by CYPs in rat hepatic microsomes were separated by high performance liquid chromatography (HPLC). 3-ABA is oxidized by these enzymes to three metabolites, which were separated by HPLC as distinguish product peaks. Using co-chromatography with synthetic standards, two of them were identified to be oxidative metabolites of 3-ABA,N-hydroxy-3-ABA and 3-NBA. The structure of another 3-ABA metabolite remains to be characterized. To define the role of rat hepatic CYP enzymes in metabolism of 3-ABA, we investigated the modulation of its oxidation using different inducers of CYPs for treatment of rats to enrich the liver microsomes with individual CYPs. Based on these studies, we attribute most of 3-ABA oxidation in rat hepatic microsomes to CYP2B, followed by CYP1A, although a role of other hepatic CYPs cannot be ruled out. Inhibition of 3-ABA oxidation by selective inhibitors of individual CYPs, supported this finding.

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Herraiz, Tomás, Hugo Guillén, and Juan Galisteo. "Metabolite Profile Resulting from the Activation/Inactivation of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 2-Methyltetrahydro-β-carboline by Oxidative Enzymes." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/248608.

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Metabolic enzymes are involved in the activation/deactivation of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyiridine (MPTP) neurotoxin and its naturally occurring analogs 2-methyltetrahydro-β-carbolines. The metabolic profile and biotransformation of these protoxins by three enzymes, monoamine oxidase (MAO), cytochrome P450, and heme peroxidases (myeloperoxidase and lactoperoxidase), were investigated and compared. The metabolite profile differed among the enzymes investigated. MAO and heme peroxidases activated these substances to toxic pyridinium andβ-carbolinium species. MAO catalyzed the oxidation of MPTP to 1-methyl-4-phenyl-2,3-dihydropyridinium cation (MPDP+), whereas heme peroxidases catalyzed the oxidation of MPDP+to 1-methyl-4-phenylpyridinium (MPP+) and of 2-methyltetrahydro-β-carboline to 2-methyl-3,4-dihydro-β-carbolinium cation (2-Me-3,4-DHβC+). These substances were inactivated by cytochrome P450 2D6 throughN-demethylation and aromatic hydroxylation (MPTP) and aromatic hydroxylation (2-methyltetrahydro-β-carboline). In conclusion, the toxicological effects of these protoxins might result from a balance between the rate of their activation to toxic products (i.e.,N-methylpyridinium-MPP+and MPDP+- andN-methyl-β-carbolinium—βC+—) by MAO and heme peroxidases and the rate of inactivation (i.e.,N-demethylation, aromatic hydroxylation) by cytochrome P450 2D6.

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Ueno, Takafumi, Takahiro Ohki, and Yoshihito Watanabe. "Molecular engineering of cytochrome P450 and myoglobin for selective oxygenations." Journal of Porphyrins and Phthalocyanines 08, no. 03 (March 2004): 279–89. http://dx.doi.org/10.1142/s108842460400026x.

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Aspects of protein engineering of cytochrome P450 (P450) and myoglobin ( Mb ) to construct selective oxygenation catalysts have been described. Heme enzymes are known as biocatalysts for various oxidations but the design of substrate specificity has still remained one of the significant challenges because of dynamic nature of enzyme-substrate interactions. In particular, P450s are the most interesting targets among the heme enzymes because they are able to catalyze many types of monooxygenations such as hydroxylation, epoxidation, and sulfoxidation with high selectivity. Thus, many researchers have made efforts to convert the selectivity for natural substrates into that for unnatural substrates by several protein engineering approaches. On the other hand, we have reported a rational design of Mb to convert its oxygen carrier function into that of peroxidase or peroxygenase. The Mb mutants prepared in our work afford oxo-ferryl porphyrin radical cation (compound I) as observable species in Mb for the first time. Furthermore, some of the mutants we have constructed are useful for enantioselective oxygenations by oxygen transfer from the Mb -compound I to substrates.

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Bauer, Eckhart, Zuyu Guo, Yune-Fang Ueng, L. Chastine Bell, Darryl Zeldin, and F. Peter Guengerich. "Oxidation of Benzo[a]pyrene by Recombinant Human Cytochrome P450 Enzymes." Chemical Research in Toxicology 8, no. 1 (January 1995): 136–42. http://dx.doi.org/10.1021/tx00043a018.

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Ueng, Yune-Fang, Tsutomu Shimada, Hiroshi Yamazaki, and F. Peter Guengerich. "Oxidation of Aflatoxin B1 by Bacterial Recombinant Human Cytochrome P450 Enzymes." Chemical Research in Toxicology 8, no. 2 (March 1995): 218–25. http://dx.doi.org/10.1021/tx00044a006.

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Nguyen, Ngoc, Ngoc Cao, Thi Nguyen, Thien-Kim Le, Gun Cha, Soo-Keun Choi, Jae-Gu Pan, Soo-Jin Yeom, Hyung-Sik Kang, and Chul-Ho Yun. "Regioselective Hydroxylation of Phloretin, a Bioactive Compound from Apples, by Human Cytochrome P450 Enzymes." Pharmaceuticals 13, no. 11 (October 22, 2020): 330. http://dx.doi.org/10.3390/ph13110330.

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Phloretin, the major polyphenol compound in apples and apple products, is interesting because it shows beneficial effects on human health. It is mainly found as a form of glucoside, phlorizin. However, the metabolic pathway of phloretin in humans has not been reported. Therefore, identifying phloretin metabolites made in human liver microsomes and the human cytochrome P450 (P450) enzymes to make them is interesting. In this study, the roles of human liver P450s for phloretin oxidation were examined using human liver microsomes and recombinant human liver P450s. One major metabolite of phloretin in human liver microsomes was 3-OH phloretin, which is the same product of a bacterial CYP102A1-catalyzed reaction of phloretin. CYP3A4 and CYP2C19 showed kcat values of 3.1 and 5.8 min−1, respectively. However, CYP3A4 has a 3.3-fold lower Km value than CYP2C19. The catalytic efficiency of a CYP3A4-catalyzed reaction is 1.8-fold higher than a reaction catalyzed by CYP2C19. Whole-cell biotransformation with CYP3A4 was achieved 0.16 mM h−1 productivity for 3-OH phlorein from 8 mM phloretin at optimal condition. Phloretin was a potent inhibitor of CYP3A4-catalyzed testosterone 6β-hydroxylation activity. Antibodies against CYP3A4 inhibited up to 90% of the microsomal activity of phloretin 3-hydroxylation. The immunoinhibition effect of anti-2C19 is much lower than that of anti-CYP3A4. Thus, CYP3A4 majorly contributes to the human liver microsomal phloretin 3-hydroxylation, and CYP2C19 has a minor role.

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Zhang, Wei, Lei Du, Zepeng Qu, Xingwang Zhang, Fengwei Li, Zhong Li, Feifei Qi, et al. "Compartmentalized biosynthesis of mycophenolic acid." Proceedings of the National Academy of Sciences 116, no. 27 (June 17, 2019): 13305–10. http://dx.doi.org/10.1073/pnas.1821932116.

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Mycophenolic acid (MPA) from filamentous fungi is the first natural product antibiotic to be isolated and crystallized, and a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. However, some key biosynthetic mechanisms of such an old and important molecule have remained unclear. Here, we elucidate the MPA biosynthetic pathway that features both compartmentalized enzymatic steps and unique cooperation between biosynthetic and β-oxidation catabolism machineries based on targeted gene inactivation, feeding experiments in heterologous expression hosts, enzyme functional characterization and kinetic analysis, and microscopic observation of protein subcellular localization. Besides identification of the oxygenase MpaB′ as the long-sought key enzyme responsible for the oxidative cleavage of the farnesyl side chain, we reveal the intriguing pattern of compartmentalization for the MPA biosynthetic enzymes, including the cytosolic polyketide synthase MpaC′ andO-methyltransferase MpaG′, the Golgi apparatus-associated prenyltransferase MpaA′, the endoplasmic reticulum-bound oxygenase MpaB′ and P450-hydrolase fusion enzyme MpaDE′, and the peroxisomal acyl-coenzyme A (CoA) hydrolase MpaH′. The whole pathway is elegantly comediated by these compartmentalized enzymes, together with the peroxisomal β-oxidation machinery. Beyond characterizing the remaining outstanding steps of the MPA biosynthetic steps, our study highlights the importance of considering subcellular contexts and the broader cellular metabolism in natural product biosynthesis.

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Wong, Siew Hoon, Stephen G. Bell, and James J. De Voss. "P450 catalysed dehydrogenation." Pure and Applied Chemistry 89, no. 6 (June 27, 2017): 841–52. http://dx.doi.org/10.1515/pac-2016-1216.

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Abstract Cytochrome P450s belong to a superfamily of enzymes that catalyse a wide variety of oxidative transformations. Hydroxylation is one the most thoroughly investigated of all identified P450-catalysed reactions whilst dehydrogenation has been relatively much less explored to date. P450-catalysed dehydrogenation is often found to occur with hydroxylation and thus, it was initially suspected to be a stepwise process consisting of hydroxylation and subsequent dehydration to yield the final olefin product. This theory has been proven to be invalid and the olefin was shown to be the direct product of a P450-catalysed reaction. This interesting reaction plays a vital role in the metabolism of xenobiotics and the biosynthesis of endogenous compounds, including a number of steroids. A number of well-known examples of P450 mediated dehydrogenation, including those in the metabolism of valproic acid, capsaicin and 3-methylindole and those in the biosynthesis of plant and fungal sterols are discussed in this review.

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Urban, Philippe, Gilles Truan, and Denis Pompon. "High-Throughput Functional Screening of Steroid Substrates with Wild-Type and Chimeric P450 Enzymes." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/764102.

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The promiscuity of a collection of enzymes consisting of 31 wild-type and synthetic variants of CYP1A enzymes was evaluated using a series of 14 steroids and 2 steroid-like chemicals, namely, nootkatone, a terpenoid, and mifepristone, a drug. For each enzyme-substrate couple, the initial steady-state velocity of metabolite formation was determined at a substrate saturating concentration. For that, a high-throughput approach was designed involving automatized incubations in 96-well microplate with sixteen 6-point kinetics per microplate and data acquisition using LC/MS system accepting 96-well microplate for injections. The resulting dataset was used for multivariate statistics aimed at sorting out the correlations existing between tested enzyme variants and ability to metabolize steroid substrates. Functional classifications of both CYP1A enzyme variants and steroid substrate structures were obtained allowing the delineation of global structural features for both substrate recognition and regioselectivity of oxidation.

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Sarkar, Md Raihan, and Stephen G. Bell. "Complementary and selective oxidation of hydrocarbon derivatives by two cytochrome P450 enzymes of the same family." Catalysis Science & Technology 10, no. 17 (2020): 5983–95. http://dx.doi.org/10.1039/d0cy01040e.

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The cytochrome P450 enzymes CYP101B1 and CYP101C1, from a Novosphingobium bacterium, can efficiently hydroxylate hydrocarbon derivatives containing a carbonyl moiety. Cyclic ketones (C9 to C15) were oxidised with contrasting yet high selectivity.

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Indra, Radek, Katarína Vavrová, Petr Pompach, Zbyněk Heger, and Petr Hodek. "Identification of Enzymes Oxidizing the Tyrosine Kinase Inhibitor Cabozantinib: Cabozantinib Is Predominantly Oxidized by CYP3A4 and Its Oxidation Is Stimulated by cyt b5 Activity." Biomedicines 8, no. 12 (November 28, 2020): 547. http://dx.doi.org/10.3390/biomedicines8120547.

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Herein, the in vitro metabolism of tyrosine kinase inhibitor cabozantinib, the drug used for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma, was studied using hepatic microsomal samples of different human donors, human recombinant cytochromes P450 (CYPs), flavin-containing mono-oxygenases (FMOs) and aldehyde oxidase. After incubation with human microsomes, three metabolites, namely cabozantinib N-oxide, desmethyl cabozantinib and monohydroxy cabozantinib, were detected. Significant correlations were found between CYP3A4 activity and generation of all metabolites. The privileged role of CYP3A4 was further confirmed by examining the effect of CYP inhibitors and by human recombinant enzymes. Only four of all tested human recombinant cytochrome P450 were able to oxidize cabozantinib, and CYP3A4 exhibited the most efficient activity. Importantly, cytochrome b5 (cyt b5) stimulates the CYP3A4-catalyzed formation of cabozantinib metabolites. In addition, cyt b5 also stimulates the activity of CYP3A5, whereas two other enzymes, CYP1A1 and 1B1, were not affected by cyt b5. Since CYP3A4 exhibits high expression in the human liver and was found to be the most efficient enzyme in cabozantinib oxidation, we examined the kinetics of this oxidation. The present study provides substantial insights into the metabolism of cabozantinib and brings novel findings related to cabozantinib pharmacokinetics towards possible utilization in personalized medicine.

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Hyland, R., B. C. Jones, and D. A. Smith. "Identification of the Cytochrome P450 Enzymes Involved in theN-Oxidation of Voriconazole." Drug Metabolism and Disposition 31, no. 5 (May 1, 2003): 540–47. http://dx.doi.org/10.1124/dmd.31.5.540.

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Алиева, Г. Р. "The role of alcohol metabolism enzymes in chronic alcoholic pancreatitis (review)." Nauchno-prakticheskii zhurnal «Medicinskaia genetika, no. 4(225) (April 30, 2021): 3–8. http://dx.doi.org/10.25557/2073-7998.2021.04.3-8.

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Алкогольный метаболизм является решающим биологическим фактором, значительно влияющим на злоупотребление алкоголем, развитие алкоголизма и алкогольное повреждение органов. Основной путь метаболизма этанола - это алкогольдегидрогеназный путь превращения в ацетальдегид, который переходит в митохондрии и окисляется до уксусной кислоты. Через этот путь проходит 80-90% всего этанола. За окисление 10-20% этанола отвечает алкогольоксидаза (цитохром P450), также называемая «микросомальная этанолокисляющая система» (MEOS/CYP2E1). Основные ферменты метаболизма алкоголя проявляют генетический полиморфизм и этническую изменчивость. В данном обзоре представлены достижения последних десятилетий в понимании функциональных полиморфных локусов генов ADH и ALDH и их метаболических, физиологических и клинических корреляций. Alcohol metabolism is a decisive biological factor that significantly affects alcohol abuse, the development of alcoholism and alcohol damage to organs. The main pathway of ethanol metabolism is the alcohol dehydrogenase pathway to acetaldehyde, which passes into the mitochondria and is oxidized to acetic acid. 80-90% of all ethanol passes through this path. Alcohol oxidase (cytochrome P450), also called microsomal ethanol oxidation system (MEOS/CYP2E1), is responsible for the oxidation of 10-20% of ethanol. The main alcohol metabolizing enzymes exhibit genetic polymorphism and ethnic variation. This review presents recent advances in understanding the functional polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and their metabolic, physiological, and clinical correlations.

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Fish, Richard H. "A Bioorganometallic Chemistry Overview: From Cytochrome P450 Enzyme Metabolism of Organotin Compounds to Organorhodium-Hydroxytamoxifen Complexes with Potential Anti-Cancer Properties; A 37 Year Perspective at the Interface of Organometallic Chemistry and Biology." Australian Journal of Chemistry 63, no. 11 (2010): 1505. http://dx.doi.org/10.1071/ch10239.

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A 37 year perspective on bioorganometallic chemistry studies, which included metabolism of organotin compounds with cytochrome P450 enzymes, and their biomimics; reactions of organorhodium aqua complexes with nucleobases, nucleosides, and nucleotides; supramolecular organorhodium-nucleobase complexes as hosts for aromatic amino acid and aromatic carboxylic acid guests; regioselective reduction of NAD+ biomimics with an organorhodium hydride; tandem catalysis of an organorhodium hydride reduction to provide a 1,4-NADH biomimic for horse liver dehydrogenase stereoselective reduction of achiral ketones to chiral alcohols, and oxidation reactions with cytochrome P450 enzymes; and organorhodium-hydroxytamoxifen pharmaceuticals, will be presented. Each of these areas of bioorganometallic chemistry will be briefly discussed in this personal synopsis of the new, important, and exciting field of bioorganometallic chemistry, and its impact on metal-based drug research.

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Kelly, Paul P., Anja Eichler, Susanne Herter, David C. Kranz, Nicholas J. Turner, and Sabine L. Flitsch. "Active site diversification of P450cam with indole generates catalysts for benzylic oxidation reactions." Beilstein Journal of Organic Chemistry 11 (September 22, 2015): 1713–20. http://dx.doi.org/10.3762/bjoc.11.186.

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Cytochrome P450 monooxygenases are useful biocatalysts for C–H activation, and there is a need to expand the range of these enzymes beyond what is naturally available. A panel of 93 variants of active self-sufficient P450cam[Tyr96Phe]-RhFRed fusion enzymes with a broad diversity in active site amino acids was developed by screening a large mutant library of 16,500 clones using a simple, highly sensitive colony-based colorimetric screen against indole. These mutants showed distinct fingerprints of activity not only when screened in oxidations of substituted indoles but also for unrelated oxidations such as benzylic hydroxylations.

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Wang, Ting, Liang Liang Wang, and Xun Li. "Cloning, Expression and Characterization of a Monooxygenase P450BM3 from Bacillus megaterium ALA2." Advanced Materials Research 518-523 (May 2012): 5533–38. http://dx.doi.org/10.4028/www.scientific.net/amr.518-523.5533.

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Cytochrome P450 monooxygenases are enzymes which are capable of oxidising saturated and unsaturated substrates. P450BM3 from Bacillus megaterium is one of this family. For the ﬁrst time, the cyp gene for coding P450BM3 from B. megaterium ALA2 has been cloned and expressed in Escherichia coli. The recombinant enzyme is 120 kDa, containing 1049 aa. The highest activity of purified enzyme is 14.8 U/mg towards palmitic acid by monitoring the NADPH oxidation. The optimal pH and temperature were 9.0 and 40°C. The enzyme has higher activity towards linoleic acid, and 2-Methyl-7-octadecene can also be catalyzed which is a precursor of displar.

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Teoh, Keat H., Devin R. Polichuk, Darwin W. Reed, and Patrick S. Covello. "Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annuaThis paper is one of a selection of papers published in a Special Issue from the National Research Council of Canada – Plant Biotechnology Institute." Botany 87, no. 6 (June 2009): 635–42. http://dx.doi.org/10.1139/b09-032.

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Limitations in the supply of the antimalarial compound artemisinin from Artemisia annua L. have led to an interest in understanding its biosynthesis and enhancing its production. Recent biochemical and molecular genetic data have implicated dihydroartemisinic aldehyde as a precursor to the corresponding acid, which is then converted to artemisinin. Thus, it is important to understand the enzyme or enzymes involved in dihydroartemisinic aldehyde oxidation. Given its activity on artemisinic aldehyde, the cytochrome P450 CYP71AV1 was investigated for its ability to oxidize dihydroartemisinic aldehyde. However, no net activity was detected. In a search for alternative enzymes that could catalyze the oxidation, an expressed sequence tag (EST) collection from A. annua was investigated for relevant cDNAs. This led to the isolation of a full-length cDNA encoding an aldehyde dehydrogenase homologue, named Aldh1, which is highly expressed in trichomes. Expression of the cDNA in E. coli and characterization of the purified recombinant enzyme revealed that the gene product catalyses the NAD(P)-dependent oxidation of the putative artemisinin precursors, artemisinic and dihydroartemsinic aldehydes, and a limited range of other aldehydes. The observed enzyme activity of Aldh1 and the expression pattern of the corresponding gene suggest a role in artemisinin biosynthesis in the glandular secretory trichomes of A. annua.

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Zilly, Felipe E., Juan P. Acevedo, Wojciech Augustyniak, Alfred Deege, Ulrich W. Häusig, and Manfred T. Reetz. "Tuning a P450 Enzyme for Methane Oxidation." Angewandte Chemie 123, no. 12 (February 17, 2011): 2772–76. http://dx.doi.org/10.1002/ange.201006587.

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Zilly, Felipe E., Juan P. Acevedo, Wojciech Augustyniak, Alfred Deege, Ulrich W. Häusig, and Manfred T. Reetz. "Tuning a P450 Enzyme for Methane Oxidation." Angewandte Chemie International Edition 50, no. 12 (March 14, 2011): 2720–24. http://dx.doi.org/10.1002/anie.201006587.

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Rasooly, Reuven, Darshan S. Kelley, Jeff Greg, and Bruce E. Mackey. "Dietary trans 10, cis 12-conjugated linoleic acid reduces the expression of fatty acid oxidation and drug detoxification enzymes in mouse liver." British Journal of Nutrition 97, no. 1 (January 2007): 58–66. http://dx.doi.org/10.1017/s0007114507257745.

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Mice fed diets containing trans 10, cis 12 (t10, c12)-conjugated linoleic acid (CLA) develop fatty livers and the role of hepatic fatty acid oxidation enzymes in this development is not well defined. We examined the effects of dietary cis 9, trans 11-CLA (c9, t11-CLA) and t10, c12-CLA on the expression of hepatic genes for fatty acid metabolism. Female mice, 8 weeks old, (six animals per group) were fed either a control diet or diets supplemented with 0·5 % c9, t11- or t10, c12-CLA for 8 weeks. DNA microarray analysis showed that t10, c12-CLA increased the expression of 278 hepatic genes and decreased those of 121 genes (>2-fold); c9, t11-CLA increased expression of twenty-two genes and decreased those of nine. Real-time PCR confirmed that t10, c12-CLA reduced by the expression of fatty acid oxidation genes including flavin monooxygenase (FMO)-3 95 %, cytochrome P450 (cyt P450) 69 %, carnitine palmitoyl transferase 1a 77 %, acetyl CoA oxidase (ACOX) 50 % and PPARα 65 %; it increased the expression of fatty acid synthase by 3·5-fold (P < 0·05 for all genes, except ACOX P = 0·08). It also reduced the enzymatic activity of hepatic microsomal FMO by 40 % and the FMO3 specific protein by 67 %. c9, t11-CLA reduced FMO3 and cyt P450 expression by 61 % (P = 0·001) and 38 % (P = 0·06) and increased steoryl CoA desaturase transcription by 5·9-fold (P = 0·07). Both decreased fatty acid oxidation and increased fatty acid synthesis seem to contribute to the CLA-induced fatty liver. Since FMO and cyt P450 are also involved in drug detoxification, suppression of the transcription of these genes by CLA may have other health consequences besides development of fatty liver.

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Ramirez-Ramirez, Joaquin, Javier Martin-Diaz, Nina Pastor, Miguel Alcalde, and Marcela Ayala. "Exploring the Role of Phenylalanine Residues in Modulating the Flexibility and Topography of the Active Site in the Peroxygenase Variant PaDa-I." International Journal of Molecular Sciences 21, no. 16 (August 10, 2020): 5734. http://dx.doi.org/10.3390/ijms21165734.

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Unspecific peroxygenases (UPOs) are fungal heme-thiolate enzymes able to catalyze a wide range of oxidation reactions, such as peroxidase-like, catalase-like, haloperoxidase-like, and, most interestingly, cytochrome P450-like. One of the most outstanding properties of these enzymes is the ability to catalyze the oxidation a wide range of organic substrates (both aromatic and aliphatic) through cytochrome P450-like reactions (the so-called peroxygenase activity), which involves the insertion of an oxygen atom from hydrogen peroxide. To catalyze this reaction, the substrate must access a channel connecting the bulk solution to the heme group. The composition, shape, and flexibility of this channel surely modulate the catalytic ability of the enzymes in this family. In order to gain an understanding of the role of the residues comprising the channel, mutants derived from PaDa-I, a laboratory-evolved UPO variant from Agrocybe aegerita, were obtained. The two phenylalanine residues at the surface of the channel, which regulate the traffic towards the heme active site, were mutated by less bulky residues (alanine and leucine). The mutants were experimentally characterized, and computational studies (i.e., molecular dynamics (MD)) were performed. The results suggest that these residues are necessary to reduce the flexibility of the region and maintain the topography of the channel.

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Ji, Li, Jing Zhang, Weiping Liu, and Sam P. de Visser. "Metabolism of Halogenated Alkanes by Cytochrome P450 enzymes. Aerobic Oxidation versus Anaerobic Reduction." Chemistry - An Asian Journal 9, no. 4 (February 5, 2014): 1175–82. http://dx.doi.org/10.1002/asia.201301608.

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Wierzbicki, A. S. "Peroxisomal disorders affecting phytanic acid α-oxidation: a review." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 881–86. http://dx.doi.org/10.1042/bst0350881.

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Peroxisomes are involved in the synthesis and degradation of complex fatty acids. They contain enzymes involved in the α-, β- and ω-oxidation pathways for fatty acids. Investigation of these pathways and the diseases associated with mutations in enzymes involved in the degradation of phytanic acid have led to the clarification of the pathophysiology of Refsum's disease, rhizomelic chondrodysplasia and AMACR (α-methylacyl-CoA racemase) deficiency. This has highlighted the role of an Fe(II)- and 2-oxoglutarate-dependent oxygenases [PhyH (phytanoyl-CoA 2-hydroxylase), also known as PAHX], thiamin-dependent lyases (phytanoyl-CoA lyase) and CYP (cytochrome P450) family 4A in fatty acid metabolism. The differential regulation and biology of these pathways is suggesting novel ways to treat the neuro-ophthalmological sequelae of Refsum's disease. More recently, the discovery that AMACR and other peroxisomal β-oxidation pathway enzymes are highly expressed in prostate and renal cell cancers has prompted active investigation into the role of these oxidation pathways and the peroxisome in the progression of obesity- and insulin resistance-related cancers.

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Journal articles on the topic 'Oxidation with P450 enzymes'

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