Journal articles: 'Cytochrome P450'

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Bandiera, S. "Expression and catalysis of sex-specific cytochrome P450 isozymes in rat liver." Canadian Journal of Physiology and Pharmacology 68, no. 6 (June 1, 1990): 762–68. http://dx.doi.org/10.1139/y90-117.

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Research interest in the study of cytochromes P450 has recently been shifting to the characterization of "constitutively" expressed isozymes from that of the inducible forms. Several "constitutive" cytochrome P450 isozymes have been purified from rat liver including five immunochemically related proteins designated cytochromes P450f, P450g, P450h, P450i, and P450k. These hemoproteins have been identified as distinct isozymes on the basis of spectral, electrophoretic, and catalytic properties and NH2-terminal sequence analysis. Purification and immunoquantitation studies have indicated that these isozymes are expressed in a developmental as well as sex-related manner, and are relatively refractory to induction by xenobiotics. Cytochromes P450h and P450g are male-specific proteins, cytochrome P450i is a female-specific isozyme, while cytochromes P450f and P450k are present in both male and female adult rats. In addition, the expression of cytochrome P450g was shown to segregate into two phenotypes in outbred rats. Genetic studies utilizing inbred strains have indicated that the gene responsible for inheritance of high levels of cytochrome P450g is autosomal. Although considerable progress has been made in understanding the role of gonadal hormones and growth hormone in the hepatic regulation of cytochromes P450g, P450h, and P450i in particular, the physiological significance of the "constitutive" isozymes in the liver remains largely unresolved.Key words: cytochrome P450, regulation, constitutive, liver, sex differences.

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Ershov, P. V., Yu V. Mezentsev, E. O. Yablokov, L. A. Kalushskiy, A. V. Florinskaya, A. V. Svirid, A. A. Gilep, S. A. Usanov, A. E. Medvedev, and A. S. Ivanov. "Study specificity of isatin interactions with P450 cytochromes." Biomeditsinskaya Khimiya 64, no. 1 (January 2018): 61–65. http://dx.doi.org/10.18097/pbmc20186401061.

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Cytochrome P450-dependent monooxygenase systems exist basically in all living organisms, where they perform various important functions. The coordinated functioning of these systems involves many proteins participating in different protein-protein interactions (PPI). Previously, we have found that the endogenous non-peptide bioregulator isatin (indoledione-2,3), synthesized from indole by means of certain cytochromes P450 (e.g. P450 2E1, P450 2C19, P450 2A6) regulates affinity of some PPI. In this work, an attempt has been undertaken to register a direct interaction of isatin with a set of different proteins related to the functioning of cytochrome P450-dependent monooxygenase: five isoforms of cytochromes P450, two isoforms of cytochrome b5, cytochrome P450 reductase, adrenodoxin, adrenodoxin reductase and ferrochelatase. The study has shown that isatin binds specifically only to cytochromes P450 with high affinity (the equilibrium dissociation constant (Kd) is about 10-8 M).

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Godbole, Rucha C., Anupama A. Pable, and Vitthal T. Barvkar. "Transcriptome-wide identification, characterization, and phylogenomic analysis of cytochrome P450s from Nothapodytes nimmoniana reveal candidate genes involved in the camptothecin biosynthetic pathway." Genome 64, no. 1 (January 2021): 1–14. http://dx.doi.org/10.1139/gen-2020-0067.

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The plant Nothapodytes nimmoniana is an important source of camptothecin (CPT), an anticancer compound widely used in the treatment of colorectal, lung, and ovarian cancers. CPT is biosynthesized by the combination of the seco-iridoid and indole pathways in plants. The majority of the biosynthetic steps and associated genes still remain unknown. Certain reactions in the seco-iridoid pathway are catalyzed by cytochrome P450 enzymes. Hence, identifying transcriptionally active cytochrome P450 genes becomes essential in the elucidation of the CPT biosynthetic pathway. Here, we report the identification of 94 cytochrome P450s from the assembled transcriptomic data from leaf and root tissues of N. nimmoniana. The identified cytochrome P450 genes were full length and possessed all four conserved characteristic signature motifs of cytochrome P450 genes. Phylogenetic analysis of the protein sequences revealed their evolution and diversification and further categorized them into A-type (52.12%) and non-A-type (47.87%) cytochrome P450s. These 94 sequences represent 38 families and 63 subfamilies of cytochrome P450s. We also compared the transcriptional activity of identified cytochrome P450s with the expression of their homologs in the CPT-producing plant Ophiorrhiza pumila. Based on expression profiles and quantitative PCR validation, we propose NnCYP81CB1 and NnCYP89R1 as candidate cytochrome P450 genes involved in camptothecin biosynthesis in N. nimmoniana.

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Iwasaki, M., R. L. P. Lindberg, R. O. Juvonen, and M. Negishi. "Site-directed mutagenesis of mouse steroid 7α-hydroxylase (cytochrome P-4507α): role of residue-209 in determining steroid-cytochrome P-450 interaction." Biochemical Journal 291, no. 2 (April 15, 1993): 569–73. http://dx.doi.org/10.1042/bj2910569.

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We have cloned a cDNA encoding mouse steroid 7 alpha-hydroxylase P450(7) alpha (cytochrome P-450(7) alpha) and expressed it in Saccharomyces cerevisiae. Mouse P450(7) alpha is 70% identical in its amino acid sequence with the mouse steroid 15 alpha-hydroxylase P450(15) alpha (2A4). The Leu at position 209 of P450(15) alpha is the most important residue to determine the steroid hydroxylase activity of the P450 [Lindberg and Negishi (1989) Nature (London) 339, 632-634]. The P450(7) alpha contains Asn at the position corresponding to the Leu-209 of P450(15) alpha, although both P450s hydroxylate testosterone. The CO-reduced P450(7) alpha complex is unstable, so that it is quickly converted into the inactive P420, whereas the P450(15) alpha is very stable. The P450(7) alpha, however, is stabilized either by addition of testosterone or by a mutation of Asn-209 to Leu. The mutant P450(7) alpha displays a 17-fold lower Vmax. value than the wild-type enzyme. Unexpectedly, it also has 3-fold lower Km and Kd values. Residue 209 in P450(7) alpha, therefore, appears to be located at a critical site of the haem-substrate-binding pocket. Corticosterone inhibits the testosterone 7 alpha-hydroxylase activity of the wild-type P450(7) alpha, whereas it does not inhibit the mutant P450(7) alpha. Conversely, the P450(15) alpha activity becomes inhibited by corticosterone upon the replacement of Leu-209 by Asn. In addition, this mutation increases the corticosterone 15 alpha-hydroxylase activity of P450(15) alpha at least 20-fold. Whereas the inhibition by corticosterone depends on the presence of Asn at position 209, deoxycorticosterone inhibits the activities of the P450s regardless of the type of residue at 209. The results indicate, therefore, that the identity of residue 209 determines the affinity as well as specificity of steroid binding to both P450(7) alpha and P450(15) alpha.

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Rwere, Freeborn, Sangchoul Im, and Lucy Waskell. "The FMN “140s Loop” of Cytochrome P450 Reductase Controls Electron Transfer to Cytochrome P450." International Journal of Molecular Sciences 22, no. 19 (September 30, 2021): 10625. http://dx.doi.org/10.3390/ijms221910625.

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Cytochrome P450 reductase (CYPOR) provides electrons to all human microsomal cytochrome P450s (cyt P450s). The length and sequence of the “140s” FMN binding loop of CYPOR has been shown to be a key determinant of its redox potential and activity with cyt P450s. Shortening the “140s loop” by deleting glycine-141(ΔGly141) and by engineering a second mutant that mimics flavo-cytochrome P450 BM3 (ΔGly141/Glu142Asn) resulted in mutants that formed an unstable anionic semiquinone. In an attempt to understand the molecular basis of the inability of these mutants to support activity with cyt P450, we expressed, purified, and determined their ability to reduce ferric P450. Our results showed that the ΔGly141 mutant with a very mobile loop only reduced ~7% of cyt P450 with a rate similar to that of the wild type. On the other hand, the more stable loop in the ΔGly141/Glu142Asn mutant allowed for ~55% of the cyt P450 to be reduced ~60% faster than the wild type. Our results reveal that the poor activity of the ΔGly141 mutant is primarily accounted for by its markedly diminished ability to reduce ferric cyt P450. In contrast, the poor activity of the ΔGly141/Glu142Asn mutant is presumably a consequence of the altered structure and mobility of the “140s loop”.

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Hodek, Petr, Tomáš Koblas, Helena Rýdlová, Božena Kubíčková, Miroslav Šulc, Jiří Hudeček, and Marie Stiborová. "Chicken Egg Yolk as an Excellent Source of Highly Specific Antibodies Against Cytochromes P450." Collection of Czechoslovak Chemical Communications 69, no. 3 (2004): 659–73. http://dx.doi.org/10.1135/cccc20040659.

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Using chicken antibodies IgY (purified from egg yolks) against mammalian cytochromes P450 and by means of cytochrome P450 marker substrates, we found for the first time the presence of hepatopancreatic cytochrome P450 in crayfishOrconectes limosus(an inducible cytochrome P450 2B-like enzyme) and we were able to detect and quantify cytochrome P450 1A1 in microsomes of human livers. Expression levels of cytochrome P450 1A1 in human livers constituted less than 0.6% of the total hepatic cytochrome P450 complement. The results obtained in our study are clear examples that chicken IgY are suitable for cytochrome P450 detection and quantification. Due to the evolutionary distance, chicken IgY reacts with more epitopes on a mammalian antigen, which gives an amplification of the signal. Moreover, this approach offers many advantages over common mammalian antibody production since chicken egg is an abundant source of antibodies (about 100 mg IgY/yolk) and the egg collection is a non-invasive technique. In the case of antibodies against cytochrome P450 2B4, we documented fast and steady production of highly specific immunoglobulins. Thus, chicken antibodies should be considered as a good alternative to and/or superior substitute for conventional polyclonal antibody produced in mammals.

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Munro, A. W., K. J. McLean, K. R. Marshall, A. J. Warman, G. Lewis, O. Roitel, M. J. Sutcliffe, et al. "Cytochromes P450: novel drug targets in the war against multidrug-resistant Mycobacterium tuberculosis." Biochemical Society Transactions 31, no. 3 (June 1, 2003): 625–30. http://dx.doi.org/10.1042/bst0310625.

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Novel drug strategies are desperately needed to combat the global threat posed by multidrug-resistant strains of Mycobacterium tuberculosis (Mtb). The genome sequence of Mtb has revealed an unprecedented number of cytochrome P450 enzymes in a prokaryote, suggesting fundamental physiological roles for many of these enzymes. Several azole drugs (known inhibitors of cytochromes P450) have been shown to have potent anti-mycobacterial activity, and the most effective azoles have extremely tight binding constants for one of the Mtb P450s (CYP121). The structure of CYP121 has been determined at atomic resolution, revealing novel features of P450 structure, including mixed haem conformations and putative proton-relay pathways from protein surface to haem iron. The structure provides both a platform for investigation of structure/mechanism of cytochrome P450, and for design of inhibitor molecules as novel anti-tubercular agents.

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Hrubý, Kamil, Eva Anzenbacherová, Pavel Anzenbacher, and Milan Nobilis. "Biotransformation of Benfluron by Rat Hepatic Cytochrome P450. Identification of Individual CYP-Enzymes Involved in Biotransformation of Benfluron, Prospective Antineoplastic Based on Benzo[c]fluorene." Collection of Czechoslovak Chemical Communications 65, no. 8 (2000): 1374–86. http://dx.doi.org/10.1135/cccc20001374.

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Benfluron, 5-[2-(dimethylamino)ethoxy]-7H-benzo[c]fluoren-7-one hydrochloride, a prospective antineoplastic agent, is metabolised by cytochromes P450 to N-demethyl and 9-hydroxy derivatives. To prove the participation of individual cytochrome P450 isoforms in formation of these metabolites, selective induction of cytochromes P450, inhibition of benfluron biotransformation using inhibitors specific for individual cytochromes P450, and inhibition by benfluron of "marker" enzyme activities characteristic of certain cytochromes P450 were used. N-Demethylbenfluron appears to be formed mainly by the cytochromes P450 of the 3A, 2B and 2C subfamilies with possible participation of the isoform 2E1; 9-hydroxybenfluron is formed with participation of cytochromes P450 belonging to 1A, and most probably to 3A and 2E1 enzymes. The fact that benfluron is in this respect a relatively promiscuous substrate may be an advantage because its metabolism should not be influenced by the absence or low activity of some cytochrome P450 isoforms and by possible drug interactions.

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Shumyantseva, Victoria V., Tatiana V. Bulko, Polina I. Koroleva, Evgeniya V. Shikh, Anna A. Makhova, Maryia S. Kisel, Irina V. Haidukevich, and Andrei A. Gilep. "Human Cytochrome P450 2C9 and Its Polymorphic Modifications: Electroanalysis, Catalytic Properties, and Approaches to the Regulation of Enzymatic Activity." Processes 10, no. 2 (February 17, 2022): 383. http://dx.doi.org/10.3390/pr10020383.

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The electrochemical properties of cytochrome P450 2C9 (CYP2C9) and polymorphic modifications P450 2C9*2 (CYP2C9*2) and P450 2C9*3 (CYP2C9*3) were studied. To analyze the comparative electrochemical and electrocatalytic activity, the enzymes were immobilized on electrodes modified with a membrane-like synthetic surfactant (didodecyldimethylammonium bromide (DDAB)). An adequate choice of the type of modified electrode was confirmed by cyclic voltammetry of cytochromes P450 under anaerobic conditions, demonstrating well-defined peaks of reduction and oxidation of the heme iron. The midpoint potential, Emid, of cytochrome P450 2C9 is −0.318 ± 0.01 V, and Emid = −0.324 ± 0.01 V, and Emid = −0.318 ± 0.03 V for allelic variant 2C9*2 and allelic variant 2C9*3, respectively. In the presence of substrate diclofenac under aerobic conditions, cytochrome P450 2C9 and its polymorphic modifications P450 2C9*2 and P450 2C9*3 exhibit catalytic properties. Stimulation of the metabolism of diclofenac by cytochrome P450 2C9 in the presence of antioxidant medications mexidol and taurine was shown.

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Pratiwi, R. A., N. S. W. Yahya, and Y. Chi. "Bio function of Cytochrome P450 on fungus: a review." IOP Conference Series: Earth and Environmental Science 959, no. 1 (January 1, 2022): 012023. http://dx.doi.org/10.1088/1755-1315/959/1/012023.

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Abstract Cytochrome P450 is the superfamily of proteins involved in the metabolism of organisms, including fungi. Fungal have more diverse P450 families than plants, animals, or bacteria. Research on fungal P450 has blossomed and become an important area in biology and ecology. Cytochrome P450 could be detoxifying natural and environmental contaminants to survive in several ecological niches. Furthermore, the presence of the fungal Cytochrome P450 as an antifungal drug target is a promising approach for the controlling of pest and plant pathogenic fungi. To date, numerous studies have revealed the annotation of diverse P450 followed by an elucidation of P450 functions. This mini-review starts with some basic information of P450s on fungi, then discusses the incredible bio function of characterized fungal P450.

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McLean, K. J., M. Sabri, K. R. Marshall, R. J. Lawson, D. G. Lewis, D. Clift, P. R. Balding, et al. "Biodiversity of cytochrome P450 redox systems." Biochemical Society Transactions 33, no. 4 (August 1, 2005): 796–801. http://dx.doi.org/10.1042/bst0330796.

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P450s (cytochrome P450 mono-oxygenases) are a superfamily of haem-containing mono-oxygenase enzymes that participate in a wide range of biochemical pathways in different organisms from all of the domains of life. To facilitate their activity, P450s require sequential delivery of two electrons passed from one or more redox partner enzymes. Although the P450 enzymes themselves show remarkable similarity in overall structure, it is increasingly apparent that there is enormous diversity in the redox partner systems that drive the P450 enzymes. This paper examines some of the recent advances in our understanding of the biodiversity of the P450 redox apparatus, with a particular emphasis on the redox systems in the pathogen Mycobacterium tuberculosis.

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Reed, James R., J. Patrick Connick, Dongmei Cheng, George F. Cawley, and Wayne L. Backes. "Effect of homomeric P450–P450 complexes on P450 function." Biochemical Journal 446, no. 3 (August 28, 2012): 489–97. http://dx.doi.org/10.1042/bj20120636.

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Previous studies have shown that the presence of one P450 enzyme can affect the function of another. The goal of the present study was to determine if P450 enzymes are capable of forming homomeric complexes that affect P450 function. To address this problem, the catalytic activities of several P450s were examined in reconstituted systems containing NADPH–POR (cytochrome P450 reductase) and a single P450. CYP2B4 (cytochrome P450 2B4)-, CYP2E1 (cytochrome P450 2E1)- and CYP1A2 (cytochrome P450 1A2)-mediated activities were measured as a function of POR concentration using reconstituted systems containing different concentrations of P450. Although CYP2B4-dependent activities could be explained by a simple Michaelis–Menten interaction between POR and CYP2B4, both CYP2E1 and CYP1A2 activities generally produced a sigmoidal response as a function of [POR]. Interestingly, the non-Michaelis behaviour of CYP1A2 could be converted into a simple mass-action response by increasing the ionic strength of the buffer. Next, physical interactions between CYP1A2 enzymes were demonstrated in reconstituted systems by chemical cross-linking and in cellular systems by BRET (bioluminescence resonance energy transfer). Cross-linking data were consistent with the kinetic responses in that both were similarly modulated by increasing the ionic strength of the surrounding solution. Taken together, these results show that CYP1A2 forms CYP1A2–CYP1A2 complexes that exhibit altered catalytic activity.

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McFadyen, Morag C. E., William T. Melvin, and Graeme I. Murray. "Cytochrome P450 enzymes: Novel options for cancer therapeutics." Molecular Cancer Therapeutics 3, no. 3 (March 1, 2004): 363–71. http://dx.doi.org/10.1158/1535-7163.363.3.3.

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Abstract The concept of overexpression of individual forms of cytochrome P450 enzymes in tumor cells is now becoming well recognized. Indeed, a growing body of research highlights the overexpression of P450s, particularly CYP1B1, in tumor cells as representing novel targets for anticancer therapy. The purpose of this review is to outline the novel therapeutic options and opportunities arising from both enhanced endogenous expression of cytochrome P450 in tumors and cytochrome P450-mediated gene therapy.

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Lamb, David C., Alec H. Follmer, Jared V. Goldstone, David R. Nelson, Andrew G. Warrilow, Claire L. Price, Marie Y. True, Steven L. Kelly, Thomas L. Poulos, and John J. Stegeman. "On the occurrence of cytochrome P450 in viruses." Proceedings of the National Academy of Sciences 116, no. 25 (June 5, 2019): 12343–52. http://dx.doi.org/10.1073/pnas.1901080116.

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Genes encoding cytochrome P450 (CYP; P450) enzymes occur widely in the Archaea, Bacteria, and Eukarya, where they play important roles in metabolism of endogenous regulatory molecules and exogenous chemicals. We now report that genes for multiple and unique P450s occur commonly in giant viruses in the Mimiviridae, Pandoraviridae, and other families in the proposed order Megavirales. P450 genes were also identified in a herpesvirus (Ranid herpesvirus 3) and a phage (Mycobacterium phage Adler). The Adler phage P450 was classified as CYP102L1, and the crystal structure of the open form was solved at 2.5 Å. Genes encoding known redox partners for P450s (cytochrome P450 reductase, ferredoxin and ferredoxin reductase, and flavodoxin and flavodoxin reductase) were not found in any viral genome so far described, implying that host redox partners may drive viral P450 activities. Giant virus P450 proteins share no more than 25% identity with the P450 gene products we identified in Acanthamoeba castellanii, an amoeba host for many giant viruses. Thus, the origin of the unique P450 genes in giant viruses remains unknown. If giant virus P450 genes were acquired from a host, we suggest it could have been from an as yet unknown and possibly ancient host. These studies expand the horizon in the evolution and diversity of the enormously important P450 superfamily. Determining the origin and function of P450s in giant viruses may help to discern the origin of the giant viruses themselves.

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Kim, Donghak, and F. Peter Guengerich. "CYTOCHROME P450 ACTIVATION OF ARYLAMINES AND HETEROCYCLIC AMINES." Annual Review of Pharmacology and Toxicology 45, no. 1 (September 22, 2005): 27–49. http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100010.

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Arylamines and heterocyclic arylamines (HAAs) are of particular interest because of demonstrated carcinogenicity in animals and humans and the broad exposure to many of these compounds. The activation of these, and also some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 (P450). P450 1A2 plays a prominent role in these reactions. However, P450 1A1 and 1B1 and other P450s are also important in humans as well as experimental animals. Some arylamines (including drugs) are N-hydroxylated predominantly by P450s other than those in Family 1. Other oxygenases can also have roles. An important issue is extrapolation between species in predicting cancer risks, as shown by the low rates of HAA activation by rat P450 1A2 and low levels of P450 1A2 expression in some nonhuman primates.

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Wan, Linrong, Anlian Zhou, Wenfu Xiao, Bangxing Zou, Yaming Jiang, Jinshu Xiao, Cao Deng, and Youhong Zhang. "Cytochrome P450 monooxygenase genes in the wild silkworm, Bombyx mandarina." PeerJ 9 (February 3, 2021): e10818. http://dx.doi.org/10.7717/peerj.10818.

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Wild (Bombyx mandarina) and domestic silkworms (B. mori) are good models for investigating insect domestication, as 5000 years of artificial breeding and selection have resulted in significant differences between B. mandarina and B. mori. In this study, we improved the genome assemblies to the chromosome level and updated the protein-coding gene annotations for B. mandarina. Based on this updated genome, we identified 68 cytochrome P450 genes in B. mandarina. The cytochrome P450 repository in B. mandarina is smaller than in B. mori. Certain currently unknown key genes, rather than gene number, are critical for insecticide resistance in B. mandarina, which shows greater resistance to insecticides than B. mori. Based on the physical maps of B. mandarina, we located 66 cytochrome P450s on 18 different chromosomes, and 27 of the cytochrome P450 genes were concentrated into seven clusters. KEGG enrichment analysis of the P450 genes revealed the involvement of cytochrome P450 genes in hormone biosynthesis. Analyses of the silk gland transcriptome identified candidate cytochrome P450 genes (CYP306A) involved in ecdysteroidogenesis and insecticide metabolism in B. mandarina.

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Chun, Y. J., T. Shimada, M. R. Waterman, and F. P. Guengerich. "Understanding electron transport systems of Streptomyces cytochrome P450." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1183–85. http://dx.doi.org/10.1042/bst0341183.

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Streptomyces spp. are known to produce various types of biologically active compounds including antibiotics, antiparasitic agents, herbicides and immunosuppressants. P450 (cytochrome P450) enzymes may have key roles in these biosynthetic and biotransformation reactions. Recent genomic analysis of Streptomyces coelicolor A3(2) indicates that S. coelicolor may have six ferredoxins (Fdxs), four putative Fdx reductases (FdRs) and 18 P450 genes. However, there are few clues to explain the mechanisms and functions of Streptomyces P450 systems. To solve these questions, we have expressed and purified five S. coelicolor P450s, four FdRs and six Fdxs in Escherichia coli. Of the purified P450s, CYP105D5 has fatty acid hydroxylation activity in a system reconstituted with putidaredoxin reductase and Fdx4 or with spinach FdR and spinach Fdx, although the reconstitutions with FdR2 or FdR3 and any of the Fdxs did not support CYP105D5-catalysed oleic acid hydroxylation. Elucidation of the detailed mechanisms of electron transport system for Streptomyces P450 may provide the perspective for usefulness of P450s as a biocatalyst.

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Gnedenko, O. V., L. A. Kaluzhskiy, A. A. Molnar, A. V. Yantsevich, D. V. Mukha, A. A. Gilep, S. A. Usanov, et al. "SPR-biosensor assay for analysis of small compounds interaction with human cytochrome P450 51A1 (CYP51A1)." Biomeditsinskaya Khimiya 59, no. 4 (2013): 388–98. http://dx.doi.org/10.18097/pbmc20135904388.

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The SPR assay for human cytochrome P450 51A1's (CYP51A1) ligand screening was developed. Assay has been validated with known azole inhibitors of cytochrome P450s. The studied azoles selectively interacted with human cytochrome P450 51A1, which showed the highest affinity towards ketoconazole. The efficiency of the SPR assay was showed with 19 steroid and triterpene compounds, which were not investigated as potential ligands of CYP51A1.

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Beneš, Martin, Jiří Hudeček, Pavel Anzenbacher, and Martin Hof. "Coumarin 6, Hypericin, Resorufins, and Flavins: Suitable Chromophores for Fluorescence Correlation Spectroscopy of Biological Molecules." Collection of Czechoslovak Chemical Communications 66, no. 6 (2001): 855–69. http://dx.doi.org/10.1135/cccc20010855.

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In this work we show that the dyes coumarin 6, hypericin, 7-O-ethylresorufin and resorufin are suitable for fluorescence correlation spectroscopy (FCS) and demonstrate the use of these dyes in physiologically relevant protein studies. Since coumarins are metabolised by cytochromes P450, the binding of coumarin 6 to cytochrome P450 3A4 was investigated by FCS. Coumarin 6 appears to be a very bright non-covalent cytochrome P450 label. When titrating cytochrome P450 3A4 with coumarin 6, the diffusion time of the coumarin 6/ cytochrome P450 3A4 complex increases roughly two-fold at protein concentrations higher than 1 μmol l-1, indicating the formation of cytochrome aggregates. FCS of the flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) shows that both endogenous dyes undergo photobleaching. Moreover, FAD appears to be present to great extent, as a non-fluorescent intramolecular complex. Analysis of the FCS data of the flavoprotein NADPH-cytochrome P450 oxidoreductase (molecular weight 76 500) yielded two components. While the slow component corresponds to a globular protein with the molecular weight about 75 000, the fast component appears to be due to free diffusing FMN and FAD molecules. The amount of free FMN and FAD increases with increasing laser power. At high laser power a complete photodissociation of FMN and FAD occurs.

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Koroleva, P. I., and V. V. Shumyantseva. "Design of model systems based on cytochrome P450 3A4 and riboflavin complexes for increasing the electrocatalysis efficiency." Journal Biomed 17, no. 3E (October 26, 2021): 37–41. http://dx.doi.org/10.33647/2713-0428-17-3e-37-41.

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Cytochromes P450 (CYP) are a large class of enzymes, whose active site is type b heme. The main function of cytochromes P450 is biotransformation of endogenous and exogenous compounds in the organism. The cytochrome P450 3A4 metabolizes about 50% of all modern medications; therefore, its catalytic properties present significant research interest. P450 cytochromes can be effectively investigated using electrochemical systems that consist of a solid base (electrode) and a modifier facilitating enzyme immobilization. In this case, the electron donor is an electrode substituting a natural electron donor NAD(P)H and eliminating the need to use redox-partner proteins. The electrode modifier maintains the catalytic enzyme activity and enhances the efficiency of electron transfer when noble metals and carbon materials nanoparticles are included. This work is aimed at creating more effective cytochrome P450 electrochemical systems to increase the yield of metabolites of enzymatic electrocatalytic reactions.

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Henderson, C. J., A. Sahraouei, and C. R. Wolf. "Cytochrome P450s and chemoprevention." Biochemical Society Transactions 28, no. 2 (February 1, 2000): 42–46. http://dx.doi.org/10.1042/bst0280042.

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The cytochrome P450 mono-oxygenase system represents a major defence against chemical challenge from the environment, constituting part of an adaptive response mounted by an organism following exposure to harmful agents. Cytochrome P450s are also able to catalyse the activation of compounds to toxic products, and participate in a variety of essential ‘housekeeping’ functions, such as biosynthesis of steroid hormones and fatty acid oxidation. It is clear that the modulation of expression of these enzymes can have a significant effect on chemical toxicity, carcinogenicity and mutagenicity. The concept of cancer chemoprevention, i.e. the administration of a (non-toxic) chemical or dietary component in order to prevent neoplastic disease or to inhibit its progression, is an attractive one. Despite this, relatively little work has been done to characterize the ability of putative chemopreventive agents to modulate P450 expression, or to understand the interaction between P450s and chemopreventive agents. Before chemopreventive treatment can become a reality, it is essential that this complex issue is addressed; for instance, it is likely that any single chemopreventive agent will induce more than one P450 isoenzyme, and while altered expression of a particular P450 may attenuate the effects of one toxic agent, the effects of others might well be potentiated. Our laboratory has created a transgenic mouse line in which the rat CYP1A1 promoter drives expression of the β-galactosidase gene. These mice can be used to define which compounds act via the Ah receptor, in which tissues, and at which stage of development. We are currently developing another mouse line in which β-galactosidase expression is controlled by the mouse GstA1 promoter, allowing us to define the role of the antioxidant responsive element in the action of chemopreventive agents. Finally, using cre-1oxP transgenic technology, we have generated a mouse line in which P450 reductase can be deleted in a conditional, i.e. tissue-specific, manner, permitting us to investigate the role of P450s in chemoprevention in a more defined manner.

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Ronzhin, N., E. Posokhina, O. Mogilnaya, A. Puzyr, J. Gitelson, and V. Bondar. "CYTOCHROME P450 SYSTEM MAY BE INVOLVED IN THE LIGHT EMISSION OF HIGHER FUNGI." Russian Journal of Biological Physics and Chemisrty 7, no. 2 (November 15, 2022): 320–24. http://dx.doi.org/10.29039/rusjbpc.2022.0522.

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The paper presents data that testify in favor of the participation of the cytochrome P450 system in the light emission of higher fungi. Extracts from mycelia of different species of luminous basidiomycetes containing fungal luminescent systems that provide luminescence in vitro were obtained. Applied conditions for the isolation of luminescent systems (sonication, centrifugation at 40000g) indicate the presence of membrane structures in the extracts, in particular, microsomes formed as a result of ultrasonic disintegration of the endoplasmic reticulum (ER). Differential spectral analysis of the extracts revealed the presence of two absorption peaks at 410 nm and 450 nm, which indicates the presence of cytochromes b5 and P450. The luminescence of the extracts is stimulated by reduced pyridine nucleotides, however, the addition of NADPH causes a higher level of luminescence compared with NADH. The addition of hydrogen peroxide significantly (from several times to 1-2 orders of magnitude) increases the luminescence intensity of extracts activated by NAD(P)H. The addition of fluconazole significantly inhibits the light emission of extracts. The data obtained indicates that the cytochrome P450 system associated with ER membranes may participate in the mechanism of light emission of higher fungi with the involvement in the process of electron transport enzyme systems: NADPH-dependent reductase of cytochrome P450 - cytochrome P450 and NADH-dependent reductase of cytochrome b5 - cytochrome b5 - cytochrome P450. In this case, cytochrome P450 may hydroxylate hispidin (precursor of the luminescent reaction substrate) to form luciferin and catalyze its oxidation in the presence of ROS with light emission.

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Ye, Min, Bidhan Nayak, Lei Xiong, Chao Xie, Yi Dong, Minsheng You, Zhiguang Yuchi, and Shijun You. "The Role of Insect Cytochrome P450s in Mediating Insecticide Resistance." Agriculture 12, no. 1 (January 1, 2022): 53. http://dx.doi.org/10.3390/agriculture12010053.

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In many organisms, cytochrome P450 enzymes are the primary detoxifying enzymes. Enhanced P450 activity can be mediated by the emergence of new genes, increased transcription due to mutations in the promoter regions, changes in enzyme structures and functions due to mutations in protein-coding regions, or changes in post-translational modifications; all of these changes are subject to insecticide selection pressure. Multiple signalling pathways and key effector molecules are involved in the regulation of insect P450s. Increased P450 activity is a key mechanism inducing insect resistance. Hence, downregulation of selected P450s is a promising strategy to overcome this resistance. Insect P450 inhibitors that act as insecticide synergists, RNA interference to induce P450 gene silencing, and the use of transgenic insects and crops are examples of strategies utilized to overcome resistance. This article reviews the latest advances in studies related to insect P450s-mediated agrochemical resistance, with focuses on the regulatory mechanisms and associated pest management strategies. Future investigations on the comprehensive regulatory pathways of P450-mediated detoxification, identification of key effectors, and downregulation strategies for P450s will ecologically, economically, and practically improve pest management.

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Paul Bolwell, G. "Cytochrome P450:." Phytochemistry 35, no. 1 (December 1993): 279. http://dx.doi.org/10.1016/s0031-9422(00)90557-0.

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Ehrenpreis, Eli D., and Seymour Ehrenpreis. "CYTOCHROME P450." Clinics in Liver Disease 2, no. 3 (August 1998): 457–70. http://dx.doi.org/10.1016/s1089-3261(05)70021-0.

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Roos, P. H., and N. Jakubowski. "Cytochrome P450." Analytical and Bioanalytical Chemistry 392, no. 6 (October 9, 2008): 1015–17. http://dx.doi.org/10.1007/s00216-008-2415-z.

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D'Arcy, P. F. "Cytochrome P450." International Journal of Pharmaceutics 103, no. 1 (February 1994): 99. http://dx.doi.org/10.1016/0378-5173(94)90211-9.

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Poulos, Thomas L. "Cytochrome P450." Current Opinion in Structural Biology 5, no. 6 (December 1995): 767–74. http://dx.doi.org/10.1016/0959-440x(95)80009-3.

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Coulson, C. J. "Cytochrome P450." Trends in Biochemical Sciences 10, no. 2 (February 1985): 92. http://dx.doi.org/10.1016/0968-0004(85)90255-5.

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Barbosa-Sicard, Eduardo, Eva Kaergel, Dominik N. Muller, Horst Honeck, Friedrich C. Luft, and Wolf-Hagen Schunck. "Cytochrome P450 Isoform Expression in Human Vascular Endothelial Cells." Hypertension 36, suppl_1 (October 2000): 698. http://dx.doi.org/10.1161/hyp.36.suppl_1.698-a.

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P29 Epoxy derivatives of arachidonic acid may act as important autocrine and paracrine mediators of endothelial function including regulation of vascular tone and control of inflammation. To identify potential candidates for catalyzing the synthesis of these and further arachidonic acid metabolites, we studied human vascular endothelial cells for the expression of individual cytochrome P450 isoforms belonging to the CYP families 1, 2, 3 and 4. An RT-PCR screening performed with subfamily- and isoform-specific primer pairs revealed mRNAs for the P450 forms 1A1, 1B1, 2C8, 2E1, 2J2, 3A7, 4A11 and 4F2. The identity of the RT-PCR products was confirmed by DNA sequencing. In addition, P450 1A2 mRNA was detected after induction with β-naphthoflavone which also enhanced the expresion of P450s 1A1 and 1B1. P450s 2B6 and 3A4 were not detectable. Similar P450 isoform patterns were obtained analyzing primary human endothelial cells originating from aorta, coronary arteries, dermal microvessels and umbilical veins, as well as an immortalized human endothelial cell line (HMEC-1). Further studies with HMEC-1 cells showed the expression of all human members of the P450 2C subfamily (2C8, 2C9, 2C18 and 2C19). We next used gaschromatography-mass spectrometry to identify the regioisomeric epoxeicosatrienoic acids produced by HMEC-1 cells. Among the P450 forms detected by the RT-PCR screening, P450 2C8 and 2J2 are the leading candidates for producing vasoactive epoxyeicosatrienoic acids. Using recombinant human P450 1A1, we then found that this P450 form catalyzes the formation of various regioisomeric hydroxy derivatives of arachidonic acid. We conclude that P450 1A1 known primarily for its role in polycyclic aromatic hydrocarbon metabolism, may interfere with endothelial arachidonic acid metabolism, particularly after its induction by drugs and xenobiotics. Furthermore, P450s 4A11 and 4F2 probably contribute to the degradation of lipid mediators of inflammation.

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Lewis, David F. V. "Structural Models for Cytochrome P450�Mediated Catalysis." Scientific World JOURNAL 3 (2003): 536–45. http://dx.doi.org/10.1100/tsw.2003.41.

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This review focuses on the structural models for cytochrome P450 that are improving our knowledge and understanding of the P450 catalytic cycle, and the way in which substrates bind to the enzyme leading to catalytic conversion and subsequent formation of mono-oxygenated metabolites. Various stages in the P450 reaction cycle have now been investigated using X-ray crystallography and electronic structure calculations, whereas homology modelling of mammalian P450s is currently revealing important aspects of pharmaceutical and other xenobiotic metabolism mediated by P450 involvement. These features are explored in the current review on P450-based catalysis, which emphasises the importance of structural modelling to our understanding of this enzyme's function. In addition, the results of various QSAR analyses on series of chemicals, which are metabolised via P450 enzymes, are presented such that the importance of electronic and other structural factors in explaining variations in rates of metabolism can be appreciated.

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Marchenko, M. M., G. P. Kopylchuk, and O. V. Ketsa. "Low doses x-ray irradiation influence on liver detoxication system in rats with transplanted guerin's carcinoma." Biomeditsinskaya Khimiya 56, no. 2 (2010): 266–73. http://dx.doi.org/10.18097/pbmc20105602266.

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The activity of detoxication enzymes in liver microsomal fraction of preliminary radiation-exposed rats was investigated. It was shown that preliminary organism exposure to radiation reduced cytochrome Р450 and glutathione-S-transferase activity in liver microsomal fraction in the latent and logarithmic phases of oncogenesis compared with the unirradiated rats with tumor.Low level of cytochrome Р450 activity can be caused by transition of microsomal cytochrome P450 in P420 inactive form.The preliminary radiation does not influence the enzyme activity of liver cytochrome P450 and glutathione-S-transferase on terminal stages of Guerin's carcinoma growth.

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McLean, K. J., A. J. Dunford, M. Sabri, R. Neeli, H. M. Girvan, P. R. Balding, D. Leys, H. E. Seward, K. R. Marshall, and A. W. Munro. "CYP121, CYP51 and associated redox systems in Mycobacterium tuberculosis: towards deconvoluting enzymology of P450 systems in a human pathogen." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1178–82. http://dx.doi.org/10.1042/bst0341178.

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An extraordinary array of P450 (cytochrome P450) enzymes are encoded on the genome of the human pathogen Mycobacterium tuberculosis (Mtb) and in related mycobacteria and actinobacteria. These include the first characterized sterol 14α-demethylase P450 (CYP51), a known target for azole and triazole drugs in yeasts and fungi. To date, only two Mtb P450s have been characterized in detail: CYP51 and CYP121. The CYP121 P450 shows structural relationships with P450 enzymes involved in synthesis of polyketide antibiotics. Both P450s exhibit tight binding to a range of azole drugs (e.g. clotrimazole and fluconazole) and the same drugs also have potent effects on growth of mycobacteria (but not of e.g. Escherichia coli). Atomic structures are available for both Mtb CYP51 and CYP121, revealing modes of azole binding and intriguing mechanistic and structural aspects. This paper reviews our current knowledge of these and the other P450 systems in Mtb including recent data relating to the reversible conversion of the CYP51 enzyme between P450 (thiolate-co-ordinated) and P420 (thiol-co-ordinated) species on reduction of the haem iron in the absence of a P450 substrate. The accessory flavoprotein and iron–sulfur proteins required to drive P450 catalysis are also discussed, providing an overview of the current state of knowledge of Mtb P450 redox systems.

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Hu, Z., Q. Lin, H. Chen, Z. Li, F. Yin, and X. Feng. "Identification of a novel cytochrome P450 gene,CYP321E1from the diamondback moth,Plutella xylostella(L.) and RNA interference to evaluate its role in chlorantraniliprole resistance." Bulletin of Entomological Research 104, no. 6 (September 11, 2014): 716–23. http://dx.doi.org/10.1017/s0007485314000510.

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AbstractInsect cytochrome P450 monooxygenases (P450s) play an important role in catalysis of many reactions leading to insecticides resistance. Our previous studies on transcriptome analysis of chlorantraniliprole-resistant development in the diamondback moth,Plutella xylostellarevealed that up-regulation of cytochrome P450s are one of the main factors leading to the development of chlorantraniliprole resistance. Here, we report for the first time a novel cytochrome P450 geneCYP321E1, which belongs to the cytochrome P450 gene family CYP321. Real-time quantitative PCR (RT–qPCR) analyses indicated thatCYP321E1was expressed at all developmental stages ofP. xylostellabut was highest in the fourth-instar larvae; furthermore, the relatively high expression was observed in the midgut of the fourth-instar larvae, followed by fat bodies and epidermis. The expression ofCYP321E1inP. xylostellawas differentially affected by three representative insecticides, including alphamethrin, abamectin and chlorantraniliprole. Among them, the exposure to chlorantraniliprole resulted in the largest transcript level of this cytochrome P450 gene. The findings suggested potential involvement ofCYP321E1in chlorantraniliprole resistance ofP. xylostella. To assess the functional link ofCYP321E1to chlorantraniliprole resistance, RNA interference (RNAi)-mediated gene silencing by double stranded RNA (dsRNA) injecting was used. Results revealed that injection delivery of dsRNA can greatly reduce gene expression after 24 h. As a consequence of RNAi, a significant increment in mortality of larvae injectedCYP321E1dsRNA was observed after 24 h of exposure to chlorantraniliprole. These results strongly support our notion that this novel cytochrome P450 gene plays an important role in chlorantraniliprole detoxification in the diamondback moth and is partly responsible for its resistance.

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Moskaleva, N. E., and V. G. Zgoda. "Current methods of cytochrome P450 analysis." Biomeditsinskaya Khimiya 58, no. 6 (2012): 617–34. http://dx.doi.org/10.18097/pbmc20125806617.

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Current review describes recent approaches of cytochrome P450 concentration and activity evaluation. Special attention paid to modern methods of proteomic analysis such as electrophoresis and chromato-mass-spectrometry. Methods of targeted proteomic applicable for quantitative and qualitative study of P450s in biological samples as well as methods for the enzyme activity measurements are reviewed. Finally, data on correlation between certain P450 isoform content and its specific enzymatic activities were described and discussed in the review.

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Shumyantseva, V. V., T. V. Bulko, O. V. Gnedenko, E. O. Yablokov, S. A. Usanov, and A. S. Ivanov. "Adrenodoxins and their role in the cytochrome P450 systems." Biomeditsinskaya Khimiya 68, no. 1 (2022): 47–54. http://dx.doi.org/10.18097/pbmc20226801047.

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The role of partner proteins in the formation of functional complexes in cytochrome P450 systems was investigated by means of optical biosensor technique. Kinetic constants and equilibrium dissociation constants of complexes of cytochrome CYP11A1 (P450scc) with wild-type adrenodoxin (Adx WT) and mutant forms of adrenodoxin R106D and D109R were determined using an optical biosensor. Wild-type adrenodoxin (Kd = (1.23±0.09)⋅10⁻⁶ M) and mutant D109R (Kd = (2.37±0.09)⋅10⁻⁸ M) formed complexes with cytochrome P450scc. For the R106D mutant, no complex formation was detected. To investigate the possibility of the participation of adrenodoxins and their mutant variants in the process of electron transfer as electron donors in mitochondrial cytochrome P450 systems, the electrochemical properties of these iron-sulfur proteins Adx WT and mutant forms of adrenodoxins were studied. Adx WT, mutant forms R106D and D109R have redox potentials E1/2 significantly more negative than cytochromes P450 (-579±10 mV, -590±15 mV, and -528±10 mV, respectively). These results suggest that Adx WT and mutant forms may be electron donors in the cytochrome P450 systems.

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Unterweger, Birgit, Dieter M. Bulach, Judith Scoble, David J. Midgley, Paul Greenfield, Dena Lyras, Priscilla Johanesen, and Geoffrey J. Dumsday. "CYP101J2, CYP101J3, and CYP101J4, 1,8-Cineole-Hydroxylating Cytochrome P450 Monooxygenases from Sphingobium yanoikuyae Strain B2." Applied and Environmental Microbiology 82, no. 22 (September 2, 2016): 6507–17. http://dx.doi.org/10.1128/aem.02067-16.

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ABSTRACTWe report the isolation and characterization of three new cytochrome P450 monooxygenases: CYP101J2, CYP101J3, and CYP101J4. These P450s were derived fromSphingobium yanoikuyaeB2, a strain that was isolated from activated sludge based on its ability to fully mineralize 1,8-cineole. Genome sequencing of this strain in combination with purification of native 1,8-cineole-binding proteins enabled identification of 1,8-cineole-binding P450s. The P450 enzymes were cloned, heterologously expressed (N-terminally His6tagged) inEscherichia coliBL21(DE3), purified, and spectroscopically characterized. Recombinant whole-cell biotransformation inE. colidemonstrated that all three P450s hydroxylate 1,8-cineole using electron transport partners fromE. colito yield a product putatively identified as (1S)-2α-hydroxy-1,8-cineole or (1R)-6α-hydroxy-1,8-cineole. The new P450s belong to the CYP101 family and share 47% and 44% identity with other 1,8-cineole-hydroxylating members found inNovosphingobium aromaticivoransandPseudomonas putida. Compared to P450cin(CYP176A1), a 1,8-cineole-hydroxylating P450 fromCitrobacter braakii, these enzymes share less than 30% amino acid sequence identity and hydroxylate 1,8-cineole in a different orientation. Expansion of the enzyme toolbox for modification of 1,8-cineole creates a starting point for use of hydroxylated derivatives in a range of industrial applications.IMPORTANCECYP101J2, CYP101J3, and CYP101J4 are cytochrome P450 monooxygenases fromS. yanoikuyaeB2 that hydroxylate the monoterpenoid 1,8-cineole. These enzymes not only play an important role in microbial degradation of this plant-based chemical but also provide an interesting route to synthesize oxygenated 1,8-cineole derivatives for applications as natural flavor and fragrance precursors or incorporation into polymers. The P450 cytochromes also provide an interesting basis from which to compare other enzymes with a similar function and expand the CYP101 family. This could eventually provide enough bacterial parental enzymes with similar amino acid sequences to enablein vitroevolution via DNA shuffling.

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Nelson, David R. "A world of cytochrome P450s." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1612 (February 19, 2013): 20120430. http://dx.doi.org/10.1098/rstb.2012.0430.

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The world we live in is a biosphere influenced by all organisms who inhabit it. It is also an ecology of genes, with some having rather startling effects. The premise put forth in this issue is cytochrome P450 is a significant player in the world around us. Life and the Earth itself would be visibly different and diminished without cytochrome P450s. The contributions to this issue range from evolution on the billion year scale to the colour of roses, from Darwin to Rachel Carson; all as seen through the lens of cytochrome P450.

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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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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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Kuzikov, A. V., T. V. Bulko, P. I. Koroleva, R. A. Masamrekh, S. S. Babkina, A. A. Gilep, and V. V. Shumyantseva. "Electroanalytical and electrocatalytical characteristics of cytochrome P450 3A4 using electrodes modified with nanocomposite carbon nanomaterials." Biomeditsinskaya Khimiya 66, no. 1 (January 2020): 64–70. http://dx.doi.org/10.18097/pbmc20206601064.

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The electroanalytical characteristics of recombinant cytochrome P450 3A4 (P450 3A4) immobilized on the surface of screen-printed graphite electrodes modified with multi-walled carbon nanotubes have been studied. The role and the influence of graphite working electrode modification with carbon nanotubes on electroanalytical characteristics of cytochrome P450 3A4 have been demonstrated. The conditions for the immobilization of cytochrome P450 3A4 on the obtained screen-printed graphite electrodes modified with carbon multi-walled nanotubes have been optimized. The electrochemical parameters of the oxidation and reduction of the heme iron of the enzyme have been estimated. The midpoint potential E0′ was -0.35±0.01 V vs Ag/AgCl; the calculated heterogeneous electron transfer rate constant ks, was 0.57±0.04 s-1; the amount of electroactive cytochrome P450 3A4 on the electrode Г0, was determined as (2.6±0.6)⋅10-10 mol/cm2. The functioning mechanism of P450 3A4-based electrochemical sensor followed the “protein film voltammetry”. In order to develop electrochemical analysis of drugs being substrates of that hemoprotein and respective medical biosensors the voltammetric study of catalytic activity of immobilized cytochrome P450 3A4 was carried out. Electrocatalytic properties of cytochrome P450 3A4, immobilized on modified screen-printed graphite electrodes, has been investigated using erythromycin (macrolide antibiotics). It has been shown that the modification of electrodes plays a decisive role for the study of the properties of cytochromes P450 in electrochemical investigations. Smart electrodes can serve as sensors for analytical purposes, as well as electrocatalysts for the study of biotransformation processes and metabolic processes. Electrodes modified with carbon nanomaterials are applicable for analytical purposes in the registration of hemoproteins. Electrodes modified with synthetic membrane-like compounds (e.g. didodecyldimethylammonium bromide) are effective in enzyme-dependent electrocatalysis.

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Mthethwa, Bongumusa, Wanping Chen, Mathula Ngwenya, Abidemi Kappo, Puleng Syed, Rajshekhar Karpoormath, Jae-Hyuk Yu, David Nelson, and Khajamohiddin Syed. "Comparative Analyses of Cytochrome P450s and Those Associated with Secondary Metabolism in Bacillus Species." International Journal of Molecular Sciences 19, no. 11 (November 16, 2018): 3623. http://dx.doi.org/10.3390/ijms19113623.

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Cytochrome P450 monooxygenases (CYPs/P450s) are among the most catalytically-diverse enzymes, capable of performing enzymatic reactions with chemo-, regio-, and stereo-selectivity. Our understanding of P450s’ role in secondary metabolite biosynthesis is becoming broader. Among bacteria, Bacillus species are known to produce secondary metabolites, and recent studies have revealed the presence of secondary metabolite biosynthetic gene clusters (BGCs) in these species. However, a comprehensive comparative analysis of P450s and P450s involved in the synthesis of secondary metabolites in Bacillus species has not been reported. This study intends to address these two research gaps. In silico analysis of P450s in 128 Bacillus species revealed the presence of 507 P450s that can be grouped into 13 P450 families and 28 subfamilies. No P450 family was found to be conserved in Bacillus species. Bacillus species were found to have lower numbers of P450s, P450 families and subfamilies, and a lower P450 diversity percentage compared to mycobacterial species. This study revealed that a large number of P450s (112 P450s) are part of different secondary metabolite BGCs, and also identified an association between a specific P450 family and secondary metabolite BGCs in Bacillus species. This study opened new vistas for further characterization of secondary metabolite BGCs, especially P450s in Bacillus species.

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Zheng, Xiaoyan, Ping Li, and Xu Lu. "Research advances in cytochrome P450-catalysed pharmaceutical terpenoid biosynthesis in plants." Journal of Experimental Botany 70, no. 18 (April 30, 2019): 4619–30. http://dx.doi.org/10.1093/jxb/erz203.

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Advances in the role of cytochrome P450s in pharmaceutical terpenoid biosynthesis are reviewed, and different cloning strategies to identify new cytochrome P450 genes in the biosynthesis of natural terpenoids are summarized.

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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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Yamazaki, Hiroshi, Elizabeth M. J. Gillam, Mi-Sook Dong, William W. Johnson, F. Peter Guengerich, and Tsutomu Shimada. "Reconstitution of Recombinant Cytochrome P450 2C10(2C9) and Comparison with Cytochrome P450 3A4 and Other Forms: Effects of Cytochrome P450–P450 and Cytochrome P450–b5Interactions." Archives of Biochemistry and Biophysics 342, no. 2 (June 1997): 329–37. http://dx.doi.org/10.1006/abbi.1997.0125.

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Guengerich, F. Peter, Martha V. Martin, Christal D. Sohl, and Qian Cheng. "Measurement of cytochrome P450 and NADPH–cytochrome P450 reductase." Nature Protocols 4, no. 9 (August 6, 2009): 1245–51. http://dx.doi.org/10.1038/nprot.2009.121.

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Guengerich, F. Peter. "Cytochrome P450 research and The Journal of Biological Chemistry." Journal of Biological Chemistry 294, no. 5 (February 1, 2019): 1671–80. http://dx.doi.org/10.1074/jbc.tm118.004144.

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In honor of the 100th birthday of Dr. Herbert Tabor, JBC's Editor-in-Chief for 40 years, I will review here JBC's extensive coverage of the field of cytochrome P450 (P450) research. Research on the reactions catalyzed by these enzymes was published in JBC before it was even realized that they were P450s, i.e. they have a “pigment” with an absorption maximum at 450 nm. After the P450 pigment discovery, reported in JBC in 1962, the journal proceeded to publish the methods for measuring P450 activities and many seminal findings. Since then, the P450 field has grown extensively, with significant progress in characterizing these enzymes, including structural features, catalytic mechanisms, regulation, and many other aspects of P450 biochemistry. JBC has been the most influential journal in the P450 field. As with many other research areas, Dr. Tabor deserves a great deal of the credit for significantly advancing this burgeoning and important topic of research.

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Nzuza, Nomfundo, Tiara Padayachee, Puleng Rosinah Syed, Justyna Dorota Kryś, Wanping Chen, Dominik Gront, David R. Nelson, and Khajamohiddin Syed. "Ancient Bacterial Class Alphaproteobacteria Cytochrome P450 Monooxygenases Can Be Found in Other Bacterial Species." International Journal of Molecular Sciences 22, no. 11 (May 24, 2021): 5542. http://dx.doi.org/10.3390/ijms22115542.

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Cytochrome P450 monooxygenases (CYPs/P450s), heme-thiolate proteins, are well-known players in the generation of chemicals valuable to humans and as a drug target against pathogens. Understanding the evolution of P450s in a bacterial population is gaining momentum. In this study, we report comprehensive analysis of P450s in the ancient group of the bacterial class Alphaproteobacteria. Genome data mining and annotation of P450s in 599 alphaproteobacterial species belonging to 164 genera revealed the presence of P450s in only 241 species belonging to 82 genera that are grouped into 143 P450 families and 214 P450 subfamilies, including 77 new P450 families. Alphaproteobacterial species have the highest average number of P450s compared to Firmicutes species and cyanobacterial species. The lowest percentage of alphaproteobacterial species P450s (2.4%) was found to be part of secondary metabolite biosynthetic gene clusters (BGCs), compared other bacterial species, indicating that during evolution large numbers of P450s became part of BGCs in other bacterial species. Our study identified that some of the P450 families found in alphaproteobacterial species were passed to other bacterial species. This is the first study to report on the identification of CYP125 P450, cholesterol and cholest-4-en-3-one hydroxylase in alphaproteobacterial species (Phenylobacterium zucineum) and to predict cholesterol side-chain oxidation capability (based on homolog proteins) by P. zucineum.

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Lamb, David C., and Michael R. Waterman. "Unusual properties of the cytochrome P450 superfamily." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1612 (February 19, 2013): 20120434. http://dx.doi.org/10.1098/rstb.2012.0434.

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During the early years of cytochrome P450 research, a picture of conserved properties arose from studies of mammalian forms of these monooxygenases. They included the protohaem prosthetic group, the cysteine residue that coordinates to the haem iron and the reduced CO difference spectrum. Alternatively, the most variable feature of P450s was the enzymatic activities, which led to the conclusion that there are a large number of these enzymes, most of which have yet to be discovered. More recently, studies of these enzymes in other eukaryotes and in prokaryotes have led to the discovery of unexpected P450 properties. Many are variations of the original properties, whereas others are difficult to explain because of their unique nature relative to the rest of the known members of the superfamily. These novel properties expand our appreciation of the broad view of P450 structure and function, and generate curiosity concerning the evolution of P450s. In some cases, structural properties, previously not found in P450s, can lead to enzymatic activities impacting the biological function of organisms containing these enzymes; whereas, in other cases, the biological reason for the variations are not easily understood. Herein, we present particularly interesting examples in detail rather than cataloguing them all.

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Moran, F. M., J. J. Ford, C. J. Corbin, S. M. Mapes, V. C. Njar, A. M. Brodie, and A. J. Conley. "Regulation of Microsomal P450, Redox Partner Proteins, and Steroidogenesis in the Developing Testes of the Neonatal Pig." Endocrinology 143, no. 9 (September 1, 2002): 3361–69. http://dx.doi.org/10.1210/en.2002-220329.

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Abstract Testicular growth and plasma androgen concentrations increase markedly in the first weeks of neonatal life of pigs. The regulation of steroidogenesis through this period was examined by measuring total microsomal cytochromes P450 (P450), 17α-hydroxylase/17,20-lyase P450 (P450c17) and aromatase P450 (P450arom) enzyme activities, and the redox partner proteins nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-cytochrome P450 reductase (reductase) and cytochrome b5 in testicular microsomes. Testes were collected from 1–24 d of age, and testicular development was suppressed by a GnRH antagonist in some animals from d 1–14. Both 17/20-lyase and aromatase activities increased from d 1–7 but not thereafter, and 17–20-lyase activity was always at least 200-fold higher than aromatase activity. Reductase decreased in wk 1, then increased to d 24. No changes were seen in cytochrome b5 expression. GnRH antagonist treatment suppressed plasma LH, testosterone and testes growth to d 14. 17,20-Lyase and aromatase activities in testicular microsomes were reduced by 20% and 50%, respectively. Total microsomal P450 concentration was reduced by 50% on d 7, but there was no effect of treatment on reductase or cytochrome b5 expression. These data support the hypothesis that the rise in neonatal testicular androgen secretion is more likely due to gonadotropin-stimulated gonadal growth, rather than specific P450c17 expression. Neither P450c17 nor P450arom can account for the decline in total microsomal P450. Reductase and cytochrome b5 expression appears to be constitutive, but reductase levels saturate both P450c17 and P450arom.

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Journal articles on the topic 'Cytochrome P450'

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