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Journal articles on the topic 'Cytochrome P45Os'

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Author: Grafiati

Published: 10 December 2022

Last updated: 28 January 2023

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1

BRASH, ALAN R., MIN S. CHANG, COLIN D. FUNK, and WENCHAO SONG. "Novel Transformations of HPETEs by Cytochrome P45Os." Annals of the New York Academy of Sciences 744, no. 1 Cellular Gene (November 1994): 25–30. http://dx.doi.org/10.1111/j.1749-6632.1994.tb52720.x.

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2

Kim, Hyun-Mi, and Kwang-Hyeon Liu. "Screening for inhibitory effect on nine CYP isoforms by 20 herbal medications." Journal of Life Science 17, no. 3 (March 30, 2007): 334–39. http://dx.doi.org/10.5352/jls.2007.17.3.334.

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3

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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4

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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5

Sahraouei, A., C. J. Henderson, and C. R. Wolf. "Cytochrome P450s and Chemoprevention." Biochemical Society Transactions 28, no. 1 (February 1, 2000): A6. http://dx.doi.org/10.1042/bst028a006.

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6

KARLGREN, M., S. MIURA, and M. INGELMANSUNDBERG. "Novel extrahepatic cytochrome P450s." Toxicology and Applied Pharmacology 207, no. 2 (September 1, 2005): 57–61. http://dx.doi.org/10.1016/j.taap.2004.12.022.

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7

Blackbourn, H. "Gibberellins and cytochrome P450s." Trends in Plant Science 3, no. 9 (September 1998): 334. http://dx.doi.org/10.1016/s1360-1385(98)01309-0.

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8

Alzahrani, Abdullah M., and Peramaiyan Rajendran. "The Multifarious Link between Cytochrome P450s and Cancer." Oxidative Medicine and Cellular Longevity 2020 (January 4, 2020): 1–18. http://dx.doi.org/10.1155/2020/3028387.

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Cancer is a leading cause of death worldwide. Cytochrome P450s (P450s) play an important role in the metabolism of endogenous as well as exogenous substances, especially drugs. Moreover, many P450s can serve as targets for disease therapy. Increasing reports of epidemiological, diagnostic, and clinical research indicate that P450s are enzymes that play a major part in the formation of cancer, prevention, and metastasis. The purposes of this review are to shed light on the current state of knowledge about the cancer molecular mechanism involving P450s and to summarize the link between the cancer effects and the participation of P450s.

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9

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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10

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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11

Lee, Sang Kyu, Nam Hee Kim, Jaeick Lee, Dong Hyun Kim, Eung Seok Lee, Han-Gon Choi, Hyeun Wook Chang, Yurngdong Jahng, and Tae Cheon Jeong. "Induction of Cytochrome P450s by Rutaecarpine and Metabolism of Rutaecarpine by Cytochrome P450s." Planta Medica 70, no. 8 (August 2004): 753–57. http://dx.doi.org/10.1055/s-2004-827207.

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12

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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13

Dauda, Wadzani Palnam, Peter Abraham, Elkanah Glen, Charles Oluwaseun Adetunji, Shakira Ghazanfar, Shafaqat Ali, Majid Al-Zahrani, et al. "Robust Profiling of Cytochrome P450s (P450ome) in Notable Aspergillus spp." Life 12, no. 3 (March 18, 2022): 451. http://dx.doi.org/10.3390/life12030451.

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Cytochrome P450s (P450ome) constitute an extended superfamily group of heme-thiolate enzymes identified in all biological domains. P450omes play a critical role in the oxidation of steroids and fatty acids, xenobiotic degradation of hydrophobic compounds, biosynthesis of hormones, and primary and secondary metabolism in organisms. Aspergillus species are among the most economically important fungal organisms in human medicine, industry, and agriculture worldwide. Exploring insight on the genome-wide annotations of cytochrome P450s in Aspergillus species is necessary for their biosynthetic applications. In this present study, we report the identification of 306 cytochrome P450s and their robust profiling in eight notable Aspergillus species (A. carbonarius, A. clavatus, A. flavus, A. fumigatus, A. nidulans, A. niger, A. oryzae, and A. terreus). Based on the evolutionary relationship, the Aspergillus P450s families clustered into 15 clades, with clades V, I, and XIII recording higher percentages (17.3%, 15.00%, and 14.71%, respectively) of Cyp families. Cyps were classified into 120 families 64 clans, and their putative functions were also elucidated. P450s were predicted to be located in 13 subcellular components, but the endoplasm reticulum was the dominant location across the eight Aspergillus species. Cyps genes of Aspergillus species were associated with seven secondary metabolism-related gene clusters. Elucidating the genome-wide annotations of P450s enzymes in Aspergillus species will form vital potential biotechnological tools that could be harnessed for industrial, pharmaceutical, and agricultural use.

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14

Pikuleva, Irina A. "Cytochrome P450s and cholesterol homeostasis." Pharmacology & Therapeutics 112, no. 3 (December 2006): 761–73. http://dx.doi.org/10.1016/j.pharmthera.2006.05.014.

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15

Kellner, David G., Shelley A. Maves, and Stephen G. Sligar. "Engineering cytochrome P450s for bioremediation." Current Opinion in Biotechnology 8, no. 3 (June 1997): 274–78. http://dx.doi.org/10.1016/s0958-1669(97)80003-1.

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16

Ayabe, Shin-ichi, and Tomoyoshi Akashi. "Cytochrome P450s in flavonoid metabolism." Phytochemistry Reviews 5, no. 2-3 (November 2, 2006): 271–82. http://dx.doi.org/10.1007/s11101-006-9007-3.

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17

Ralston, Lyle, and Oliver Yu. "Metabolons involving plant cytochrome P450s." Phytochemistry Reviews 5, no. 2-3 (October 28, 2006): 459–72. http://dx.doi.org/10.1007/s11101-006-9014-4.

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18

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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19

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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20

Barnaba, Carlo, Thirupathi Ravula, Ilce G. Medina-Meza, Sang-Choul Im, G. M. Anantharamaiah, Lucy Waskell, and Ayyalusamy Ramamoorthy. "Lipid-exchange in nanodiscs discloses membrane boundaries of cytochrome-P450 reductase." Chemical Communications 54, no. 49 (2018): 6336–39. http://dx.doi.org/10.1039/c8cc02003e.

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21

Ershov, P. V., E. O. Yablokov, Y. V. Mezentsev, L. A. Kaluzhskiy, A. Ya Luschik, A. M. Tumilovich, A. Yu Karputs, A. A. Gilep, and А. S. Ivanov. "Biosensor selection of small compounds, modulating a complex formation between cytochrome P450s and NADPH-dependent P450 oxidoreductase." Biomedical Chemistry: Research and Methods 3, no. 3 (2020): e00134. http://dx.doi.org/10.18097/bmcrm00134.

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The study of the effect of low-molecular-weight compounds (substrates, endogenous metabolites, drugs and xenobiotics) on the kinetic and equilibrium parameters of functionally significant binary protein-protein interactions (PPIs) is of both fundamental and clinical importance. The surface plasmon resonance (SPR) is the method of the first choice for studying PPIs. Earlier, SPR analysis revealed the modulating effect of steroidal substrates on the affinity of interactions between steroidogenic microsomal cytochromes P450 (CYP) and their redox partner (cytochrome b5). In this work, we have shown the suitability of the experimental approach for assessing the selective effect of the cofactor NADPH on the interaction between cytochromes CYP3A4 or CYP2E1 with NADPH-dependent P450 oxidoreductase (CPR). Experiments have shown that the CYP3A4/CPR complex is not modulated by NADPH, while the dissociation rate of the CYP2E1/CPR complex in the presence of NADPH significantly decreased: the koff values in the absence and presence of NADPH were (3.6 ± 0.2) • 10-3 s-1 and (3.8 ± 0.2) • 10-4 s-1, respectively. Thus, in the presence of NADPH, an increase in the affinity of CYP2E1/CPR complex formation by approximately one order of magnitude was observed, while NADPH did not affect the kon value of this complex. Co-injection of NADPH at the CYP2E1/CPR complex preformed in the absence of NADPH had minor influence on the koff values (<10%). This suggests a stabilizing role of NADPH for the CYP2E1/CPR complex formation. Thus, the use of our approach made it possible to assess the effect of the main electron supplier for the microsomal cytochrome P450 monooxygenase system on the kinetic rate constants of CYP/CPR complexes.

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22

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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23

Esteves, Francisco, Philippe Urban, José Rueff, Gilles Truan, and Michel Kranendonk. "Interaction Modes of Microsomal Cytochrome P450s with Its Reductase and the Role of Substrate Binding." International Journal of Molecular Sciences 21, no. 18 (September 11, 2020): 6669. http://dx.doi.org/10.3390/ijms21186669.

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The activity of microsomal cytochromes P450 (CYP) is strictly dependent on the supply of electrons provided by NADPH cytochrome P450 oxidoreductase (CPR). The variant nature of the isoform-specific proximal interface of microsomal CYPs implies that the interacting interface between the two proteins is degenerated. Recently, we demonstrated that specific CPR mutations in the FMN-domain (FD) may induce a gain in activity for a specific CYP isoform. In the current report, we confirm the CYP isoform dependence of CPR’s degenerated binding by demonstrating that the effect of four of the formerly studied FD mutants are indeed exclusive of a specific CYP isoform, as verified by cytochrome c inhibition studies. Moreover, the nature of CYP’s substrate seems to have a modulating role in the CPR:CYP interaction. In silico molecular dynamics simulations of the FD evidence that mutations induces very subtle structural alterations, influencing the characteristics of residues formerly implicated in the CPR:CYP interaction or in positioning of the FMN moiety. CPR seems therefore to be able to form effective interaction complexes with its structural diverse partners via a combination of specific structural features of the FD, which are functional in a CYP isoform dependent manner, and dependent on the substrate bound.

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24

Malinga, Nsikelelo Allison, Nomfundo Nzuza, Tiara Padayachee, Puleng Rosinah Syed, Rajshekhar Karpoormath, Dominik Gront, David R. Nelson, and Khajamohiddin Syed. "An Unprecedented Number of Cytochrome P450s Are Involved in Secondary Metabolism in Salinispora Species." Microorganisms 10, no. 5 (April 21, 2022): 871. http://dx.doi.org/10.3390/microorganisms10050871.

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Cytochrome P450 monooxygenases (CYPs/P450s) are heme thiolate proteins present in species across the biological kingdoms. By virtue of their broad substrate promiscuity and regio- and stereo-selectivity, these enzymes enhance or attribute diversity to secondary metabolites. Actinomycetes species are well-known producers of secondary metabolites, especially Salinispora species. Despite the importance of P450s, a comprehensive comparative analysis of P450s and their role in secondary metabolism in Salinispora species is not reported. We therefore analyzed P450s in 126 strains from three different species Salinispora arenicola, S. pacifica, and S. tropica. The study revealed the presence of 2643 P450s that can be grouped into 45 families and 103 subfamilies. CYP107 and CYP125 families are conserved, and CYP105 and CYP107 families are bloomed (a P450 family with many members) across Salinispora species. Analysis of P450s that are part of secondary metabolite biosynthetic gene clusters (smBGCs) revealed Salinispora species have an unprecedented number of P450s (1236 P450s-47%) part of smBGCs compared to other bacterial species belonging to the genera Streptomyces (23%) and Mycobacterium (11%), phyla Cyanobacteria (8%) and Firmicutes (18%) and the classes Alphaproteobacteria (2%) and Gammaproteobacteria (18%). A peculiar characteristic of up to six P450s in smBGCs was observed in Salinispora species. Future characterization Salinispora species P450s and their smBGCs have the potential for discovering novel secondary metabolites.

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25

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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26

Msweli, Siphesihle, Andiswa Chonco, Lihle Msweli, Puleng Rosinah Syed, Rajshekhar Karpoormath, Wanping Chen, Dominik Gront, Bridget Valeria Zinhle Nkosi, David R. Nelson, and Khajamohiddin Syed. "Lifestyles Shape the Cytochrome P450 Repertoire of the Bacterial Phylum Proteobacteria." International Journal of Molecular Sciences 23, no. 10 (May 22, 2022): 5821. http://dx.doi.org/10.3390/ijms23105821.

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For the last six decades, cytochrome P450 monooxygenases (CYPs/P450s), heme thiolate proteins, have been under the spotlight due to their regio- and stereo-selective oxidation activities, which has led to the exploration of their applications in almost all known areas of biology. The availability of many genome sequences allows us to understand the evolution of P450s in different organisms, especially in the Bacteria domain. The phenomenon that “P450s play a key role in organisms’ adaptation vis a vis lifestyle of organisms impacts P450 content in their genome” was proposed based on studies on a handful of individual bacterial groups. To have conclusive evidence, one must analyze P450s and their role in secondary metabolism in species with diverse lifestyles but that belong to the same category. We selected species of the phylum Proteobacteria classes, Alpha, Beta, Gamma, Delta, and Epsilon, to address this research gap due to their diverse lifestyle and ancient nature. The study identified that the lifestyle of alpha-, beta-, gamma-, delta-, and epsilon-proteobacterial species profoundly affected P450 profiles in their genomes. The study determined that irrespective of the species associated with different proteobacterial classes, pathogenic species or species adapted to a simple lifestyle lost or had few P450s in their genomes. On the contrary, species with saprophytic or complex lifestyles had many P450s and secondary metabolite biosynthetic gene clusters. The study findings prove that the phenomenon mentioned above is factual, and there is no link between the number and diversity of P450s and the age of the bacteria.

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27

Lu, Yongke, and Arthur I. Cederbaum. "Cytochrome P450S and Alcoholic Liver Disease." Current Pharmaceutical Design 24, no. 14 (July 13, 2018): 1502–17. http://dx.doi.org/10.2174/1381612824666180410091511.

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Alcohol consumption causes liver diseases, designated as Alcoholic Liver Disease (ALD). Because alcohol is detoxified by alcohol dehydrogenase (ADH), a major ethanol metabolism system, the development of ALD was initially believed to be due to malnutrition caused by alcohol metabolism in liver. The discovery of the microsomal ethanol oxidizing system (MEOS) changed this dogma. Cytochrome P450 enzymes (CYP) constitute the major components of MEOS. Cytochrome P450 2E1 (CYP2E1) in MEOS is one of the major ROS generators in liver and is considered to be contributive to ALD. Our labs have been studying the relationship between CYP2E1 and ALD for many years. Recently, we found that human CYP2A6 and its mouse analog CYP2A5 are also induced by alcohol. In mice, the alcohol induction of CYP2A5 is CYP2E1-dependent. Unlike CYP2E1, CYP2A5 protects against the development of ALD. The relationship of CYP2E1, CYP2A5, and ALD is a major focus of this review.

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28

Friedman, Fred, K. "Molecular modeling of mammalian cytochrome P450s." Frontiers in Bioscience 9, no. 1-3 (2004): 2796. http://dx.doi.org/10.2741/1437.

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29

Seward, Harriet E., Hazel M. Girvan, and Andrew W. Munro. "Cytochrome P450s: creating novel ligand sets." Dalton Transactions, no. 21 (2005): 3419. http://dx.doi.org/10.1039/b505362p.

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30

Pichard, L., G. Gillet, J. P. Thenot, and P. Maurel. "Zolpidem metabolism by human cytochrome P450S." Biological Psychiatry 42, no. 1 (July 1997): 45S. http://dx.doi.org/10.1016/s0006-3223(97)87073-4.

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31

Stoilov, Ivaylo. "Cytochrome P450s: coupling development and environment." Trends in Genetics 17, no. 11 (November 2001): 629–32. http://dx.doi.org/10.1016/s0168-9525(01)02444-1.

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Rupasinghe, Sanjeewa, and Mary A. Schuler. "Homology modeling of plant cytochrome P450s." Phytochemistry Reviews 5, no. 2-3 (November 18, 2006): 473–505. http://dx.doi.org/10.1007/s11101-006-9028-y.

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Scott, Emily E., and Aaron G. Bart. "S6.2 - Substrate recognition by cytochrome P450s." Drug Metabolism and Pharmacokinetics 35, no. 1 (2020): S11—S12. http://dx.doi.org/10.1016/j.dmpk.2020.04.310.

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Dai, R., M. R. Pincus, and F. K. Friedman*. "Molecular modeling of mammalian cytochrome P450s." Cellular and Molecular Life Sciences 57, no. 3 (March 2000): 487–99. http://dx.doi.org/10.1007/pl00000709.

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35

Ortiz de Montellano, Paul R., and Sidney D. Nelson. "Rearrangement reactions catalyzed by cytochrome P450s." Archives of Biochemistry and Biophysics 507, no. 1 (March 2011): 95–110. http://dx.doi.org/10.1016/j.abb.2010.10.016.

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36

Nauen, Ralf, Chris Bass, René Feyereisen, and John Vontas. "The Role of Cytochrome P450s in Insect Toxicology and Resistance." Annual Review of Entomology 67, no. 1 (January 7, 2022): 105–24. http://dx.doi.org/10.1146/annurev-ento-070621-061328.

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Insect cytochrome P450 monooxygenases (P450s) perform a variety of important physiological functions, but it is their role in the detoxification of xenobiotics, such as natural and synthetic insecticides, that is the topic of this review. Recent advances in insect genomics and postgenomic functional approaches have provided an unprecedented opportunity to understand the evolution of insect P450s and their role in insect toxicology. These approaches have also been harnessed to provide new insights into the genomic alterations that lead to insecticide resistance, the mechanisms by which P450s are regulated, and the functional determinants of P450-mediated insecticide resistance. In parallel, an emerging body of work on the role of P450s in defining the sensitivity of beneficial insects to insecticides has been developed. The knowledge gained from these studies has applications for the management of P450-mediated resistance in insect pests and can be leveraged to safeguard the health of important beneficial insects.

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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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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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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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Khumalo, Makhosazana Jabulile, Nomfundo Nzuza, Tiara Padayachee, Wanping Chen, Jae-Hyuk Yu, David R. Nelson, and Khajamohiddin Syed. "Comprehensive Analyses of Cytochrome P450 Monooxygenases and Secondary Metabolite Biosynthetic Gene Clusters in Cyanobacteria." International Journal of Molecular Sciences 21, no. 2 (January 19, 2020): 656. http://dx.doi.org/10.3390/ijms21020656.

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The prokaryotic phylum Cyanobacteria are some of the oldest known photosynthetic organisms responsible for the oxygenation of the earth. Cyanobacterial species have been recognised as a prosperous source of bioactive secondary metabolites with antibacterial, antiviral, antifungal and/or anticancer activities. Cytochrome P450 monooxygenases (CYPs/P450s) contribute to the production and diversity of various secondary metabolites. To better understand the metabolic potential of cyanobacterial species, we have carried out comprehensive analyses of P450s, predicted secondary metabolite biosynthetic gene clusters (BGCs), and P450s located in secondary metabolite BGCs. Analysis of the genomes of 114 cyanobacterial species identified 341 P450s in 88 species, belonging to 36 families and 79 subfamilies. In total, 770 secondary metabolite BGCs were found in 103 cyanobacterial species. Only 8% of P450s were found to be part of BGCs. Comparative analyses with other bacteria Bacillus, Streptomyces and mycobacterial species have revealed a lower number of P450s and BGCs and a percentage of P450s forming part of BGCs in cyanobacterial species. A mathematical formula presented in this study revealed that cyanobacterial species have the highest gene-cluster diversity percentage compared to Bacillus and mycobacterial species, indicating that these diverse gene clusters are destined to produce different types of secondary metabolites. The study provides fundamental knowledge of P450s and those associated with secondary metabolism in cyanobacterial species, which may illuminate their value for the pharmaceutical and cosmetics industries.

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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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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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Li, Junhao, Jinya Cai, Haixia Su, Hanwen Du, Juan Zhang, Shihui Ding, Guixia Liu, Yun Tang, and Weihua Li. "Effects of protein flexibility and active site water molecules on the prediction of sites of metabolism for cytochrome P450 2C19 substrates." Molecular BioSystems 12, no. 3 (2016): 868–78. http://dx.doi.org/10.1039/c5mb00784d.

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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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Shoji, Osami, Takashi Fujishiro, Kousuke Nishio, Yukiko Kano, Hiroshi Kimoto, Shih-Cheng Chien, Hiroki Onoda, et al. "A substrate-binding-state mimic of H2O2-dependent cytochrome P450 produced by one-point mutagenesis and peroxygenation of non-native substrates." Catalysis Science & Technology 6, no. 15 (2016): 5806–11. http://dx.doi.org/10.1039/c6cy00630b.

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46

Kaluzhskiy, L. A., P. V. Ershov, K. S. Kurpedinov, D. S. Sonina, E. O. Yablokov, T. V. Shkel, I. V. Haidukevich, G. V. Sergeev, S. A. Usanov, and A. S. Ivanov. "SPR analysis of protein-protein interactions with P450 cytochromes and cytochrome b5 integrated into lipid membrane." Biomeditsinskaya Khimiya 65, no. 5 (2019): 374–79. http://dx.doi.org/10.18097/pbmc20196505374.

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Identification of new protein-protein interactions (PPI) and characterization of quantitative parameters of complex formation represent one of central tasks of protein interactomics. This work is a logical continuation of the cycle of our previous works devoted to the study of PPIs among the components of cytochrome P450-dependent monooxygenase system. Using an optical biosensor of Surface Plasmon Resonance (SPR biosensor), a comparative analysis on the determination of kinetic and equilibrium parameters of complex formation between the membrane-bound hemoprotein cytochrome b5 with cytochrome P450s was performed using two different protocols for protein immobilization: 1) covalent non-oriented one on to the carboxymethyl dextran chip type CM and 2) non-covalent oriented immobilization in the lipid environment on the chip type L1 with internal control of liposomes surface distribution. In the second protocol it was shown that the complex formation was characterized by 2.5 times higher affinity due to an decrease in rate dissociation constants. The appropriateness of using both experimental models is discussed.

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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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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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Larigot, Lucie, Daniel Mansuy, Ilona Borowski, Xavier Coumoul, and Julien Dairou. "Cytochromes P450 of Caenorhabditis elegans: Implication in Biological Functions and Metabolism of Xenobiotics." Biomolecules 12, no. 3 (February 22, 2022): 342. http://dx.doi.org/10.3390/biom12030342.

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Caenorhabditis elegans is an important model used for many aspects of biological research. Its genome contains 76 genes coding for cytochromes P450 (P450s), and few data about the biochemical properties of those P450s have been published so far. However, an increasing number of articles have appeared on their involvement in the metabolism of xenobiotics and endobiotics such as fatty acid derivatives and steroids. Moreover, the implication of some P450s in various biological functions of C. elegans, such as survival, dauer formation, life span, fat content, or lipid metabolism, without mention of the precise reaction catalyzed by those P450s, has been reported in several articles. This review presents the state of our knowledge about C. elegans P450s.

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Pandey, A. V. "Biochemical analysis of mutations in P450 oxidoreductase." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1186–91. http://dx.doi.org/10.1042/bst0341186.

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All microsomal P450s require POR (cytochrome P450 reductase) for catalytic activity. Most of the clinically used drugs are metabolized by a small number of P450s and polymorphisms in the cytochrome P450s are known to cause changes in drug metabolism. We have recently found a number of POR missense mutations in the patients with disordered steroidogenesis. Our initial report described five missense mutations (A284P, R454H, V489E, C566Y and V605F) identified in four patients. We built bacterial expression vectors for each POR variant, purified the membranes expressing normal or variant POR and characterized their activities with cytochrome c and P450c17 assays. We have recently completed an extensive study of the range of POR mutations and characterized the mutants/polymorphisms A112V, T139A, M260V, Y456H, A500V, G536R, L562P, R613X, V628I and F643del from sequencing of patient DNA. We also studied POR variants Y179D, P225L, R313W, G410S and G501R that were available in databases or the published literature. We analysed the mutations with a three-dimensional model of human POR that was based on an essentially similar rat POR with known crystal structure. The missense mutations found in patients with disordered steroidogenesis mapped to functionally important domains of POR and the apparent polymorphisms mapped to less crucial regions. Since a variation in POR can alter the activity of all microsomal P450s, it can also affect the drug metabolism even with a normal P450. Understanding the genetic and biochemical basis of POR-mediated drug metabolism will provide valuable information about possible differences in P450-mediated reactions among the individuals carrying a variant or polymorphic form of POR.

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