MODERNIZATION OF CYTOCHROME P450 CLASSIFICATION BASED ON A STRUCTURE-FUNCTION APPROACH
DOI:
https://doi.org/10.11603/mcch.2410-681X.2025.i2.15520Keywords:
cytochromes P450; classification; structure-function approach; ligands; specificity; pharmacology; toxicology; biotechnology.Abstract
Introduction. Cytochromes P450 (CYPs) are key enzymes involved in the metabolism of xenobiotics and endogenous compounds. Traditionally, they are classified according to genetic origin, amino acid sequence, and family affiliation. However, rapid advancements in structural bioinformatics, pharmacophore modeling, and metabolomics offer a new perspective in which enzymes are viewed as structure-functional units of chemical recognition. Objective. To critically analyze the updated classification of CYPs, taking into account current data on their spatial organization and dynamic properties, which determine ligand interaction specificity, catalytic mechanisms, and the variability of substrate and metabolite transport channels. Methods. A comprehensive analysis of scientific publications focused on CYP classification, structural features, and functional characteristics was conducted. Sources of information included peer-reviewed articles from databases such as PubMed, Scopus, and Web of Science, as well as structural data from the Protein Data Bank (PDB), patent literature, and open-access chemical and biological databases (ChEMBL, DrugBank). Results and Discussion. The study confirms the necessity for an updated classification that incorporates a functional CYP system characterizing the enzyme's catalytic reactions. The structural component of this system categorizes CYPs based on molecular architecture, topology, conformational flexibility, oligomerization mechanisms, membrane interactions, and structure-determined functions. Conclusions. Existing publications and models highlight the potential of a structure-function-based classification to enhance the integration of structural, biochemical, and evolutionary data, thereby creating a more objective and informative system that goes beyond traditional sequence-based analysis of CYPs. This approach is expected to become a valuable tool in pharmacology and personalized medicine.
References
Zanger U., Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013. Vol. 138, № 1. P. 103–41. DOI: 10.1016/j.pharmthera.2012.12.007.
Chang G., Kam P. The physiological and pharmacological roles of cytochrome P450 isoenzymes. Anaesthesia. 1999. Vol. 54, № 1. P. 42–50. DOI: org/10.1046/ j.1365-2044.1999.00602.x.
Evolution of the cytochrome P450 superfamily: sequence alignments and pharmacogenetics/ D. F. Lewis, et al. Mutat Res. 1998. Vol. 410, № 3. P. 245–70. DOI: 10.1016/s1383-5742(97)00040-9.
Konrat R. The protein meta-structure: a novel concept for chemical and molecular biology. Cell. Mol. Life Sci. 2009. Vol. 66, № 22. P. 3625–3639. DOI: 10.1007/ s00018-009-0117-0.
Modelling three-dimensional protein structures for applications in drug design / Schmidt T., ei al. Drug Discov. Today. 2013. Vol. 9, № 7. P. 890–897. DOI: 10.1016/ j.drudis.2013.10.027.
Gilani B., Cassagnol M. Biochemistry, Cytochrome P450 [Updated 2023 Apr 24]. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. URL: https://www.ncbi.nlm.nih.gov/books/NBK557698/.
Werck-Reichhart D., Feyereisen R. Cytochromes P450: a success story. Genome Biol. 2000. Vol. 1, № 1. P. 303–305. DOI: 10.1186/gb-2000-1-6- reviews3003.
Fungal cytochrome P450 database / Park J., et al. BMC Genomics. 2008. Vol. 28, № 7. P. 402–410. DOI: 10.1186/1471-2164-9-402.
Manikandan P., Nagin S. Cytochrome P450 Structure, Function and Clinical Significance: A Review. Curr. Drug Targets. 2018. Vol. 19, № 1. P. 38–54. DOI: 10.2174/1389450118666170125144557.
Zhang T., Dai H., Liu L. A. Classification Models for Predicting Cytochrome P450 Enzyme-Substrate Selectivity. Mol. Inform. 2012. Vol. 31, № 1. P. 53–62. DOI: 10.1002/minf.201100052.
From closed to open: three dynamic states of membrane-bound cytochrome P4503A4 / Spanke V., et al. J. Comput. Aided Mol. Des. 2025. Vol. 39, № 12. DOI: 10.1007/s10822-025-00589-1.
Abdelmonem B. H. Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review. Biomedicines. 2024. Vol. 12, № 7. P. 14–67. DOI: 10.3390/biomedicines12071467.
The ins and outs of cytochrome P450s. / Cojocaru V., et al. Biochim. Biophys. Acta. 2007. Vol. 1770, № 3. P. 390–401. DOI: 10.1016/j.bbagen.2006.07.005.
Poulos T. L. Heme enzyme structure and function. Chem. Rev. 2014. Vol. 114, № 7. P. 3919–3962. DOI: 10.1021/cr400415k.
Werck-Reichhart D., Feyereisen R. Cytochromes P450: a success story. Genome Biol. 2000. Vol. 1, № 6. P. 303–309. DOI: 10.1186/gb-2000-1-6-reviews3003.
Nelson D. R. Cytochrome P450 diversity in the tree of life. BBA Proteins Proteomics. 2018. Vol. 866, № 1. P. 141–154. DOI: 10.1016/j.bbapap.2017.05.003.
Structure and Chemistry of Cytochrome P450 / Denisov I., et al. /Chem. Rev. 2005. Vol. 105, № 6. P. 2253–2278. DOI: 10.1021/c0307143.
Structural characterization of human cytochrome P450 2C19: Active site differences between P450s 2C8, 2C9, and 2C19* / Reynald R., et al. J. Biol. Chem. 2012. Vol. 287, № 53. P. 44581–44591. DOI: 10.1074/ jbc.M112.424895.
Interactions among cytochromes P450 in microsomal membranes: oligomerization of cytochromes P450 3A4, 3A5, and 2E1 and its functional consequences / Davydov D., et al. J. Biol. Chem. 2015. Vol. 290, № 6. P. 3850–3864. DOI: 10.1074/jbc.M114.615443.
Davydov D. Microsomal monooxygenase as a multienzyme system: the role of P450–P450 interactions. Expert Opin. Drug Metab. Toxicol. 2011. Vol. 7, № 5. P. 543–558. DOI: 10.1517/17425255.2011.562194.
Reed R., Backe W. Formation of P450–P450 complexes and their effect on P450 function. Pharmacol. Ther. 2011. Vol. 133, № 3. P. 299–310. DOI: 10.1016/ j.pharmthera.2011.11.009.
Kandel S., Lampe J. Role of protein–protein interactions in cytochrome P450-mediated drug metabolism and toxicity. Chem. Res. Toxicol. 2014. Vol. 27, № 9. P. 1474–1486. DOI: 10.1021/tx500203s.
Flexibility of Human Cytochromes P450: Molecular Dynamics Reveals Differences between CYPs 3A4, 2C9, and 2A6, which correlate with their substrate preferences / Skopalík J., et al. J. Phys. Chem. B. 2008. Vol. 112, № 27. P. 8165–8173. DOI: 10.1021/jp800311c.
Three dynamic states of membrane-bound cytochrome P450 3A4 / Spanke V., et al. J. Comput. Aided Mol. Des. 2025. Vol. 39, № 1. P. 12. DOI: 10.1007/ s10822-025-00589-1.
Conformational Plasticity and Structure/Function Relationships in Cytochromes P450 / Pochapsky T., et al. Antioxid. Redox Signal. 2010. Vol. 13, № 8. P. 1273–1296. DOI: 10.1089/ars.2010.3109.
Prasad S., Mitra S. Role of Protein and Substrate Dynamics in Catalysis by Pseudomonas putida Cytochrome P450cam. Biochemistry. 2002. Vol. 41. № 49. P. 14499–14508. DOI: 10.1021/bi026379e.
Computational Analysis of Protein Tunnels and Channels / Brezovsky J., et al. Methods Mol. Biol. 2018. Vol. 1685. P. 25–42. DOI: 10.1007/978-1-4939-7366-8_3.
CAVER Analyst 2.0: analysis and visualization of channels and tunnels in protein structures and molecular dynamics trajectorie / Jurcik A., et al. Bioinformatics. 2018. Vol. 34, № 20. P. 3586–3588. DOI: 10.1093/ bioinformatics/bty386.
Abdelmonem B. Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review. Biomedicines. 2024. Vol. 12, № 7. P. 1467–1473. DOI: 10.3390/biomedicines12071467.
Головенко М. Я., Ларіонов В. Б. Спектральна характеристика цитохрому P450 при взаємодії з пропоксазепамом та його метаболітом. Медична та клінічна хімія. 2023. Т. 25, № 2. С. 14–19. DOI: 10.11603/ mcch.2410-681X.2023.i2.13854.
Cytochrome P450 Enzymes and Drug Metabolism in Humans / Mingzhe Zhao, et al. Int J Mol Sci. 2021. Vol. 26, № 22 (23). P. 128–138. DOI: 10.3390/ ijms222312808.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Medical and Clinical Chemistry
This work is licensed under a Creative Commons Attribution 4.0 International License.
