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Cytochrome P450
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Cytochrome P450

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Computational and Theoretical Chemistry".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 15471

Special Issue Editor

Prof. Dr. Hajime Hirao

E-Mail Website
Guest Editor
School of Medicine, The Chinese University of Hong Kong, Longgang District, Shenzhen 518172, China
Interests: computational chemistry; chemical reactions; molecular interaction; chemical bonding
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The cytochrome P450 enzymes (P450s) represent a biologically and chemically fascinating class of enzymes, renowned for their crucial role in drug metabolism and their exceptional catalytic capabilities. Delving into the underlying mechanisms of P450s is not just a matter of academic interest; it also paves the way for leveraging their potential in practical applications. This Special Issue aims to explore recent endeavors in examining P450s and associated enzymes using theoretical and experimental techniques.

Prof. Dr. Hajime Hirao
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cytochrome P450
  • enzyme catalysis
  • drug metabolism
  • computational chemistry
  • experimental characterization
  • data analysis and prediction

Published Papers (5 papers)

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Research

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19 pages, 8701 KiB  
Article
Deciphering the Molecular Mechanisms of Reactive Metabolite Formation in the Mechanism-Based Inactivation of Cytochrome p450 1B1 by 8-Methoxypsoralen and Assessing the Driving Effect of phe268
by Emadeldin M. Kamel, Maha A. Alwaili, Hassan A. Rudayni, Ahmed A. Allam and Al Mokhtar Lamsabhi
Molecules 2024, 29(7), 1433; https://doi.org/10.3390/molecules29071433 - 22 Mar 2024
Viewed by 483
Abstract
This study provides a comprehensive computational exploration of the inhibitory activity and metabolic pathways of 8-methoxypsoralen (8-MP), a furocoumarin derivative used for treating various skin disorders, on cytochrome P450 (P450). Employing quantum chemical DFT calculations, molecular docking, and molecular dynamics (MD) simulations analyses, [...] Read more.
This study provides a comprehensive computational exploration of the inhibitory activity and metabolic pathways of 8-methoxypsoralen (8-MP), a furocoumarin derivative used for treating various skin disorders, on cytochrome P450 (P450). Employing quantum chemical DFT calculations, molecular docking, and molecular dynamics (MD) simulations analyses, the biotransformation mechanisms and the active site binding profile of 8-MP in CYP1B1 were investigated. Three plausible inactivation mechanisms were minutely scrutinized. Further analysis explored the formation of reactive metabolites in subsequent P450 metabolic processes, including covalent adduct formation through nucleophilic addition to the epoxide, 8-MP epoxide hydrolysis, and non-CYP-catalyzed epoxide ring opening. Special attention was paid to the catalytic effect of residue Phe268 on the mechanism-based inactivation (MBI) of P450 by 8-MP. Energetic profiles and facilitating conditions revealed a slight preference for the C4′=C5′ epoxidation pathway, while recognizing a potential kinetic competition with the 8-OMe demethylation pathway due to comparable energy demands. The formation of covalent adducts via nucleophilic addition, particularly by phenylalanine, and the generation of potentially harmful reactive metabolites through autocatalyzed ring cleavage are likely to contribute significantly to P450 metabolism of 8-MP. Our findings highlight the key role of Phe268 in retaining 8-MP within the active site of CYP1B1, thereby facilitating initial oxygen addition transition states. This research offers crucial molecular-level insights that may guide the early stages of drug discovery and risk assessment related to the use of 8-MP. Full article
(This article belongs to the Special Issue Cytochrome P450)
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12 pages, 2605 KiB  
Article
Synergistic Charge Transfer Effect in Ferrous Heme–CO Bonding within Cytochrome P450
by Enhua Zhang and Hajime Hirao
Molecules 2024, 29(4), 873; https://doi.org/10.3390/molecules29040873 - 16 Feb 2024
Viewed by 686
Abstract
We conducted ab initio valence bond (VB) calculations employing the valence bond self-consistent field (VBSCF) and breathing orbital valence bond (BOVB) methods to investigate the nature of the coordination bonding between ferrous heme and carbon monoxide (CO) within cytochrome P450. These calculations revealed [...] Read more.
We conducted ab initio valence bond (VB) calculations employing the valence bond self-consistent field (VBSCF) and breathing orbital valence bond (BOVB) methods to investigate the nature of the coordination bonding between ferrous heme and carbon monoxide (CO) within cytochrome P450. These calculations revealed the significant influence exerted by both proximal and equatorial ligands on the π-backdonation effect from the heme to the CO. Moreover, our VB calculations unveiled a phenomenon of synergistic charge transfer (sCT). In the case of ferrous heme–CO bonding, the significant stabilization in this sCT arises from cooperative resonance between the VB structures associated with σ donation and π backdonation. Unlike many other ligands, CO possesses the unique ability to establish two mutually perpendicular π-backdonation orbital interaction pairs, leading to an intensified stabilization attributed to σ–π resonance. Furthermore, while of a smaller energy magnitude, sCT due to one π–π pair is also present, contributing to the differential stabilization of ferrous heme–CO bonding. Full article
(This article belongs to the Special Issue Cytochrome P450)
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13 pages, 6165 KiB  
Article
Cloning and Functional Characterization of NADPH-Cytochrome P450 Reductases in Aconitum vilmorinianum
by Jingping Cheng, Guodong Li, Xue Wang, Congwei Yang, Furong Xu, Zigang Qian and Xiaohui Ma
Molecules 2023, 28(21), 7409; https://doi.org/10.3390/molecules28217409 - 03 Nov 2023
Cited by 1 | Viewed by 591
Abstract
Diterpenoid alkaloids (DAs) are major pharmacologically active ingredients of Aconitum vilmorinianum, an important medicinal plant. Cytochrome P450 monooxygenases (P450s) are involved in the DA biosynthetic pathway, and the electron transfer reaction of NADPH-cytochrome P450 reductase (CPR) with P450 is the rate-limiting step [...] Read more.
Diterpenoid alkaloids (DAs) are major pharmacologically active ingredients of Aconitum vilmorinianum, an important medicinal plant. Cytochrome P450 monooxygenases (P450s) are involved in the DA biosynthetic pathway, and the electron transfer reaction of NADPH-cytochrome P450 reductase (CPR) with P450 is the rate-limiting step of the P450 redox reaction. Here, we identified and characterized two homologs of CPR from Aconitum vilmorinianum. The open reading frames of AvCPR1 and AvCPR2 were found to be 2103 and 2100 bp, encoding 700 and 699 amino acid residues, respectively. Phylogenetic analysis characterized both AvCPR1 and AvCPR2 as class II CPRs. Cytochrome c and ferricyanide could be reduced with the recombinant proteins of AvCPR1 and AvCPR2. Both AvCPR1 and AvCPR2 were expressed in the roots, stems, leaves, and flowers of A. vilmorinianum. The expression levels of AvCPR1 and AvCPR2 were significantly increased in response to methyl jasmonate (MeJA) treatment. The yeasts co-expressing AvCPR1/AvCPR2/SmCPR1 and CYP76AH1 all produced ferruginol, indicating that AvCPR1 and AvCPR2 can transfer electrons to CYP76AH1 in the same manner as SmCPR1. Docking analysis confirmed the experimentally deduced functional activities of AvCPR1 and AvCPR2 for FMN, FAD, and NADPH. The functional characterization of AvCPRs will be helpful in disclosing molecular mechanisms relating to the biosynthesis of diterpene alkaloids in A. vilmorinianum. Full article
(This article belongs to the Special Issue Cytochrome P450)
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18 pages, 4822 KiB  
Article
Melatonin Activation by Human Cytochrome P450 Enzymes: A Comparison between Different Isozymes
by Thirakorn Mokkawes, Tamar De Visser, Yuanxin Cao and Sam P. De Visser
Molecules 2023, 28(19), 6961; https://doi.org/10.3390/molecules28196961 - 06 Oct 2023
Cited by 3 | Viewed by 10810
Abstract
Cytochrome P450 enzymes in the human body play a pivotal role in both the biosynthesis and the degradation of the hormone melatonin. Melatonin plays a key role in circadian rhythms in the body, but its concentration is also linked to mood fluctuations as [...] Read more.
Cytochrome P450 enzymes in the human body play a pivotal role in both the biosynthesis and the degradation of the hormone melatonin. Melatonin plays a key role in circadian rhythms in the body, but its concentration is also linked to mood fluctuations as well as emotional well-being. In the present study, we present a computational analysis of the binding and activation of melatonin by various P450 isozymes that are known to yield different products and product distributions. In particular, the P450 isozymes 1A1, 1A2, and 1B1 generally react with melatonin to provide dominant aromatic hydroxylation at the C6-position, whereas the P450 2C19 isozyme mostly provides O-demethylation products. To gain insight into the origin of these product distributions of the P450 isozymes, we performed a comprehensive computational study of P450 2C19 isozymes and compared our work with previous studies on alternative isozymes. The work covers molecular mechanics, molecular dynamics and quantum mechanics approaches. Our work highlights major differences in the size and shape of the substrate binding pocket amongst the different P450 isozymes. Consequently, substrate binding and positioning in the active site varies substantially within the P450 isozymes. Thus, in P450 2C19, the substrate is oriented with its methoxy group pointing towards the heme, and therefore reacts favorably through hydrogen atom abstraction, leading to the production of O-demethylation products. On the other hand, the substrate-binding pockets in P450 1A1, 1A2, and 1B1 are tighter, direct the methoxy group away from the heme, and consequently activate an alternative site and lead to aromatic hydroxylation instead. Full article
(This article belongs to the Special Issue Cytochrome P450)
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Review

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63 pages, 9408 KiB  
Review
The Nature of the Chemical Bonds of High-Valent Transition–Metal Oxo (M=O) and Peroxo (MOO) Compounds: A Historical Perspective of the Metal Oxyl–Radical Character by the Classical to Quantum Computations
by Kizashi Yamaguchi, Hiroshi Isobe, Mitsuo Shoji, Takashi Kawakami and Koichi Miyagawa
Molecules 2023, 28(20), 7119; https://doi.org/10.3390/molecules28207119 - 16 Oct 2023
Cited by 2 | Viewed by 2334
Abstract
This review article describes a historical perspective of elucidation of the nature of the chemical bonds of the high-valent transition metal oxo (M=O) and peroxo (M-O-O) compounds in chemistry and biology. The basic concepts and theoretical backgrounds of the broken-symmetry (BS) method are [...] Read more.
This review article describes a historical perspective of elucidation of the nature of the chemical bonds of the high-valent transition metal oxo (M=O) and peroxo (M-O-O) compounds in chemistry and biology. The basic concepts and theoretical backgrounds of the broken-symmetry (BS) method are revisited to explain orbital symmetry conservation and orbital symmetry breaking for the theoretical characterization of four different mechanisms of chemical reactions. Beyond BS methods using the natural orbitals (UNO) of the BS solutions, such as UNO CI (CC), are also revisited for the elucidation of the scope and applicability of the BS methods. Several chemical indices have been derived as the conceptual bridges between the BS and beyond BS methods. The BS molecular orbital models have been employed to explain the metal oxyl-radical character of the M=O and M-O-O bonds, which respond to their radical reactivity. The isolobal and isospin analogy between carbonyl oxide R2C-O-O and metal peroxide LFe-O-O has been applied to understand and explain the chameleonic chemical reactivity of these compounds. The isolobal and isospin analogy among Fe=O, O=O, and O have also provided the triplet atomic oxygen (3O) model for non-heme Fe(IV)=O species with strong radical reactivity. The chameleonic reactivity of the compounds I (Cpd I) and II (Cpd II) is also explained by this analogy. The early proposals obtained by these theoretical models have been examined based on recent computational results by hybrid DFT (UHDFT), DLPNO CCSD(T0), CASPT2, and UNO CI (CC) methods and quantum computing (QC). Full article
(This article belongs to the Special Issue Cytochrome P450)
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