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Cytochrome P450 Mechanism and Reactivity
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Cytochrome P450 Mechanism and Reactivity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 December 2025 | Viewed by 2614

Special Issue Editor

Dr. Samuel De Visser

E-Mail Website
Guest Editor
Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK
Interests: computational chemistry; density functional theory; QM/MM; reaction mechanisms; biomimetic models; enzyme catalysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The cytochrome P450 enzymes are important enzymes in biology with functions related to biosynthesis and biodegradation. They, for instance, are found in the liver, where they metabolize drugs and xenobiotics, while in plants and bacteria, they synthesize natural compounds for defense and signaling. There are still many questions related to the mechanism, structure, function, and reactivity of these enzymes; hence, a Special Issue covering highlights and new research and developments in the field is proposed. We invite submissions on cytochrome P450 research in its broadest form, covering its biology, structure, and reactivity, as well as applications related to biotechnology and bioengineering.

Dr. Samuel De Visser
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • enzyme function
  • enzyme catalysis
  • bioengineering
  • inorganic reaction mechanisms
  • enzyme inhibition

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Published Papers (3 papers)

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Research

17 pages, 1933 KiB  
Article
Profiling the Tox21 Compound Library for Their Inhibitory Effects on Cytochrome P450 Enzymes
by Srilatha Sakamuru, Jameson Travers, Carleen Klumpp-Thomas, Ruili Huang, Kristine L. Witt, Stephen S. Ferguson, Steven O. Simmons, David M. Reif, Anton Simeonov and Menghang Xia
Int. J. Mol. Sci. 2025, 26(11), 4976; https://doi.org/10.3390/ijms26114976 - 22 May 2025
Abstract
Cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins crucial for drug and xenobiotic metabolism. While more than 50 CYPs have been identified in humans, the isoforms from CYP1, 2, and 3 families contribute to the metabolism of about 80% of clinically approved drugs. To [...] Read more.
Cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins crucial for drug and xenobiotic metabolism. While more than 50 CYPs have been identified in humans, the isoforms from CYP1, 2, and 3 families contribute to the metabolism of about 80% of clinically approved drugs. To evaluate the effects of environmental chemicals on the activities of these important CYP enzyme families, we screened the Tox21 10K compound library to identify chemicals that inhibit CYP1A2, 2C9, 2C19, 2D6, and 3A4 enzymes. The data obtained from these five screenings were analyzed to reveal the structural classes responsible for inhibiting multiple and/or selective CYPs. Some known structural compound classes exhibiting pan-CYP inhibition, such as azole fungicides, along with established clinical inhibitors of CYPs, including erythromycin and verapamil inhibiting CYP3A4 and paroxetine and terbinafine inhibiting CYP2D6, were all confirmed in the current study. In addition, some selective CYP inhibitors, previously unknown but with potent activity (IC50 values < 1 µM), were identified. Examples included yohimbine, an indole alkaloid, and loteprednol, a corticosteroid, which showed inhibitory activity in CYP2D6 and 3A4 assays, respectively. These findings suggest that assessment of a candidate compound’s impact on CYP function may allow pre-emptive mitigation of potential adverse reactions and toxicity during drug development or toxicological characterization of environmental chemicals. Full article
(This article belongs to the Special Issue Cytochrome P450 Mechanism and Reactivity)
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41 pages, 4070 KiB  
Article
Defined Diets Link Iron and α-Linolenic Acid to Cyp1b1 Regulation of Neonatal Liver Development Through Srebp Forms and LncRNA H19
by Colin R. Jefcoate, Michele C. Larsen, Yong-Seok Song, Meghan Maguire and Nader Sheibani
Int. J. Mol. Sci. 2025, 26(5), 2011; https://doi.org/10.3390/ijms26052011 - 25 Feb 2025
Viewed by 750
Abstract
Cyp1b1 substantially affects hepatic vascular and stellate cells (HSC) with linkage to liver fibrosis. Despite minimal hepatocyte expression, Cyp1b1 deletion substantially impacts liver gene expression at birth and weaning. The appreciable Cyp1b1 expression in surrounding embryo mesenchyme, during early organogenesis, provides a likely [...] Read more.
Cyp1b1 substantially affects hepatic vascular and stellate cells (HSC) with linkage to liver fibrosis. Despite minimal hepatocyte expression, Cyp1b1 deletion substantially impacts liver gene expression at birth and weaning. The appreciable Cyp1b1 expression in surrounding embryo mesenchyme, during early organogenesis, provides a likely source for Cyp1b1. Here defined breeder diets established major interconnected effects on neonatal liver of α-linolenic acid (ALA), vitamin A deficiency (VAD) and suboptimal iron fed mice. At birth Cyp1b1 deletion and VAD each activated perinatal HSC, while suppressing iron control by hepcidin. Cyp1b1 deletion also advanced the expression of diverse genes linked to iron regulation. Postnatal stimulations of Srebp-regulated genes in the fatty acid and cholesterol biosynthesis pathways were suppressed by Cyp1b1-deficiency. LncRNA H19 and the neutrophil alarmin S100a9 expression increased due to slower postnatal decline with Cyp1b1 deficiency. VAD reversed each of Cyp1b1 effect, probably due to enhanced HSC release of Apo-Rbp4. At birth, Cyp1b1 deletion enhanced H19 participation. Notably, a suppressor (Cnot3) decreased while an activity partner (Ezh2/H3K methylation) increased H19 expression. ALA elevated hepcidin mRNA and countered the inhibitory effects of Cyp1b1 deletion on hepcidin expression. Oxylipin metabolites of ALA from highly expressed hepatic Cyps are potential mediators. Cyp expression patterns demonstrated female dimorphism for neonatal liver. Mothers followed one of three fetal growth support programs probably linked to maturity at conception. Full article
(This article belongs to the Special Issue Cytochrome P450 Mechanism and Reactivity)
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23 pages, 2942 KiB  
Article
Mechanism of the Oxidative Ring-Closure Reaction during Gliotoxin Biosynthesis by Cytochrome P450 GliF
by Muizz Qureshi, Thirakorn Mokkawes, Yuanxin Cao and Sam P. de Visser
Int. J. Mol. Sci. 2024, 25(16), 8567; https://doi.org/10.3390/ijms25168567 - 6 Aug 2024
Cited by 3 | Viewed by 1298
Abstract
During gliotoxin biosynthesis in fungi, the cytochrome P450 GliF enzyme catalyzes an unusual C–N ring-closure step while also an aromatic ring is hydroxylated in the same reaction cycle, which may have relevance to drug synthesis reactions in biotechnology. However, as the details of [...] Read more.
During gliotoxin biosynthesis in fungi, the cytochrome P450 GliF enzyme catalyzes an unusual C–N ring-closure step while also an aromatic ring is hydroxylated in the same reaction cycle, which may have relevance to drug synthesis reactions in biotechnology. However, as the details of the reaction mechanism are still controversial, no applications have been developed yet. To resolve the mechanism of gliotoxin biosynthesis and gain insight into the steps leading to ring-closure, we ran a combination of molecular dynamics and density functional theory calculations on the structure and reactivity of P450 GliF and tested a range of possible reaction mechanisms, pathways and models. The calculations show that, rather than hydrogen atom transfer from the substrate to Compound I, an initial proton transfer transition state is followed by a fast electron transfer en route to the radical intermediate, and hence a non-synchronous hydrogen atom abstraction takes place. The radical intermediate then reacts by OH rebound to the aromatic ring to form a biradical in the substrate that, through ring-closure between the radical centers, gives gliotoxin products. Interestingly, the structure and energetics of the reaction mechanisms appear little affected by the addition of polar groups to the model and hence we predict that the reaction can be catalyzed by other P450 isozymes that also bind the same substrate. Alternative pathways, such as a pathway starting with an electrophilic attack on the arene to form an epoxide, are high in energy and are ruled out. Full article
(This article belongs to the Special Issue Cytochrome P450 Mechanism and Reactivity)
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