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Biomolecules
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New Insights into Cytochrome P450s
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New Insights into Cytochrome P450s

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 24360

Special Issue Editor

Dr. Philippe Urban

E-Mail Website
Guest Editor
Toulouse Biotechnology Institute (TBI), CNRS UMR 5504, 135 Avenue de Rangueil, Toulouse, France
Interests: enzymology; chemical biology; protein structure and dynamics; cytochrome P450; AlphaFold2
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A Special Issue on “New Insights into Cytochrome P450s” is being prepared for the journal Biomolecules. Cytochrome P450s form one of the most populated superfamilies of enzymes in nature. A recent search in the PDB with P450 as a keyword retrieved 1,382 entries and 502,254 (highly redundant) entries in the UniProtKB database. Since their discovery in the late 1950s, these heme–thiolate proteins have been found in both prokaryotes and eukaryotes with a few exceptions such as E. coli. Recently, cytochrome P450s have also been spotted in viruses. Identification and functional studies have shown that some P450s are specific to one substrate while others are able to accommodate a vast array of organic molecules while still differentiating a methyl from an ethyl group. In humans, some cytochrome P450s are involved in the critical metabolism of drug metabolism and pollutant detoxification. Others are involved in steroid and eicosanoid biosynthesis. In plants, most of the secondary metabolism pathways include one or several cytochrome P450s. Eukaryotic P450s, being membrane-bound, are difficult to crystallize. Most of them lack a known experimental 3D structure. The very recent advent of the deep-learning artificial intelligence AlphaFold2 has opened fast access to the 3D structures of all membrane-bound P50s. Original manuscripts and reviews dealing with any aspect of cytochrome P450s and related aspects are very welcome.

Dr. Philippe Urban
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. Biomolecules is an international peer-reviewed open access monthly 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 (P450)
  • cytochrome b5
  • NADPH-P450 oxidoreductase (CPR)
  • heme
  • flavin
  • P450 structure
  • P450 catalytic activities
  • prokaryotic P450
  • eukaryotic P450
  • viral P450
  • drug metabolism
  • detoxification
  • plant secondary metabolisms
  • membrane protein–protein complex
  • AlphaFold
  • AlphaFold2
  • regulation of P450 transcription
  • catalytic cavities
  • substrate access channels
  • prediction of protein–protein complex
  • P450 interaction on P450–CPR complex
  • tripartite P450–CPR–cytochrome b5 complex

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Published Papers (7 papers)

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Research

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20 pages, 3360 KiB  
Article
Single Mutations in Cytochrome P450 Oxidoreductase Can Alter the Specificity of Human Cytochrome P450 1A2-Mediated Caffeine Metabolism
by Francisco Esteves, Cristina M. M. Almeida, Sofia Silva, Inês Saldanha, Philippe Urban, José Rueff, Denis Pompon, Gilles Truan and Michel Kranendonk
Biomolecules 2023, 13(7), 1083; https://doi.org/10.3390/biom13071083 - 6 Jul 2023
Cited by 7 | Viewed by 2229
Abstract
A unique cytochrome P450 (CYP) oxidoreductase (CPR) sustains activities of human microsomal CYPs. Its function requires toggling between a closed conformation enabling electron transfers from NADPH to FAD and then FMN cofactors and open conformations forming complexes and transferring electrons to CYPs. We [...] Read more.
A unique cytochrome P450 (CYP) oxidoreductase (CPR) sustains activities of human microsomal CYPs. Its function requires toggling between a closed conformation enabling electron transfers from NADPH to FAD and then FMN cofactors and open conformations forming complexes and transferring electrons to CYPs. We previously demonstrated that distinct features of the hinge region linking the FAD and FMN domain (FD) modulate conformer poses and their interactions with CYPs. Specific FD residues contribute in a CYP isoform-dependent manner to the recognition and electron transfer mechanisms that are additionally modulated by the structure of CYP-bound substrate. To obtain insights into the underlying mechanisms, we analyzed how hinge region and FD mutations influence CYP1A2-mediated caffeine metabolism. Activities, metabolite profiles, regiospecificity and coupling efficiencies were evaluated in regard to the structural features and molecular dynamics of complexes bearing alternate substrate poses at the CYP active site. Studies reveal that FD variants not only modulate CYP activities but surprisingly the regiospecificity of reactions. Computational approaches evidenced that the considered mutations are generally in close contact with residues at the FD–CYP interface, exhibiting induced fits during complexation and modified dynamics depending on caffeine presence and orientation. It was concluded that dynamic coupling between FD mutations, the complex interface and CYP active site exist consistently with the observed regiospecific alterations. Full article
(This article belongs to the Special Issue New Insights into Cytochrome P450s)
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15 pages, 5296 KiB  
Article
Cytochrome P450 Surface Domains Prevent the β-Carotene Monohydroxylase CYP97H1 of Euglena gracilis from Acting as a Dihydroxylase
by Thomas Lautier, Derek J. Smith, Lay Kien Yang, Xixian Chen, Congqiang Zhang, Gilles Truan and Nic D Lindley
Biomolecules 2023, 13(2), 366; https://doi.org/10.3390/biom13020366 - 15 Feb 2023
Cited by 2 | Viewed by 2389
Abstract
Molecular biodiversity results from branched metabolic pathways driven by enzymatic regioselectivities. An additional complexity occurs in metabolites with an internal structural symmetry, offering identical extremities to the enzymes. For example, in the terpene family, β-carotene presents two identical terminal closed-ring structures. Theses cycles [...] Read more.
Molecular biodiversity results from branched metabolic pathways driven by enzymatic regioselectivities. An additional complexity occurs in metabolites with an internal structural symmetry, offering identical extremities to the enzymes. For example, in the terpene family, β-carotene presents two identical terminal closed-ring structures. Theses cycles can be hydroxylated by cytochrome P450s from the CYP97 family. Two sequential hydroxylations lead first to the formation of monohydroxylated β-cryptoxanthin and subsequently to that of dihydroxylated zeaxanthin. Among the CYP97 dihydroxylases, CYP97H1 from Euglena gracilis has been described as the only monohydroxylase. This study aims to determine which enzymatic domains are involved in this regioselectivity, conferring unique monohydroxylase activity on a substrate offering two identical sites for hydroxylation. We explored the effect of truncations, substitutions and domain swapping with other CYP97 members and found that CYP97H1 harbours a unique N-terminal globular domain. This CYP97H1 N-terminal domain harbours a hydrophobic patch at the entrance of the substrate channel, which is involved in the monohydroxylase activity of CYP97H1. This domain, at the surface of the enzyme, highlights the role of distal and non-catalytic domains in regulating enzyme specificity. Full article
(This article belongs to the Special Issue New Insights into Cytochrome P450s)
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17 pages, 2565 KiB  
Article
Characterization of a Virally Encoded Flavodoxin That Can Drive Bacterial Cytochrome P450 Monooxygenase Activity
by David C. Lamb, Jared V. Goldstone, Bin Zhao, Li Lei, Jonathan G. L. Mullins, Michael J. Allen, Steven L. Kelly and John J. Stegeman
Biomolecules 2022, 12(8), 1107; https://doi.org/10.3390/biom12081107 - 11 Aug 2022
Cited by 2 | Viewed by 2600
Abstract
Flavodoxins are small electron transport proteins that are involved in a myriad of photosynthetic and non-photosynthetic metabolic pathways in Bacteria (including cyanobacteria), Archaea and some algae. The sequenced genome of 0305φ8-36, a large bacteriophage that infects the soil bacterium Bacillus thuringiensis, was [...] Read more.
Flavodoxins are small electron transport proteins that are involved in a myriad of photosynthetic and non-photosynthetic metabolic pathways in Bacteria (including cyanobacteria), Archaea and some algae. The sequenced genome of 0305φ8-36, a large bacteriophage that infects the soil bacterium Bacillus thuringiensis, was predicted to encode a putative flavodoxin redox protein. Here we confirm that 0305φ8-36 phage encodes a FMN-containing flavodoxin polypeptide and we report the expression, purification and enzymatic characterization of the recombinant protein. Purified 0305φ8-36 flavodoxin has near-identical spectral properties to control, purified Escherichia coli flavodoxin. Using in vitro assays we show that 0305φ8-36 flavodoxin can be reconstituted with E. coli flavodoxin reductase and support regio- and stereospecific cytochrome P450 CYP170A1 allyl-oxidation of epi-isozizaene to the sesquiterpene antibiotic product albaflavenone, found in the soil bacterium Streptomyces coelicolor. In vivo, 0305φ8-36 flavodoxin is predicted to mediate the 2-electron reduction of the β subunit of phage-encoded ribonucleotide reductase to catalyse the conversion of ribonucleotides to deoxyribonucleotides during viral replication. Our results demonstrate that this phage flavodoxin has the potential to manipulate and drive bacterial P450 cellular metabolism, which may affect both the host biological fitness and the communal microbiome. Such a scenario may also be applicable in other viral-host symbiotic/parasitic relationships. Full article
(This article belongs to the Special Issue New Insights into Cytochrome P450s)
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16 pages, 4049 KiB  
Article
Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4
by Ilia G. Denisov, Yelena V. Grinkova, Mark A. McLean, Tyler Camp and Stephen G. Sligar
Biomolecules 2022, 12(6), 853; https://doi.org/10.3390/biom12060853 - 20 Jun 2022
Cited by 14 | Viewed by 3826
Abstract
Human cytochrome P450 CYP3A4 is involved in the processing of more than 35% of current pharmaceuticals and therefore is responsible for multiple drug-drug interactions (DDI). In order to develop a method for the detection and prediction of the possible involvement of new drug [...] Read more.
Human cytochrome P450 CYP3A4 is involved in the processing of more than 35% of current pharmaceuticals and therefore is responsible for multiple drug-drug interactions (DDI). In order to develop a method for the detection and prediction of the possible involvement of new drug candidates in CYP3A4-mediated DDI, we evaluated the application of midazolam (MDZ) as a probe substrate. MDZ is hydroxylated by CYP3A4 in two positions: 1-hydroxy MDZ formed at lower substrate concentrations, and up to 35% of 4-hydroxy MDZ at high concentrations. The ratio of the formation rates of these two products (the site of metabolism ratio, SOM) was used as a measure of allosteric heterotropic interactions caused by effector molecules using CYP3A4 incorporated in lipid nanodiscs. The extent of the changes in the SOM in the presence of effectors is determined by chemical structure and is concentration-dependent. MD simulations of CYP3A4 in the lipid bilayer suggest that experimental results can be explained by the movement of the F-F’ loop and concomitant changes in the shape and volume of the substrate-binding pocket. As a result of PGS binding at the allosteric site, several residues directly contacting MDZ move away from the substrate molecule, enabling the repositioning of the latter for minor product formation. Full article
(This article belongs to the Special Issue New Insights into Cytochrome P450s)
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19 pages, 1952 KiB  
Article
Exploring the Interactome of Cytochrome P450 2E1 in Human Liver Microsomes with Chemical Crosslinking Mass Spectrometry
by Dmitri R. Davydov, Bikash Dangi, Guihua Yue, Deepak S. Ahire, Bhagwat Prasad and Victor G. Zgoda
Biomolecules 2022, 12(2), 185; https://doi.org/10.3390/biom12020185 - 22 Jan 2022
Cited by 6 | Viewed by 4039
Abstract
Aiming to elucidate the system-wide effects of the alcohol-induced increase in the content of cytochrome P450 2E1 (CYP2E1) on drug metabolism, we explored the array of its protein-protein interactions (interactome) in human liver microsomes (HLM) with chemical crosslinking mass spectrometry (CXMS). Our strategy [...] Read more.
Aiming to elucidate the system-wide effects of the alcohol-induced increase in the content of cytochrome P450 2E1 (CYP2E1) on drug metabolism, we explored the array of its protein-protein interactions (interactome) in human liver microsomes (HLM) with chemical crosslinking mass spectrometry (CXMS). Our strategy employs membrane incorporation of purified CYP2E1 modified with photoreactive crosslinkers benzophenone-4-maleimide and 4-(N-succinimidylcarboxy)benzophenone. Exposure of bait-incorporated HLM samples to light was followed by isolating the His-tagged bait protein and its crosslinked aggregates on Ni-NTA agarose. Analyzing the individual bands of SDS-PAGE slabs of thereby isolated protein with the toolset of untargeted proteomics, we detected the crosslinked dimeric and trimeric complexes of CYP2E1 with other drug-metabolizing enzymes. Among the most extensively crosslinked partners of CYP2E1 are the cytochromes P450 2A6, 2C8, 3A4, 4A11, and 4F2, UDP-glucuronosyltransferases (UGTs) 1A and 2B, fatty aldehyde dehydrogenase (ALDH3A2), epoxide hydrolase 1 (EPHX1), disulfide oxidase 1α (ERO1L), and ribophorin II (RPN2). These results demonstrate the exploratory power of the proposed CXMS strategy and corroborate the concept of tight functional integration in the human drug-metabolizing ensemble through protein-protein interactions of the constituting enzymes. Full article
(This article belongs to the Special Issue New Insights into Cytochrome P450s)
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Review

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17 pages, 1512 KiB  
Review
Promiscuity, a Driver of Plant Cytochrome P450 Evolution?
by Danièle Werck-Reichhart
Biomolecules 2023, 13(2), 394; https://doi.org/10.3390/biom13020394 - 18 Feb 2023
Cited by 17 | Viewed by 3456
Abstract
Plant cytochrome P450 monooxygenases were long considered to be highly substrate-specific, regioselective and stereoselective enzymes, in this respect differing from their animal counterparts. The functional data that have recently accumulated clearly counter this initial dogma. Highly promiscuous P450 enzymes have now been reported, [...] Read more.
Plant cytochrome P450 monooxygenases were long considered to be highly substrate-specific, regioselective and stereoselective enzymes, in this respect differing from their animal counterparts. The functional data that have recently accumulated clearly counter this initial dogma. Highly promiscuous P450 enzymes have now been reported, mainly in terpenoid pathways with functions in plant adaptation, but also some very versatile xenobiotic/herbicide metabolizers. An overlap and predictable interference between endogenous and herbicide metabolism are starting to emerge. Both substrate preference and permissiveness vary between plant P450 families, with high promiscuity seemingly favoring retention of gene duplicates and evolutionary blooms. Yet significant promiscuity can also be observed in the families under high negative selection and with essential functions, usually enhanced after gene duplication. The strategies so far implemented, to systematically explore P450 catalytic capacity, are described and discussed. Full article
(This article belongs to the Special Issue New Insights into Cytochrome P450s)
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21 pages, 8667 KiB  
Review
Cytochromes P450 of Caenorhabditis elegans: Implication in Biological Functions and Metabolism of Xenobiotics
by Lucie Larigot, Daniel Mansuy, Ilona Borowski, Xavier Coumoul and Julien Dairou
Biomolecules 2022, 12(3), 342; https://doi.org/10.3390/biom12030342 - 22 Feb 2022
Cited by 26 | Viewed by 4633
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue New Insights into Cytochrome P450s)
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