New Insights into Cytochrome P450s, 2nd Edition

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

Deadline for manuscript submissions: 31 December 2024 | Viewed by 1412

Special Issue Editor


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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
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Special Issue Information

Dear Colleagues,

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 thousands of entries and 740,283 (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 revealed 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 and AlphaFold3 has opened fast access to the 3D structures of all membrane-bound P50s and of their complexes with associated redox proteins and effectors. Original manuscripts and reviews dealing with any aspect of cytochrome P450s and related aspects are welcome.

Dr. Philippe Urban
Guest Editor

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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 complexes
  • P450 interaction on P450–CPR complexes
  • tripartite P450–CPR–cytochrome b5 complex

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Published Papers (1 paper)

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19 pages, 2281 KiB  
Article
Harnessing Porphyrin Accumulation in Liver Cancer: Combining Genomic Data and Drug Targeting
by Swamy R. Adapa, Pravin Meshram, Abdus Sami and Rays H. Y. Jiang
Biomolecules 2024, 14(8), 959; https://doi.org/10.3390/biom14080959 - 7 Aug 2024
Viewed by 1234
Abstract
The liver, a pivotal organ in human metabolism, serves as a primary site for heme biosynthesis, alongside bone marrow. Maintaining precise control over heme production is paramount in healthy livers to meet high metabolic demands while averting potential toxicity from intermediate metabolites, notably [...] Read more.
The liver, a pivotal organ in human metabolism, serves as a primary site for heme biosynthesis, alongside bone marrow. Maintaining precise control over heme production is paramount in healthy livers to meet high metabolic demands while averting potential toxicity from intermediate metabolites, notably protoporphyrin IX. Intriguingly, our recent research uncovers a disrupted heme biosynthesis process termed ‘porphyrin overdrive’ in cancers that fosters the accumulation of heme intermediates, potentially bolstering tumor survival. Here, we investigate heme and porphyrin metabolism in both healthy and oncogenic human livers, utilizing primary human liver transcriptomics and single-cell RNA sequencing (scRNAseq). Our investigations unveil robust gene expression patterns in heme biosynthesis in healthy livers, supporting electron transport chain (ETC) and cytochrome P450 function without intermediate accumulation. Conversely, liver cancers exhibit rewired heme biosynthesis and a massive downregulation of cytochrome P450 gene expression. Notably, despite diminished drug metabolism, gene expression analysis shows that heme supply to the ETC remains largely unaltered or even elevated with patient cancer progression, suggesting a metabolic priority shift. Liver cancers selectively accumulate intermediates, which are absent in normal tissues, implicating their role in disease advancement as inferred by expression analysis. Furthermore, our findings in genomics establish a link between the aberrant gene expression of porphyrin metabolism and inferior overall survival in aggressive cancers, indicating potential targets for clinical therapy development. We provide in vitro proof-of-concept data on targeting porphyrin overdrive with a drug synergy strategy. Full article
(This article belongs to the Special Issue New Insights into Cytochrome P450s, 2nd Edition)
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