Inference of Cytochrome P450 Evolutionary History Using Structural and Physicochemical Metrics.

IF 2.8 2区 生物学 Q2 EVOLUTIONARY BIOLOGY
Jamie D Dixson, Abhijay Azad, Pamela A Padilla, Rajeev K Azad
{"title":"Inference of Cytochrome P450 Evolutionary History Using Structural and Physicochemical Metrics.","authors":"Jamie D Dixson, Abhijay Azad, Pamela A Padilla, Rajeev K Azad","doi":"10.1093/gbe/evaf178","DOIUrl":null,"url":null,"abstract":"<p><p>Cytochrome P450s are a superfamily of heme-binding monooxygenases involved with the detoxification of intrinsic and extrinsic toxins. They are near ubiquitous within biological domains and are found in all domains. Members of families within the superfamily are defined based on amino acid identity thresholds, with thresholds as low as 40% in some families. Relationships among Cytochrome P450 families have proven elusive due to sub-Twilight Zone interfamily identities (<30%) that result in poor multiple sequence alignment quality and thus low levels of support for downstream phylogenetic reconstructions. Despite the low identities, Cytochrome P450 structures are remarkably well conserved both within and among families. In such cases, structural phylogenetics has the potential to unveil elusive relationships because the selectively favored physicochemical properties giving rise to the structure and function of the proteins persist despite sequence-level divergence. Recently, in two separate publications, we demonstrated that by utilizing physicochemical vectors, dynamic time warping, and hierarchical clustering (PCDTW), large swaths of protein domain families and betacoronavirus receptor-binding domain clades were congruent with validated functional/structural relationships. These were important findings because anomalous sequence alignment-based maximum likelihood phylogenetic findings, which were not congruent with the known functional relationships, were resolved. That also validated the use of physicochemical vectors in making inferences about structural/functional homology. Additionally, it illuminated that the same methods might be applied to other protein families with relationships that are difficult to resolve from sequence data alone. Herein, we used Molecular Weight and Hydrophobicity Physicochemical Dynamic Time Warping (MWHP PCDTW) along with structural and sequence alignment-based phylogenetic methodologies to analyze all of the Cytochrome P450s found both in the high-fidelity Structural Classificaction of Proteins (SCOP) database and the reviewed sequences with both experimentally resolved and de novo predicted structures in the Protein Data Bank and the AlphaFold (AF) Protein Structure Database, respectively. We compared the resulting phylogenetic topologies and found that in some cases, structure-based methods may be less able to resolve random/convergent similarity than physicochemical and sequence-based methodologies. This finding agrees with previous findings that demonstrate the usefulness of physicochemical properties in resolving both random structural similarity and potentially convergent relationships.</p>","PeriodicalId":12779,"journal":{"name":"Genome Biology and Evolution","volume":" ","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502919/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Biology and Evolution","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1093/gbe/evaf178","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"EVOLUTIONARY BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Cytochrome P450s are a superfamily of heme-binding monooxygenases involved with the detoxification of intrinsic and extrinsic toxins. They are near ubiquitous within biological domains and are found in all domains. Members of families within the superfamily are defined based on amino acid identity thresholds, with thresholds as low as 40% in some families. Relationships among Cytochrome P450 families have proven elusive due to sub-Twilight Zone interfamily identities (<30%) that result in poor multiple sequence alignment quality and thus low levels of support for downstream phylogenetic reconstructions. Despite the low identities, Cytochrome P450 structures are remarkably well conserved both within and among families. In such cases, structural phylogenetics has the potential to unveil elusive relationships because the selectively favored physicochemical properties giving rise to the structure and function of the proteins persist despite sequence-level divergence. Recently, in two separate publications, we demonstrated that by utilizing physicochemical vectors, dynamic time warping, and hierarchical clustering (PCDTW), large swaths of protein domain families and betacoronavirus receptor-binding domain clades were congruent with validated functional/structural relationships. These were important findings because anomalous sequence alignment-based maximum likelihood phylogenetic findings, which were not congruent with the known functional relationships, were resolved. That also validated the use of physicochemical vectors in making inferences about structural/functional homology. Additionally, it illuminated that the same methods might be applied to other protein families with relationships that are difficult to resolve from sequence data alone. Herein, we used Molecular Weight and Hydrophobicity Physicochemical Dynamic Time Warping (MWHP PCDTW) along with structural and sequence alignment-based phylogenetic methodologies to analyze all of the Cytochrome P450s found both in the high-fidelity Structural Classificaction of Proteins (SCOP) database and the reviewed sequences with both experimentally resolved and de novo predicted structures in the Protein Data Bank and the AlphaFold (AF) Protein Structure Database, respectively. We compared the resulting phylogenetic topologies and found that in some cases, structure-based methods may be less able to resolve random/convergent similarity than physicochemical and sequence-based methodologies. This finding agrees with previous findings that demonstrate the usefulness of physicochemical properties in resolving both random structural similarity and potentially convergent relationships.

Abstract Image

Abstract Image

Abstract Image

利用结构和理化指标推断细胞色素P450的进化史。
细胞色素P450's是血红素结合单加氧酶的超家族,参与内源性和外源性毒素的解毒。它们在生物领域中几乎无处不在,在所有领域都有发现。超家族内的家族成员是根据氨基酸识别阈值来定义的,某些家族的阈值低至40%。细胞色素P450家族之间的关系被证明是难以捉摸的,因为家族间的身份处于亚模糊区(
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Genome Biology and Evolution
Genome Biology and Evolution EVOLUTIONARY BIOLOGY-GENETICS & HEREDITY
CiteScore
5.80
自引率
6.10%
发文量
169
审稿时长
1 months
期刊介绍: About the journal Genome Biology and Evolution (GBE) publishes leading original research at the interface between evolutionary biology and genomics. Papers considered for publication report novel evolutionary findings that concern natural genome diversity, population genomics, the structure, function, organisation and expression of genomes, comparative genomics, proteomics, and environmental genomic interactions. Major evolutionary insights from the fields of computational biology, structural biology, developmental biology, and cell biology are also considered, as are theoretical advances in the field of genome evolution. GBE’s scope embraces genome-wide evolutionary investigations at all taxonomic levels and for all forms of life — within populations or across domains. Its aims are to further the understanding of genomes in their evolutionary context and further the understanding of evolution from a genome-wide perspective.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信