EzSEA: an interactive web interface for enzyme sequence evolution analysis
Enzymes catalyze essential chemical reactions, driving metabolism, immunity, and growth. Understanding their evolution requires identifying mutations that shaped their functions and substrate interactions. Current methods lack integration of evolutionary history and intuitive visualization tools. We...
Saved in:
| Published in | Bioinformatics advances Vol. 5; no. 1; p. vbaf118 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
England
2025
|
| Online Access | Get full text |
| ISSN | 2635-0041 2635-0041 |
| DOI | 10.1093/bioadv/vbaf118 |
Cover
Loading…
| Abstract | Enzymes catalyze essential chemical reactions, driving metabolism, immunity, and growth. Understanding their evolution requires identifying mutations that shaped their functions and substrate interactions. Current methods lack integration of evolutionary history and intuitive visualization tools.
We develop Enzyme Sequence Evolution Analysis (EzSEA), a web interface that identifies putative functionally important mutations by performing the following steps: structural prediction, homology search, multiple sequence alignment and trimming, phylogenetic tree inference, ancestral sequence reconstruction, and enzyme delineation. The EzSEA web application enables intuitive visualization of results, highlighting key mutations and phylogenetic tree branches that putatively delineate the enzyme of interest. Finally, we validate EzSEA by identifying previously experimentally verified key mutations in the gut bacteria enzyme bilirubin reductase.
EzSEA is freely available on the web at https://jianglabnlm.com/ezsea/. |
|---|---|
| AbstractList | Enzymes catalyze essential chemical reactions, driving metabolism, immunity, and growth. Understanding their evolution requires identifying mutations that shaped their functions and substrate interactions. Current methods lack integration of evolutionary history and intuitive visualization tools.MotivationEnzymes catalyze essential chemical reactions, driving metabolism, immunity, and growth. Understanding their evolution requires identifying mutations that shaped their functions and substrate interactions. Current methods lack integration of evolutionary history and intuitive visualization tools.We develop Enzyme Sequence Evolution Analysis (EzSEA), a web interface that identifies putative functionally important mutations by performing the following steps: structural prediction, homology search, multiple sequence alignment and trimming, phylogenetic tree inference, ancestral sequence reconstruction, and enzyme delineation. The EzSEA web application enables intuitive visualization of results, highlighting key mutations and phylogenetic tree branches that putatively delineate the enzyme of interest. Finally, we validate EzSEA by identifying previously experimentally verified key mutations in the gut bacteria enzyme bilirubin reductase.ResultsWe develop Enzyme Sequence Evolution Analysis (EzSEA), a web interface that identifies putative functionally important mutations by performing the following steps: structural prediction, homology search, multiple sequence alignment and trimming, phylogenetic tree inference, ancestral sequence reconstruction, and enzyme delineation. The EzSEA web application enables intuitive visualization of results, highlighting key mutations and phylogenetic tree branches that putatively delineate the enzyme of interest. Finally, we validate EzSEA by identifying previously experimentally verified key mutations in the gut bacteria enzyme bilirubin reductase.EzSEA is freely available on the web at https://jianglabnlm.com/ezsea/.Availability and implementationEzSEA is freely available on the web at https://jianglabnlm.com/ezsea/. Enzymes catalyze essential chemical reactions, driving metabolism, immunity, and growth. Understanding their evolution requires identifying mutations that shaped their functions and substrate interactions. Current methods lack integration of evolutionary history and intuitive visualization tools. We develop Enzyme Sequence Evolution Analysis (EzSEA), a web interface that identifies putative functionally important mutations by performing the following steps: structural prediction, homology search, multiple sequence alignment and trimming, phylogenetic tree inference, ancestral sequence reconstruction, and enzyme delineation. The EzSEA web application enables intuitive visualization of results, highlighting key mutations and phylogenetic tree branches that putatively delineate the enzyme of interest. Finally, we validate EzSEA by identifying previously experimentally verified key mutations in the gut bacteria enzyme bilirubin reductase. EzSEA is freely available on the web at https://jianglabnlm.com/ezsea/. |
| Author | Jiang, Angela K Jiang, Xiaofang Zhao, Jerry |
| Author_xml | – sequence: 1 givenname: Angela K surname: Jiang fullname: Jiang, Angela K – sequence: 2 givenname: Jerry surname: Zhao fullname: Zhao, Jerry – sequence: 3 givenname: Xiaofang orcidid: 0000-0002-0955-8284 surname: Jiang fullname: Jiang, Xiaofang |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/40546820$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNkDtPwzAQgC1UREvpyogysqQ923GcslVVeakSAzBHjn2WghK7xE1Q--sJSkFM99B3p7vvkoycd0jINYU5hSVfFKVXplt0hbKUZmdkwlIuYoCEjv7lYzIL4QMAmJQpTfgFGScgkjRjMCHPm-PrZnUXKReVbo-N0vuyw-gLi6G2SmNkfROhOx5qjAJ-tuj6Hna-aveld_2oqg6hDFfk3Koq4OwUp-T9fvO2foy3Lw9P69U21gxkFnOtmUm4MQoMs5BaIYykiaRUmEymjEsBDCgiTZmVnJoEuLBorTFaKFB8Sm6HvbvG98eEfV6XQWNVKYe-DTlnjKdsKSj06M0JbYsaTb5rylo1h_z3_x6YD4BufAgN2j-EQv7jOB8c5yfH_BvJpHAG |
| Cites_doi | 10.1016/S0169-5347(98)01382-2 10.1126/science.ade2574 10.1093/bioinformatics/btaa582 10.1093/bioinformatics/btm270 10.1002/pro.3290 10.1371/journal.pone.0009490 10.1186/1471-2105-7-312 10.1021/bi034769a 10.1016/j.jtbi.2018.01.023 10.1186/s12862-015-0378-1 10.1038/s41564-023-01549-x 10.1093/bioinformatics/btaa192 10.1093/gigascience/giae055 10.1093/bioinformatics/btu739 10.1038/s41598-020-72418-4 10.1093/nar/gkf436 10.1186/s12859-018-2283-2 10.1186/1471-2105-5-113 10.1093/nar/gkab314 10.1016/j.softx.2020.100436 10.1186/1471-2105-10-168 10.1002/prot.23020 10.1093/molbev/msaa015 10.1111/febs.15299 10.1146/annurev-biophys-070816-033631 10.1038/s41592-021-01101-x 10.1038/srep33964 10.1038/s41467-024-51511-6 10.1371/journal.pone.0163962 10.1093/nargab/lqab075 10.1371/journal.pone.0039822 10.1093/bib/bbaa337 10.1093/bioinformatics/btz305 |
| ContentType | Journal Article |
| Copyright | Published by Oxford University Press 2025. |
| Copyright_xml | – notice: Published by Oxford University Press 2025. |
| DBID | AAYXX CITATION NPM 7X8 |
| DOI | 10.1093/bioadv/vbaf118 |
| DatabaseName | CrossRef PubMed MEDLINE - Academic |
| DatabaseTitle | CrossRef PubMed MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic PubMed |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Biology |
| EISSN | 2635-0041 |
| ExternalDocumentID | 40546820 10_1093_bioadv_vbaf118 |
| Genre | Journal Article |
| GroupedDBID | 0R~ AAYXX ABDBF ABEJV ABGNP ABXVV AFKRA ALMA_UNASSIGNED_HOLDINGS AMNDL BBNVY BENPR BHPHI CCPQU CITATION GROUPED_DOAJ HCIFZ M7P M~E OK1 PHGZM PHGZT PIMPY PQGLB RPM TOX ZCN NPM 7X8 |
| ID | FETCH-LOGICAL-c2078-3cc2d43dda0d2f06f55d7147115d87623750201ee162f731d4035feffddc5a0a3 |
| ISSN | 2635-0041 |
| IngestDate | Fri Sep 05 15:49:27 EDT 2025 Thu Jun 26 01:37:47 EDT 2025 Tue Aug 05 12:03:01 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 1 |
| Language | English |
| License | Published by Oxford University Press 2025. |
| LinkModel | OpenURL |
| MergedId | FETCHMERGED-LOGICAL-c2078-3cc2d43dda0d2f06f55d7147115d87623750201ee162f731d4035feffddc5a0a3 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ORCID | 0000-0002-0955-8284 |
| OpenAccessLink | https://academic.oup.com/bioinformaticsadvances/advance-article-pdf/doi/10.1093/bioadv/vbaf118/63244316/vbaf118.pdf |
| PMID | 40546820 |
| PQID | 3223629510 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_3223629510 pubmed_primary_40546820 crossref_primary_10_1093_bioadv_vbaf118 |
| PublicationCentury | 2000 |
| PublicationDate | 2025-00-00 |
| PublicationDateYYYYMMDD | 2025-01-01 |
| PublicationDate_xml | – year: 2025 text: 2025-00-00 |
| PublicationDecade | 2020 |
| PublicationPlace | England |
| PublicationPlace_xml | – name: England |
| PublicationTitle | Bioinformatics advances |
| PublicationTitleAlternate | Bioinform Adv |
| PublicationYear | 2025 |
| References | Furukawa (2025063009161324100_vbaf118-B7) 2020; 10 Katoh (2025063009161324100_vbaf118-B10) 2002; 30 Shen (2025063009161324100_vbaf118-B28) 2016; 11 Hochberg (2025063009161324100_vbaf118-B9) 2017; 46 Shank (2025063009161324100_vbaf118-B27) 2018; 19 Edgar (2025063009161324100_vbaf118-B6) 2004; 5 Kozlov (2025063009161324100_vbaf118-B11) 2019; 35 Capra (2025063009161324100_vbaf118-B2) 2007; 23 Lin (2025063009161324100_vbaf118-B14) 2023; 379 Moshiri (2025063009161324100_vbaf118-B16) 2020; 11 Sehnal (2025063009161324100_vbaf118-B26) 2021; 49 Le Guilloux (2025063009161324100_vbaf118-B12) 2009; 10 Sievers (2025063009161324100_vbaf118-B29) 2018; 27 Deorowicz (2025063009161324100_vbaf118-B5) 2016; 6 Song (2025063009161324100_vbaf118-B30) 2018; 443 Piñeiro (2025063009161324100_vbaf118-B21) 2020; 36 Schmidt (2025063009161324100_vbaf118-B25) 2003; 42 Cunningham (2025063009161324100_vbaf118-B4) 1998; 13 Noda-García (2025063009161324100_vbaf118-B18) 2015; 15 Lemoine (2025063009161324100_vbaf118-B13) 2021; 3 Noor (2025063009161324100_vbaf118-B19) 2012; 7 Musil (2025063009161324100_vbaf118-B17) 2021; 22 Pratt (2025063009161324100_vbaf118-B23) 2020; 36 Hall (2025063009161324100_vbaf118-B8) 2024; 9 Buchfink (2025063009161324100_vbaf118-B1) 2021; 18 Suzek (2025063009161324100_vbaf118-B31) 2015; 31 Minh (2025063009161324100_vbaf118-B15) 2020; 37 Petrova (2025063009161324100_vbaf118-B20) 2006; 7 Copley (2025063009161324100_vbaf118-B3) 2020; 287 Piñeiro (2025063009161324100_vbaf118-B22) 2024; 13 Price (2025063009161324100_vbaf118-B24) 2010; 5 Wang (2025063009161324100_vbaf118-B32) 2024; 15 Yahalom (2025063009161324100_vbaf118-B33) 2011; 79 |
| References_xml | – volume: 13 start-page: 361 year: 1998 ident: 2025063009161324100_vbaf118-B4 article-title: Reconstructing ancestral character states: a critical reappraisal publication-title: Trends Ecol Evol doi: 10.1016/S0169-5347(98)01382-2 – volume: 379 start-page: 1123 year: 2023 ident: 2025063009161324100_vbaf118-B14 article-title: Evolutionary-scale prediction of atomic-level protein structure with a language model publication-title: Science doi: 10.1126/science.ade2574 – volume: 36 start-page: 4658 year: 2020 ident: 2025063009161324100_vbaf118-B21 article-title: Very fast tree: speeding up the estimation of phylogenies for large alignments through parallelization and vectorization strategies publication-title: Bioinformatics doi: 10.1093/bioinformatics/btaa582 – volume: 23 start-page: 1875 year: 2007 ident: 2025063009161324100_vbaf118-B2 article-title: Predicting functionally important residues from sequence conservation publication-title: Bioinformatics doi: 10.1093/bioinformatics/btm270 – volume: 27 start-page: 135 year: 2018 ident: 2025063009161324100_vbaf118-B29 article-title: Clustal omega for making accurate alignments of many protein sequences publication-title: Protein Sci doi: 10.1002/pro.3290 – volume: 5 start-page: e9490 year: 2010 ident: 2025063009161324100_vbaf118-B24 article-title: FastTree 2 – approximately maximum-likelihood trees for large alignments publication-title: PLOS One doi: 10.1371/journal.pone.0009490 – volume: 7 start-page: 312 year: 2006 ident: 2025063009161324100_vbaf118-B20 article-title: Prediction of catalytic residues using support vector machine with selected protein sequence and structural properties publication-title: BMC Bioinformatics doi: 10.1186/1471-2105-7-312 – volume: 42 start-page: 8387 year: 2003 ident: 2025063009161324100_vbaf118-B25 article-title: Evolutionary potential of (β/α)8-Barrels: functional promiscuity produced by single substitutions in the enolase superfamily publication-title: Biochemistry doi: 10.1021/bi034769a – volume: 443 start-page: 125 year: 2018 ident: 2025063009161324100_vbaf118-B30 article-title: PREvaIL, an integrative approach for inferring catalytic residues using sequence, structural, and network features in a machine-learning framework publication-title: J Theor Biol doi: 10.1016/j.jtbi.2018.01.023 – volume: 15 start-page: 107 year: 2015 ident: 2025063009161324100_vbaf118-B18 article-title: Insights into the evolution of enzyme substrate promiscuity after the discovery of (βα)8 isomerase evolutionary intermediates from a diverse metagenome publication-title: BMC Evol Biol doi: 10.1186/s12862-015-0378-1 – volume: 9 start-page: 173 year: 2024 ident: 2025063009161324100_vbaf118-B8 article-title: BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen publication-title: Nat Microbiol doi: 10.1038/s41564-023-01549-x – volume: 36 start-page: 3573 year: 2020 ident: 2025063009161324100_vbaf118-B23 article-title: LogoJS: a javascript package for creating sequence logos and embedding them in web applications publication-title: Bioinformatics doi: 10.1093/bioinformatics/btaa192 – volume: 13 start-page: giae055 year: 2024 ident: 2025063009161324100_vbaf118-B22 article-title: Efficient phylogenetic tree inference for massive taxonomic datasets: harnessing the power of a server to analyze 1 million taxa publication-title: GigaScience doi: 10.1093/gigascience/giae055 – volume: 31 start-page: 926 year: 2015 ident: 2025063009161324100_vbaf118-B31 article-title: UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches publication-title: Bioinformatics doi: 10.1093/bioinformatics/btu739 – volume: 10 start-page: 15493 year: 2020 ident: 2025063009161324100_vbaf118-B7 article-title: Ancestral sequence reconstruction produces thermally stable enzymes with mesophilic enzyme-like catalytic properties publication-title: Sci Rep doi: 10.1038/s41598-020-72418-4 – volume: 30 start-page: 3059 year: 2002 ident: 2025063009161324100_vbaf118-B10 article-title: MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform publication-title: Nucleic Acids Res doi: 10.1093/nar/gkf436 – volume: 19 start-page: 276 year: 2018 ident: 2025063009161324100_vbaf118-B27 article-title: Phylotree.js - a JavaScript library for application development and interactive data visualization in phylogenetics publication-title: BMC Bioinformatics doi: 10.1186/s12859-018-2283-2 – volume: 5 start-page: 113 year: 2004 ident: 2025063009161324100_vbaf118-B6 article-title: MUSCLE: a multiple sequence alignment method with reduced time and space complexity publication-title: BMC Bioinformatics doi: 10.1186/1471-2105-5-113 – volume: 49 start-page: W431 year: 2021 ident: 2025063009161324100_vbaf118-B26 article-title: Mol viewer: modern web app for 3D visualization and analysis of large biomolecular structures publication-title: Nucleic Acids Res doi: 10.1093/nar/gkab314 – volume: 11 start-page: 100436 year: 2020 ident: 2025063009161324100_vbaf118-B16 article-title: TreeSwift: a massively scalable Python tree package publication-title: SoftwareX doi: 10.1016/j.softx.2020.100436 – volume: 10 start-page: 168 year: 2009 ident: 2025063009161324100_vbaf118-B12 article-title: Fpocket: an open source platform for ligand pocket detection publication-title: BMC Bioinformatics doi: 10.1186/1471-2105-10-168 – volume: 79 start-page: 1952 year: 2011 ident: 2025063009161324100_vbaf118-B33 article-title: Structure-based identification of catalytic residues publication-title: Proteins doi: 10.1002/prot.23020 – volume: 37 start-page: 1530 year: 2020 ident: 2025063009161324100_vbaf118-B15 article-title: IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era publication-title: Mol Biol Evol doi: 10.1093/molbev/msaa015 – volume: 287 start-page: 1262 year: 2020 ident: 2025063009161324100_vbaf118-B3 article-title: Evolution of new enzymes by gene duplication and divergence publication-title: Febs J doi: 10.1111/febs.15299 – volume: 46 start-page: 247 year: 2017 ident: 2025063009161324100_vbaf118-B9 article-title: Reconstructing ancient proteins to understand the causes of structure and function publication-title: Annu Rev Biophys doi: 10.1146/annurev-biophys-070816-033631 – volume: 18 start-page: 366 year: 2021 ident: 2025063009161324100_vbaf118-B1 article-title: Sensitive protein alignments at tree-of-life scale using DIAMOND publication-title: Nat Methods doi: 10.1038/s41592-021-01101-x – volume: 6 start-page: 33964 year: 2016 ident: 2025063009161324100_vbaf118-B5 article-title: FAMSA: fast and accurate multiple sequence alignment of huge protein families publication-title: Sci Rep doi: 10.1038/srep33964 – volume: 15 start-page: 7348 year: 2024 ident: 2025063009161324100_vbaf118-B32 article-title: Multi-modal deep learning enables efficient and accurate annotation of enzymatic active sites publication-title: Nat Commun doi: 10.1038/s41467-024-51511-6 – volume: 11 start-page: e0163962 year: 2016 ident: 2025063009161324100_vbaf118-B28 article-title: SeqKit: a cross-platform and ultrafast toolkit for FASTA/Q file manipulation publication-title: PLOS One doi: 10.1371/journal.pone.0163962 – volume: 3 start-page: lqab075 year: 2021 ident: 2025063009161324100_vbaf118-B13 article-title: Gotree/goalign: toolkit and go API to facilitate the development of phylogenetic workflows publication-title: NAR Genom Bioinform doi: 10.1093/nargab/lqab075 – volume: 7 start-page: e39822 year: 2012 ident: 2025063009161324100_vbaf118-B19 article-title: Intramolecular epistasis and the evolution of a new enzymatic function publication-title: PLOS One doi: 10.1371/journal.pone.0039822 – volume: 22 start-page: bbaa337 year: 2021 ident: 2025063009161324100_vbaf118-B17 article-title: FireProtASR: a web server for fully automated ancestral sequence reconstruction publication-title: Brief Bioinform doi: 10.1093/bib/bbaa337 – volume: 35 start-page: 4453 year: 2019 ident: 2025063009161324100_vbaf118-B11 article-title: RAxML-NG: a fast, scalable and user-friendly tool for maximum likelihood phylogenetic inference publication-title: Bioinformatics doi: 10.1093/bioinformatics/btz305 |
| SSID | ssj0002776143 |
| Score | 2.2792866 |
| Snippet | Enzymes catalyze essential chemical reactions, driving metabolism, immunity, and growth. Understanding their evolution requires identifying mutations that... |
| SourceID | proquest pubmed crossref |
| SourceType | Aggregation Database Index Database |
| StartPage | vbaf118 |
| Title | EzSEA: an interactive web interface for enzyme sequence evolution analysis |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/40546820 https://www.proquest.com/docview/3223629510 |
| Volume | 5 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1ba9RAFB60RfBFvLtWlxEEH5bYXCZJ41uVlFLqKroLiy_hZC64hSZStwvdX--ZOZPsLq1QfQnJkOt8k3POnMs3jL1VeV2YsMgDQHUUCJmlASQiCw7iPNJC5FI7nu7P4-x4Kk5m6axbaNxXlyzq93J1Y13J_6CKbYirrZL9B2T7m2ID7iO-uEWEcXsrjMvV99I5yKFxvA-u4mmpR7b-0B0bkJ7Uu1ldnetRlzg90kv_YngpsZJsRXfnrSdUJRJnyhNYJxvOvZP50GbEwtpT-uMnUCBHX6yzi_uzZ3NoDXhN6R0NVI5MksgS1gSWmYuUxg1tXpSm10YMicVlDSYiOXtNZBOdVT1v8WNwZ-PUbXbs8ZfqaHp6Wk3K2eQu243zPEo3vDNnLoiao7Vhkwr6t-t5OpN9esS-f8C2HfKXyYUzMiYP2QM_O-CHBPUjdkc3j9k9Wi_06gk7cYB_4NDwDbg5ws17uDnixglu3sHNe7h5B_dTNj0qJ5-OA78YRiDj0KawSBkrkSgFoYpNmJk0VXmEpkWUKqvREvzX0JjTOspikyeREmGSGm2MUjKFEJJnbKdpG_2C8TACG54GCYUQADFklmEICpwsZLLQ0YC967qm-kWcJxXlKiQVdWLlO3HA3nQ9V6FYsrEmaHR7-btCPYGmkTXfB-w5dWl_L5wjiAwtz5e3uHqP3bdjkZxer9jO4uJSv0YzcFEP2e7Hcvz129C5UYZuJPwBQWFjhQ |
| linkProvider | National Library of Medicine |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=EzSEA%3A+an+interactive+web+interface+for+enzyme+sequence+evolution+analysis&rft.jtitle=Bioinformatics+advances&rft.au=Jiang%2C+Angela+K&rft.au=Zhao%2C+Jerry&rft.au=Jiang%2C+Xiaofang&rft.date=2025&rft.issn=2635-0041&rft.eissn=2635-0041&rft.volume=5&rft.issue=1&rft.spage=vbaf118&rft_id=info:doi/10.1093%2Fbioadv%2Fvbaf118&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=2635-0041&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=2635-0041&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=2635-0041&client=summon |