{"doi":"10.1098/rstb.2022.0248","title":"Small molecule activates citrullination through targeting PAD2","abstract":"<jats:p>Citrullination is a post-translational modification catalysed by peptidyl arginine deiminase (PAD) enzymes, and dysregulation of protein citrullination is involved in various pathological disorders. During the past decade, a panel of citrullination inhibitors has been developed, while small molecules activating citrullination have rarely been reported so far. In this study, we screened citrullination activator using an antibody against citrullinated histone H3 (cit-H3), and a natural compound demethoxycurcumin (DMC) significantly activated citrullination. The requirement of PAD2 for DMC-activated citrullination was confirmed by a loss of function assay. Notably, DMC directly engaged with PAD2, and showed binding selectivity among PAD family enzymes. Point mutation assay indicated that residue E352 is essential for DMC targeting PAD2. Consistently, DMC induced typical phenotypes of cells with dysregulation of PAD2 activity, including citrullination-associated cell apoptosis and DNA damage. Overall, our study not only presents a strategy for rationally screening citrullination activators, but also provides a chemical approach for activating protein citrullination.</jats:p>\n                  <jats:p>This article is part of the Theo Murphy meeting issue ‘The virtues and vices of protein citrullination’.</jats:p>","journal":"Philosophical Transactions of the Royal Society B: Biological Sciences","year":2023,"id":609785,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1520007,"name":"Mengzhen Shen","orcid":null,"position":1,"is_corresponding":false},{"id":1563063,"name":"Huimin Zhu","orcid":null,"position":2,"is_corresponding":false},{"id":266524,"name":"Junjie Zhang","orcid":"0000-0003-3812-3850","position":3,"is_corresponding":false},{"id":5471,"name":"Min Yang","orcid":"0000-0002-9034-3175","position":4,"is_corresponding":false},{"id":1567482,"name":"Kaiyan Su","orcid":null,"position":5,"is_corresponding":false},{"id":1567483,"name":"Yirong Zhang","orcid":null,"position":6,"is_corresponding":false},{"id":648131,"name":"Wei Fu","orcid":"0000-0003-4581-8909","position":7,"is_corresponding":false},{"id":1520009,"name":"Xisong Ke","orcid":"0000-0001-7328-7354","position":8,"is_corresponding":false},{"id":366980,"name":"Yi Qu","orcid":"0000-0002-1420-7753","position":9,"is_corresponding":false},{"id":772399,"name":"Xue Zhang","orcid":"0000-0003-0940-037X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Small molecule activates citrullination through targeting PAD2","abstract":"<jats:p>Citrullination is a post-translational modification catalysed by peptidyl arginine deiminase (PAD) enzymes, and dysregulation of protein citrullination is involved in various pathological disorders. During the past decade, a panel of citrullination inhibitors has been developed, while small molecules activating citrullination have rarely been reported so far. In this study, we screened citrullination activator using an antibody against citrullinated histone H3 (cit-H3), and a natural compound demethoxycurcumin (DMC) significantly activated citrullination. The requirement of PAD2 for DMC-activated citrullination was confirmed by a loss of function assay. Notably, DMC directly engaged with PAD2, and showed binding selectivity among PAD family enzymes. Point mutation assay indicated that residue E352 is essential for DMC targeting PAD2. Consistently, DMC induced typical phenotypes of cells with dysregulation of PAD2 activity, including citrullination-associated cell apoptosis and DNA damage. Overall, our study not only presents a strategy for rationally screening citrullination activators, but also provides a chemical approach for activating protein citrullination.</jats:p>\n                  <jats:p>This article is part of the Theo Murphy meeting issue ‘The virtues and vices of protein citrullination’.</jats:p>","is_dataset_classified":null,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"37778388","pmcid":"PMC10542452","openalex_id":"https://openalex.org/W4387235219","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"81874210, 82173845, 82274147, and 82204430","title":null},{"funder_name":"Science and Technology Commission of Shanghai Municipality","grant_id":"22XD1403200 and 21S11900900","title":null},{"funder_name":"Shanghai Youth Talent Support Program","grant_id":"None","title":null},{"funder_name":"Shanghai Municipal Education Commission","grant_id":"2021-01-07-00-10-E00116, 2023keji05-66","title":null}],"total_grants":4,"fwci":0.6364,"citation_percentile":0.64459988,"influential_citations":0,"citation_trend":[{"year":2023,"count":3},{"year":2024,"count":1},{"year":2026,"count":2}],"oa_status":"green","license":"https://royalsociety.org/journals/ethics-policies/data-sharing-mining/","oa_locations":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10542452/pdf/rstb.2022.0248.pdf","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10542452/pdf/rstb.2022.0248.pdf","host_type":"repository"},{"url":"https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2022.0248","host_type":"publisher"},{"url":"https://royalsocietypublishing.org/doi/full-xml/10.1098/rstb.2022.0248","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10542452","host_type":"repository"},{"url":"https://doi.org/10.1098/rstb.2022.0248","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/37778388","host_type":"repository"}],"fields_of_study":["Protease and Inhibitor Mechanisms","Cell Adhesion Molecules Research","Citrullination","Protein-Arginine Deiminases","Histones","Protein Processing, Post-Translational","Extracellular Space","Hydrolases"],"mesh_terms":["Citrullination","Protein-Arginine Deiminases","Extracellular Space","Histones","Hydrolases","Protein Processing, Post-Translational"],"keywords":["Citrullination","Citrulline","Cell biology","Histone","Biochemistry","Chemistry","Biology","Arginine","Amino acid","Gene","Activator","Pad2","Demethoxycurcumin"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-31T15:19:04.836053Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}