{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T10:08:53Z","timestamp":1782900533721,"version":"3.54.5"},"reference-count":15,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,12,11]],"date-time":"2009-12-11T00:00:00Z","timestamp":1260489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2010,1,25]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Dysregulated protein arginine deiminase (PAD) activity, particularly PAD4, has been suggested to play a role in the onset and progression of numerous human diseases, including rheumatoid arthritis (RA). Given the potential role of PAD4 in RA, we set out to develop inhibitors\/inactivators that could be used to modulate PAD activity and disease progression. This effort led to the discovery of two mechanism\u2010based inactivators, denoted F\u2010 and Cl\u2010amidine, that inactivate PAD4 by the covalent modification of an active\u2010site cysteine that is critical for catalysis. To gain further insights into the mechanism of inactivation by these compounds, the effect of pH on the rates of inactivation was determined. These results, combined with the results of solvent isotope effect and proton inventory studies, strongly suggest that the inactivation of PAD4 by F\u2010 and Cl\u2010amidine proceeds by a multistep mechanism that involves the protonation and stabilization of the tetrahedral intermediate formed upon nucleophilic attack by the active\u2010site cysteine, that is, Cys645. Stabilization of this intermediate would help to drive the halide\u2010displacement reaction, which results in the formation of a three\u2010membered sulfonium ring that ultimately collapses to form the inactivated enzyme. This finding\u2014that protonation of the tetrahedral intermediate is important for enzyme inactivation\u2014also suggests that, during catalysis, protonation of the analogous intermediate is required for efficient substrate turnover.<\/jats:italic><\/jats:p>","DOI":"10.1002\/cbic.200900698","type":"journal-article","created":{"date-parts":[[2009,12,11]],"date-time":"2009-12-11T14:02:17Z","timestamp":1260540137000},"page":"161-165","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Haloacetamidine\u2010Based Inactivators of Protein Arginine Deiminase 4 (PAD4): Evidence that General Acid Catalysis Promotes Efficient Inactivation"],"prefix":"10.1002","volume":"11","author":[{"given":"Bryan","family":"Knuckley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey P.","family":"Causey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry J.","family":"Pellechia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Cook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2010,1,20]]},"reference":[{"key":"e_1_2_4_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/cb6002306"},{"key":"e_1_2_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.10357"},{"key":"e_1_2_4_3_2","first-page":"616","volume":"12","author":"Jones J. E.","year":"2009","journal-title":"Curr. Opin. Drug Discovery Dev."},{"key":"e_1_2_4_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi050292m"},{"key":"e_1_2_4_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi700095s"},{"key":"e_1_2_4_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar1184"},{"key":"e_1_2_4_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi061180d"},{"key":"e_1_2_4_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0576233"},{"key":"e_1_2_4_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi051341y"},{"key":"e_1_2_4_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr010182v"},{"key":"e_1_2_4_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00250a033"},{"key":"e_1_2_4_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00662a014"},{"key":"e_1_2_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb799"},{"key":"e_1_2_4_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi052595m"},{"key":"e_1_2_4_15_2","unstructured":"R. J. Leatherbarrow Erathicus Software Staines UK 2004."}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcbic.200900698","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.200900698","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:22:58Z","timestamp":1760289778000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.200900698"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,1,20]]},"references-count":15,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2010,1,25]]}},"alternative-id":["10.1002\/cbic.200900698"],"URL":"https:\/\/doi.org\/10.1002\/cbic.200900698","archive":["Portico"],"relation":{},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,1,20]]},"assertion":[{"value":"2009-11-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2010-01-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}