{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T09:27:08Z","timestamp":1768296428467,"version":"3.49.0"},"reference-count":22,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2025,6,16]]},"abstract":"<jats:p>Crotonaldehyde is a human toxin that reacts with nucleophilic groups on DNA and proteins. Putative crotonaldehyde\u2010derived adducts on DNA are reported in cells and patients after ethanol exposure, which implies that crotonaldehyde is formed in cells. Here, we show that proline amide, which is a model of <jats:italic>N<\/jats:italic>\u2010terminal proline\u2010containing proteins, catalyzes the aldol condensation of the ethanol metabolite acetaldehyde to crotonaldehyde under physiologically relevant conditions. This reaction is more efficient at neutral pH than under acidic or basic conditions, but is inhibited by competing imidazolidin\u20104\u2010one formation. Crotonaldehyde formation is also slower than the analogous aldol condensation of propionaldehyde. Comparative studies additionally suggest that proline amide is a more efficient catalyst than other amino acid amides. Overall, the work evidences a biochemically plausible mechanism for intracellular crotonaldehyde formation and implies that proline amide derivatives can catalyze aldol chemistry in humans.<\/jats:p>","DOI":"10.1002\/cbic.202500138","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T09:15:35Z","timestamp":1745572535000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Proline Amide Catalyzes Formation of Toxic Crotonaldehyde from Acetaldehyde Under Physiologically Relevant Conditions"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0927-5222","authenticated-orcid":false,"given":"Liam A.","family":"Thomas","sequence":"first","affiliation":[{"name":"Institute for Structural and Chemical Biology and School of Chemistry University of Leicester  Henry Wellcome Building, Lancaster Road Leicester LE1 7RH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7024-3804","authenticated-orcid":false,"given":"Vicki L.","family":"Emms","sequence":"additional","affiliation":[{"name":"Institute for Structural and Chemical Biology and School of Chemistry University of Leicester  Henry Wellcome Building, Lancaster Road Leicester LE1 7RH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dipti","family":"Vashi","sequence":"additional","affiliation":[{"name":"Institute for Structural and Chemical Biology and Department of Molecular and Cell Biology University of Leicester  Henry Wellcome Building, Lancaster Road Leicester LE1 7RH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9456-3047","authenticated-orcid":false,"given":"Louise","family":"Fairall","sequence":"additional","affiliation":[{"name":"Institute for Structural and Chemical Biology and Department of Molecular and Cell Biology University of Leicester  Henry Wellcome Building, Lancaster Road Leicester LE1 7RH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2865-4383","authenticated-orcid":false,"given":"John W. R.","family":"Schwabe","sequence":"additional","affiliation":[{"name":"Institute for Structural and Chemical Biology and Department of Molecular and Cell Biology University of Leicester  Henry Wellcome Building, Lancaster Road Leicester LE1 7RH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7610-8163","authenticated-orcid":false,"given":"Richard J.","family":"Hopkinson","sequence":"additional","affiliation":[{"name":"Institute for Structural and Chemical Biology and School of Chemistry University of Leicester  Henry Wellcome Building, Lancaster Road Leicester LE1 7RH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-483X(01)00436-X"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101947200"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2013.09.010"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn334"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1789.2006.00746.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2024.103782"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx000118t"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx050239z"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx060154d"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2059-5"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/catal8120605"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201900558"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3RA08776J"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202306347"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/B702559A"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201107404"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201200676"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42004-022-00801-5"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202113970"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201201174"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp7096845"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo200431v"}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202500138","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T16:28:54Z","timestamp":1760286534000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.202500138"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,21]]},"references-count":22,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,6,16]]}},"alternative-id":["10.1002\/cbic.202500138"],"URL":"https:\/\/doi.org\/10.1002\/cbic.202500138","archive":["Portico"],"relation":{},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,21]]},"assertion":[{"value":"2025-02-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202500138"}}