{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:48:53Z","timestamp":1792684133377,"version":"4.5.0"},"reference-count":60,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T00:00:00Z","timestamp":1730851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The enantioselective reduction of prochiral ketones catalyzed by horse liver alcohol dehydrogenase (HLADH), was investigated via a hybrid computational approach, for molecular reactions involved in chiral synthesis of <jats:italic>S<\/jats:italic>\u2010alcohols, when the natural co\u2010factor, 1,4\u2010dihyronicotinamide adenine dinucleotide, 1,4\u2010NADH, was replaced with biomimetic co\u2010factor, N\u2010benzyl\u20101,4\u2010dihydronicotinamide, <jats:bold>1<\/jats:bold>. We surmised that different hydride and proton transfer mechanisms were involved using co\u2010factor, <jats:bold>1<\/jats:bold>. An alternative mechanism, where the hydride transfer step occurred, via an \u03b7<jats:sup>1<\/jats:sup>\u2010keto\u2010<jats:italic>S<\/jats:italic>\u2010\u03b7<jats:sup>2<\/jats:sup>\u20105,6\u20101,4\u2010dihydronicotinamide\u2010Zn(II) complex, was previously investigated with a model of the HLADH\u2212Zn(II) catalytic site (<jats:italic>J. Organometal. Chem<\/jats:italic>. <jats:bold>2021<\/jats:bold>, <jats:italic>943<\/jats:italic>, 121810). Presently, we studied canonical and alternative mechanisms compared to models of the entire enzyme structure. We disproved the \u03b7<jats:sup>2<\/jats:sup>\u2010Zn(II) complex, and discovered a canonical hydride transfer from biomimetic 1,4\u2010NADH, <jats:bold>1<\/jats:bold>, to the Zn(II) bound prochiral ketone substrate, followed by a new proton relay, consisting of a water chain connecting His51 to Ser48 that accomplished the <jats:italic>S<\/jats:italic>\u2010alkoxy anion's protonation to yield the final <jats:italic>S<\/jats:italic>\u2010alcohol product. The HLADH catalysis, with biomimetic co\u2010factor, <jats:bold>1<\/jats:bold>, that replaced the ribose group, the 5\u2032\u2010diphosphate groups, and the adenine nucleotide with a N\u2010benzyl group, has provided a new paradigm for the design of other structures of 1,4\u2010NADH biomimetic co\u2010factors, including their economic value in biocatalysis reactions.<\/jats:p>","DOI":"10.1002\/cbic.202400727","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T05:22:33Z","timestamp":1727241753000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanisms in the Synthesis of <i>S<\/i>\u2010Alcohols with 1,4\u2010NADH Biomimetic Co\u2010factor N\u2010Benzyl\u20101,4\u2010dihydronicotinamide using Horse Liver Alcohol Dehydrogenase: A Hybrid Computational Study"],"prefix":"10.1002","volume":"26","author":[{"given":"Matteo","family":"Farina","sequence":"first","affiliation":[{"name":"Dipartimento di Chimica Universit\u00e0 degli Studi di Roma La Sapienza  Roma IT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Capone","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Fisiche e Chimiche Universit\u00e0 degli Studi dell'Aquila  L'Aquila IT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Bodo","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica Universit\u00e0 degli Studi di Roma La Sapienza  Roma IT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard H.","family":"Fish","sequence":"additional","affiliation":[{"name":"Lawrence Berkeley National Laboratory University of California  Berkeley CA 94720 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massiliano","family":"Aschi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Fisiche e Chimiche Universit\u00e0 degli Studi dell'Aquila  L'Aquila IT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8311-8172","authenticated-orcid":false,"given":"Alessandro","family":"Marrone","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia Universit\u00e0 degli Studi G. d'Annunzio  Chieti-Pescara IT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Daidone","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Fisiche e Chimiche Universit\u00e0 degli Studi dell'Aquila  L'Aquila IT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,6]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-020-00001-2"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202103949"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adh8615"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar5002928"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c00983"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CS01106E"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cssc.202102709"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja3092517"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/bab.2117"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah6219"},{"key":"e_1_2_8_11_1","volume":"2","author":"Molina R. 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