{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T19:26:56Z","timestamp":1787686016408,"version":"build-2784847793"},"reference-count":47,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemPlusChem"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>\n                    The multienzyme cascade conversion of CO\n                    <jats:sub>2<\/jats:sub>\n                    to methanol is a promising route for sustainable chemical synthesis, yet the reduction of formate to formaldehyde remains its major bottleneck. Here, we use quantum chemical calculations to elucidate the catalytic mechanism of formaldehyde dehydrogenase from\n                    <jats:italic>Burkholderia multivorans<\/jats:italic>\n                    (\n                    <jats:italic>Bm<\/jats:italic>\n                    FaldDH). The lowest\u2010energy pathway initiates with formate activation via a proton\u2010relay network involving His52, Ser49, and the NADH ribose, followed by a concerted yet asynchronous proton\u2010hydride transfer to yield methanediol with a barrier of 16.0\u2009kcal\u2009mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    . Interestingly, calculations show that subsequent dehydration of methanediol to formaldehyde is more favorable in solution than within the active site, with barriers of 16.2 and 24.0\u2009kcal\u2009mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    , respectively. This lower barrier in solution is mediated by a water\u2010cluster model in which three water molecules facilitate proton relay, and two stabilize the methanediol. Furthermore, binding energy calculations indicate that methanediol has a relatively weak binding affinity for\n                    <jats:italic>Bm<\/jats:italic>\n                    FaldDH, suggesting that it readily dissociates into solution. Overall, this study demonstrates that the limited efficiency of\n                    <jats:italic>Bm<\/jats:italic>\n                    FaldDH in catalyzing formate reduction stems from its incompetence to catalyze methanediol dehydration within its active pocket. These findings provide a mechanistic insight for engineering efficient enzymes for the formate\u2010to\u2010formaldehyde conversion.\n                  <\/jats:p>","DOI":"10.1002\/cplu.70231","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T02:01:00Z","timestamp":1787191260000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic Insights Into the Formaldehyde Dehydrogenase\u2010Catalyzed Reduction of Formate: A Quantum Chemical Study"],"prefix":"10.1002","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7464-4017","authenticated-orcid":false,"given":"Baoyan","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Engineering Biology for Low\u2010Carbon Manufacturing Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences  Tianjin China"},{"name":"National Engineering Research Center of Industrial Enzymes and National Technology Innovation Center for Synthetic Biology  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Engineering Biology for Low\u2010Carbon Manufacturing Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences  Tianjin China"},{"name":"National Engineering Research Center of Industrial Enzymes and National Technology Innovation Center for Synthetic Biology  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0178-6610","authenticated-orcid":false,"given":"Hao","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Engineering Biology for Low\u2010Carbon Manufacturing Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences  Tianjin China"},{"name":"National Engineering Research Center of Industrial Enzymes and National Technology Innovation Center for Synthetic Biology  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-6649","authenticated-orcid":false,"given":"Xiang","family":"Sheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Engineering Biology for Low\u2010Carbon Manufacturing Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences  Tianjin China"},{"name":"National Engineering Research Center of Industrial Enzymes and National Technology Innovation Center for Synthetic Biology  Tianjin 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