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However, its structural complexity and limited availability hinder its use in studying archaeal metabolism and H<jats:sub>4<\/jats:sub>MPT\u2010dependent enzymes. Inspired by the success of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) biomimetic compounds, we employed a similar structural simplification strategy for methylene\u2010H<jats:sub>4<\/jats:sub>MPT, designing four mimics (<jats:bold>mimics 1<\/jats:bold>\u2013<jats:bold>4<\/jats:bold>) that retain the crucial hydride\u2010donating imidazolidine unit while modifying the pterin structure and hydrophilic tail. Structural and crystallographic analysis of methylene\u2010H<jats:sub>4<\/jats:sub>MPT\u2010bound enzymes, including H<jats:sub>4<\/jats:sub>MPT\u2010dependent formaldehyde\u2010activating enzyme MtdA and H<jats:sub>4<\/jats:sub>MPT\u2010dependent formaldehyde\u2010activating enzyme Fae, highlighted the importance of the pterin group in hydrogen bonding and active site interactions. Activity evaluation of the mimics in hydride transfer assays and relay reactions with MtdA and NADPH\u2010dependent ketoreductase <jats:italic>Cg<\/jats:italic>KR1 showed that the pterin structure is critical for enzymatic activity, and improving water solubility via hydrophilic tail modification enhances performance. This biomimetic approach offers functional substitutes for methylene\u2010H<jats:sub>4<\/jats:sub>MPT and potentially valuable tools for studying archaeal metabolism and synthetic microbial systems for C1 compound utilization.<\/jats:p>","DOI":"10.1002\/chem.202500234","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T22:51:55Z","timestamp":1743375115000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis and Activity Evaluation of Methylene\u2010H<sub>4<\/sub>MPT Mimics"],"prefix":"10.1002","volume":"31","author":[{"given":"Yutian","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Coordination Chemistry Chemistry and Biomedicine Innovation Center (ChemBic) ChemBioMed Interdisciplinary Research Center at Nanjing University School of Chemistry and Chemical Engineering Nanjing University Nanjing People's Republic of 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for Life Science The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University Xi'an People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3737-3524","authenticated-orcid":false,"given":"Hui\u2010Jie","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Coordination Chemistry Chemistry and Biomedicine Innovation Center (ChemBic) ChemBioMed Interdisciplinary Research Center at Nanjing University School of Chemistry and Chemical Engineering Nanjing University Nanjing People's Republic of 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