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However, their application remains limited by the narrow diversity of natural halogenases, poor stability, and restricted substrate scope. Protein stabilization is a common strategy to enhance mutational tolerance during enzyme engineering; however, Fe(II)\/\u03b1KG-dependent halogenases are structurally closely related to hydroxylases, and consensus-based stabilizing mutations risk shifting activity toward competing hydroxylation. To address this challenge, a workflow was designed to improve structural stability while preserving substrate and product specificity by combining computational identification of substrate-recognition residues with Rosetta-based stabilization. This approach was applied to the l-lysine 4-chlorinase BesD from Streptomyces cattleya as a model enzyme. The resulting variants exhibited a T50 increase of more than 45 \u00b0C with no loss of substrate specificity or regioselective chlorination activity and served as stable seed enzymes for subsequent substrate scope expansion. This strategy, which systematically excludes substrate recognition- and\/or reaction-selectively related residues from the mutation space to preserve native enzyme function, may provide a versatile platform for stabilizing enzymes without substantially compromising catalytic activity.<\/jats:p>","DOI":"10.1021\/acschembio.6c00487","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:11:17Z","timestamp":1785849077000},"page":"2032-2039","source":"Crossref","is-referenced-by-count":0,"title":["Rational Thermostabilization\nof the Fe(II)\/\u03b1-Ketoglutarate-Dependent\nHalogenase BesD While Preserving Halogenation Selectivity"],"prefix":"10.1021","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7555-2318","authenticated-orcid":true,"given":"Teppei","family":"Niide","sequence":"first","affiliation":[{"name":"The University of Osaka , , 1-5 Yamadaoka , , ,","place":["Suita, Osaka, Japan, 565-0871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Miyawaki","sequence":"additional","affiliation":[{"name":"The University of Osaka , , 1-5 Yamadaoka , , ,","place":["Suita, Osaka, Japan, 565-0871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyuga","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"The University of Osaka , , 1-5 Yamadaoka , , ,","place":["Suita, Osaka, Japan, 565-0871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Miyake","sequence":"additional","affiliation":[{"name":"The University of Osaka , , 1-2 Machikaneyama , , ,","place":["Toyonaka, Osaka, Japan, 560-0043"]},{"name":"The University of Osaka , , 1-1 Machikaneyama , , ,","place":["Toyonaka, Osaka, Japan, 560-0043"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9670-6961","authenticated-orcid":true,"given":"Yoshihiro","family":"Toya","sequence":"additional","affiliation":[{"name":"The University of Osaka , , 1-5 Yamadaoka , , ,","place":["Suita, Osaka, Japan, 565-0871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8986-0861","authenticated-orcid":true,"given":"Hiroshi","family":"Shimizu","sequence":"additional","affiliation":[{"name":"The University of Osaka , , 1-5 Yamadaoka , , ,","place":["Suita, Osaka, Japan, 565-0871"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"issue":"6817","key":"2026082208551779500_cit1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/35051706","article-title":"Enzymes for chemical synthesis","volume":"409","author":"Koeller","year":"2001","journal-title":"Nature"},{"issue":"7683","key":"2026082208551779500_cit2","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/nature24996","article-title":"Genetically\nprogrammed chiral organoborane synthesis","volume":"552","author":"Kan","year":"2017","journal-title":"Nature"},{"issue":"23","key":"2026082208551779500_cit3","doi-asserted-by":"publisher","first-page":"6652","DOI":"10.1021\/ja00309a038","article-title":"The Role of the\nChlorine Substituents in the Antibiotic Vancomycin - Preparation and\nCharacterization of Monodechlorovancomycin and Didechlorovancomycin","volume":"107","author":"Harris","year":"1985","journal-title":"J. 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