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However, using alcohol dehydrogenases (ADHs) in the asymmetric reduction of diaryl ketones to produce the corresponding alcohols is challenging due to steric hindrance in the substrate binding pockets of the enzymes. In this study, the steric hindrance of the ADH from <jats:italic>Geotrichum candidum<\/jats:italic> NBRC 4597 (<jats:italic>G. candidum<\/jats:italic> acetophenone reductase, <jats:italic>Gc<\/jats:italic>APRD) was eliminated by simultaneous site-directed mutagenesis of Phe56 (in the large pocket) and Trp288 (in the small pocket). As a result, two double mutants, Phe56Ile\/Trp288Ala, and Phe56Ala\/Trp288Ala, exhibited much higher specific activities towards 2-(4\u2032-chlorobenzoyl)pyridine (4.5\u00a0\u03bcmol\/min\/mg and 3.4\u00a0\u03bcmol\/min\/mg, respectively) than the wild type (&lt;\u20090.2\u00a0\u03bcmol\/min\/mg). In whole-cell-catalyzed asymmetric reductions of diaryl ketones, Phe56Ile\/Trp288Ala significantly increased the isolated yields, which were over 90% for the reactions of most of the tested substrates. Regarding enantioselectivity, Phe56Ile\/Trp288Ala and Phe56Ala\/Trp288Ala, and Trp288Ala generally exhibited similar selectivity to produce (<jats:italic>R<\/jats:italic>)-alcohols with up to 97% <jats:italic>ee<\/jats:italic>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Key points<\/jats:title>\n            <jats:p>\n              <jats:italic>\u2022 Phe56 in Geotrichum reductase (GcAPRD) was mutated to eliminate steric hindrance.<\/jats:italic>\n            <\/jats:p>\n            <jats:p>\n              <jats:italic>\u2022 Mutation at Phe56 increased enzymatic activity and expanded substrate specificity.<\/jats:italic>\n            <\/jats:p>\n            <jats:p>\n              <jats:italic>\u2022 Phe56Ile\/Trp288Ala showed high activity and (R)-selectivity towards diaryl ketones.<\/jats:italic>\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00253-024-13375-0","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T07:29:54Z","timestamp":1735284594000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Substrate expansion of Geotrichum candidum alcohol dehydrogenase towards diaryl ketones by mutation"],"prefix":"10.1007","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9272-2945","authenticated-orcid":false,"given":"Zhongyao","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuuki","family":"Takagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2744-4552","authenticated-orcid":false,"given":"Afifa Ayu","family":"Koesoema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8934-8198","authenticated-orcid":false,"given":"Tomoko","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,27]]},"reference":[{"key":"13375_CR1","doi-asserted-by":"crossref","unstructured":"Bagchi B (2013) The hydrophobic effect. 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