Advanced Synthesis and Catalysis p. 1872 - 1880 (2015)
Update date:2022-08-10
Topics:
Loderer, Christoph
Morgenstern, Frances
Ansorge-Schumacher, Marion
Zinc-dependent alcohol dehydrogenases (ADHs) are valuable biocatalysts for the synthesis of chiral hydroxy compounds such as α-hydroxy ketones and diols, both valuable precursors for the synthesis of various pharmaceuticals. However, while highly active on aliphatic or phenyl-substituted diketones, most well characterized ADHs show no significant activity on cyclic α- and β-diketones. Therefore, this study aimed at the detection of a novel ADH capable to reduce these special targets. It involved a rational screening of biochemical pathways for enzymes with structurally related natural substrates. The so detected 6-hydroxycyclohex-1-ene-1-carbonyl-CoA dehydrogenase (ThaADH) from Thauera aromatica was cloned, expressed in Escherichia coli and purified by affinity chromatography. The characterization revealed a substrate specificity with highest activities on cyclic α- and β-diketones including 1,2-cyclohexanedione and 1,3-cyclopentanedione. Structural reasons for this extraordinary substrate spectrum were investigated with a homology model created via Swiss Model server. Although the quality of the model may be improved, it suggests that a bulky aromatic residue, that plays a crucial role in the definition of the substrate binding pockets of most ADHs, is replaced by a glycine residue in ThaADH. We propose that this structural difference leads to the formation of one large binding pocket instead of two smaller ones and consequently to a preference for cyclic diketones over linear bulky substrates. Thus, we have achieved both provision of a novel biocatalyst with high potential in chiral synthesis, and a possible explanation for the measured differences to known ADHs. The described structural motif might be used for identification of further enzymes with a related substrate scope.
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Doi:10.1002/1522-2640(200004)72:4<396::AID-CITE396>3.0.CO;2-W
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