TY - JOUR
T1 - Access to both enantiomers of substituted 2-tetralol analogs by a highly enantioselective reductase
AU - Koesoema, Afifa Ayu
AU - Standley, Daron M.
AU - T.sriwong, Kotchakorn
AU - Tamura, Mayumi
AU - Matsuda, Tomoko
N1 - Funding Information:
The authors acknowledged Professor Miki Senda and Professor Toshiya Senda from High Energy Accelerator Research Organization (KEK), Japan, for the help with the crystallization of enzymes and valuable discussions. This work was supported by the Japan Society for the Promotion of Science , Japan (grant number JP16K05864 ) to Tomoko Matsuda and the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED , Japan (grant number 19am0101108j0003 ) to Daron M. Standley.
Funding Information:
The authors acknowledged Professor Miki Senda and Professor Toshiya Senda from High Energy Accelerator Research Organization (KEK), Japan, for the help with the crystallization of enzymes and valuable discussions. This work was supported by the Japan Society for the Promotion of Science, Japan (grant number JP16K05864) to Tomoko Matsuda and the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED, Japan (grant number 19am0101108j0003) to Daron M. Standley.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/3/26
Y1 - 2020/3/26
N2 - Both (S) and (R) forms of enantiomerically pure 2-tetralols, and their substituted analogs, are fundamental pharmaceutical intermediates. Here, we utilized the wild type and an engineered form of a highly enantioselective acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD) to produce (S)- and (R)-2-tetralols, and their substituted analogs. All mutations targeted residue Trp288, which has been shown to restrict substrate binding, but not play a direct role in catalysis. The wild type produced (S)-alcohols with excellent enantioselectivity, while the engineered forms produced either (S)- or (R)- alcohols, depending on the substituent on the aromatic ring of the substrate, indicating that enantioselectivity can be rationally controlled. As a result, we were able to produce 6-hydroxy-2-tetralol, a potential antifungal drug intermediate, with 98% ee (S) and 81% ee (R) by wild type and Trp288Ser GcAPRD, respectively. To our knowledge, this is the first report of generating chiral 6-hydroxy-2-tetralol by rational enzyme design.
AB - Both (S) and (R) forms of enantiomerically pure 2-tetralols, and their substituted analogs, are fundamental pharmaceutical intermediates. Here, we utilized the wild type and an engineered form of a highly enantioselective acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD) to produce (S)- and (R)-2-tetralols, and their substituted analogs. All mutations targeted residue Trp288, which has been shown to restrict substrate binding, but not play a direct role in catalysis. The wild type produced (S)-alcohols with excellent enantioselectivity, while the engineered forms produced either (S)- or (R)- alcohols, depending on the substituent on the aromatic ring of the substrate, indicating that enantioselectivity can be rationally controlled. As a result, we were able to produce 6-hydroxy-2-tetralol, a potential antifungal drug intermediate, with 98% ee (S) and 81% ee (R) by wild type and Trp288Ser GcAPRD, respectively. To our knowledge, this is the first report of generating chiral 6-hydroxy-2-tetralol by rational enzyme design.
KW - 2-Tetralol
KW - Alcohol dehydrogenase
KW - Asymmetric reduction
KW - Drug intermediates
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U2 - 10.1016/j.tetlet.2020.151682
DO - 10.1016/j.tetlet.2020.151682
M3 - Article
AN - SCOPUS:85078850978
SN - 0040-4039
VL - 61
JO - Tetrahedron Letters
JF - Tetrahedron Letters
IS - 13
M1 - 151682
ER -