Identification of a Robust Carbonyl Reductase for Diastereoselectively Building syn-3,5-Dihydroxy Hexanoate: a Bulky Side Chain of Atorvastatin
| Autor: | Gong Xumin, you yan Liu, Jian-He Xu, Gao-Wei Zheng |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
biology
Carbonyl Reductase 010405 organic chemistry Stereochemistry organic chemicals Organic Chemistry Diol Substrate (chemistry) 010402 general chemistry 01 natural sciences Cofactor 0104 chemical sciences chemistry.chemical_compound chemistry Glucose dehydrogenase biology.protein Side chain heterocyclic compounds Carboxylate Physical and Theoretical Chemistry Pharmacophore |
| Zdroj: | Organic Process Research & Development. 21:1349-1354 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/acs.oprd.7b00194 |
| Popis: | t-Butyl-6-cyano-(3R,5R)-dihydroxyhexanoate is an advanced chiral precursor for the synthesis of the side chain pharmacophore of cholesterol-lowering drug atorvastatin. Herein, a robust carbonyl reductase (LbCR) was newly identified from Lactobacillus brevis, which displays high activity and excellent diastereoselectivity toward bulky t-butyl 6-cyano-(5R)-hydroxy-3-oxo-hexanoate (7). The engineered Escherichia coli cells harboring LbCR and glucose dehydrogenase (for cofactor regeneration) were employed as biocatalysts for the asymmetric reduction of substrate 7. As a result, as much as 300 g L–1 of water-insoluble substrate was completely converted to the corresponding chiral diol with >99.5% de in a space–time yield of 351 g L–1 d–1, indicating a great potential of LbCR for practical synthesis of the very bulky and bi-chiral 3,5-dihydroxy carboxylate side chain of best-selling statin drugs. |
| Databáze: | OpenAIRE |
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