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Ene-Reductases in Pharmaceutical Chemistry
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The asymmetric bioreduction of activated C=C bonds by ene-reductases has been investigated for decades as the enzyme-catalyzed reaction is a highly specific and environmentally friendly alternative to existing chemical methodologies. Many recent studies have led to the expansion of the toolbox of available ene-reductases (wild-type and engineered libraries) broadening the accessible substrate scope and today, ene-reductase screening panels are offered for sale by a number of commercial suppliers (Table 10.4) shortening industrial development times. However, not only the discovery of novel biocatalysts is of crucial importance but also the capability to develop a commercially viable biocatalytic process. In the case of ene-reductases, the increasing availability of a wide range of cofactor recycling strategies is driving industrial acceptance. Additionally, the productivity of biocatalytic reactions can be further improved by a combination of process engineering (e.g., substrate feeding product removal strategies; enzyme immobilization) and enzyme engineering (solvent tolerance, thermostability, substrate scope, activity). The coming-of-age of ene-reductases as an enzymatic tool for industrial applications will further promote the use of biocatalytic, chemoenzymatic and biosynthetic approaches for fine chemical synthesis.
Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues
Published in Expert Opinion on Drug Discovery, 2022
Sebastian C. Cosgrove, Gavin J. Miller
Relatedly, researchers from Merck described in 2019 the evolution campaigns for five separate enzymes to realize a fully biocatalytic synthesis of experimental antiviral drug islatravir 7, starting from 2-ethynylglycerol 6 (Scheme 3C) [17]. Enzyme engineering was performed on a galactose oxidase (GOase) to enable a stereoselective desymmetrization of 6, which proceeded in 80% ee, but overoxidation to the acid and subsequent removal of this undesired carboxylate enantiomer delivered an enantiopure aldehyde product in 99% ee. Additional engineering was conducted on a pantothenate kinase (PanK), an aldolase (DERA), and PPM/PNP. This remarkable feat of synthesis was performed in a single vessel, with sequential addition and removal of the enzymes and substrates and delivered 7 in 51% overall yield on half a gram scale. A key technology used here was enzyme immobilization. The GOase was immobilized, and the PanK and AK were co-immobilized. By converting these enzymes to heterogenous catalysts, filtration simplified the downstream processing by enabling removal of them prior to subsequent steps. The final product crystallized out of solution and could be recovered through filtration, obviating the need to immobilize the other enzymes. The use of sucrose phosphorylase was necessary in the final step to deliver 7, preventing the reverse reaction occurring by removing phosphate in situ. The authors did not disclose whether any traces of a 2’,3’-dideoxydidehydro by-product were formed.
Mycotoxin patulin in food matrices: occurrence and its biological degradation strategies
Published in Drug Metabolism Reviews, 2019
Marina Sajid, Sajid Mehmood, Yahong Yuan, Tianli Yue
Furthermore, novel mycotoxin detoxification genes from microbial cells, generated through DNA shuffling, have great importance to detoxify naturally occurring mycotoxins by providing specific enzymes to degrade mycotoxins. These genes could be more useful in agricultural and food industry processes (Subramanian 2002). Several other molecular level enzyme engineering techniques such as comparative genomics, proteomics and transcriptomic profiling (RNA-Seq) are likely to be helpful for detoxification of mycotoxins in food (Zhu et al. 2016).