A green-by-design system for efficient bio-oxidation of an unnatural hexapyranose into chiral lactone for building statin side-chains

Jiao, Xue-Cheng; Zhang, Yujun; Chen, Qi; Pan, Jiang; Xu, Jian‐He

doi:10.1039/c6cy01085g

Cited by 14 publications

(20 citation statements)

References 31 publications

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“…A lucrative aspect 27,[35][36][37][38][39][40] of the application of enzymes in the pharmaceutical industry is in the production of statin precursors. Namely, statins are hypolipidemics, a medication used for lowering LDL cholesterol (LDL-C) in blood, and for prevention of cardiovascular morbidity and mortality.…”

Section: Statins and Statin Precursorsmentioning

confidence: 99%

“…50,55 The increasing commercial demand for statins, and the need for simple preparation on the industrial scale, have led to immense efforts towards finding a more efficient and economical production of statin side chains. 28,29,38,51,58,59 4 Biocatalysis as a response to the challenges arising from chemical synthesis of statin precursors…”

Section: Statins and Statin Precursorsmentioning

confidence: 99%

“…Driven by the requirements of high chemical and stereochemical purity, a variety of biocatalytic routes, involving different classes of enzymes and starting materials, have been developed for their enantioselective synthesis, 27,55 since enzymes inherently circumvent the challenges arising from the chemical synthesis. 60 Thus, some pharmaceutical (and biotechnological) companies, including Codexis, The most common biocatalytic methods towards the production of statin intermediates 27,29,38,39,50,62 can be broadly grouped into two strategies 36,55 (Fig. 3).…”

Section: Statins and Statin Precursorsmentioning

confidence: 99%

“…Most of the biocatalytic methods fall under this strategy, 55 although, according to some literature, the usage of nitrilases is classified as a separate third strategy. 37,38 The second strategy (Fig. 3b) involves the generation of both chiral centres in a single step using aldolases, which catalyse the aldol reaction that results with a more advanced six-carbon statin side-chain.…”

Section: Statins and Statin Precursorsmentioning

confidence: 99%

“…40,64,67,68,70,[73][74][75] Although the application of the DERA enzyme shows great potential in the production of statin intermediates, the enzyme demonstrates some major drawbacks for its practical application, 27,40,44,48,58,59 but due to the high interest in its application, the enzyme is being continuously re-engineered to have a better fit. 38,55,58,65,69,72 The DERA-based strategy is almost by default coupled with an oxidation step, in which the lactol is further oxidized into a lactone, such as cyclized 3,5-dihydroxyhexanoic acid, which is a more stable form of lactol 76 and thus presents a key product in the synthesis of statin intermediates. 27,36,38,50,54,72,73 The significance of those two reactions is evident also in the industry: DSM Pharma Chemicals 77,78 and Diversa Corporation 40 operate the DE-RA-catalysed aldol reaction followed by chemical oxidation of the produced lactol 27,39,40,77,78 , while Lek Pharmaceuticals patented the DERA-catalysed reaction followed by oxidation catalysed by dehydrogenases (DHs), which results in a more economic process: reduced number of synthetic steps, improved and simplified reaction, etc.…”

Section: Statins and Statin Precursorsmentioning

confidence: 99%

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Biocatalysis for the Production of Pharmaceutical Intermediates

2019

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The application of enzymes in chemical synthesis, due to the recent advances, has a strong impact in multiple industries, especially the pharmaceutical industry. Namely, the use of enzymes shows remarkable advantages over classical chemical catalysis and therefore it is considered a ‘green’ solution. By using novel techniques, it is possible to tailor the enzymes to adapt them for a given process. Today, several pharmaceutical companies are successfully producing valuable precursors for the production of active pharmaceutical ingredients using enzymes, some of them being statin precursors. Statins are hypolipidemics, drugs used for the prevention of cardiovascular diseases and lowering cholesterol concentration in blood. Due to challenges in the chemical synthesis of statin intermediates, the production of statin intermediates using enzyme-catalysed reactions shows some notable advantages. Therefore, research and development laboratories, combined with reaction engineering techniques, have shifted their focus towards applying biochemical catalysis for the production of statin intermediates.

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Section: Statins and Statin Precursorsmentioning

confidence: 99%

Section: Statins and Statin Precursorsmentioning

confidence: 99%

Section: Statins and Statin Precursorsmentioning

confidence: 99%

Section: Statins and Statin Precursorsmentioning

confidence: 99%

Section: Statins and Statin Precursorsmentioning

confidence: 99%

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Biocatalysis for the Production of Pharmaceutical Intermediates

2019

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Optimization of Alcohol Dehydrogenase for Industrial Scale Oxidation of Lactols

Bartsch

Brummund²,

Köpke

et al. 2020

Biotechnology Journal

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Alcohol dehydrogenases (ADH) are widely used to enantioselectively reduce ketones to chiral alcohols, but their application in industrial scale oxidations is rare. Reasons are the need for an NAD(P)+ cofactor regeneration system, often low performance in oxidative reactions and the limited substrate scope of ADHs. ADHA from Candida magnoliae DSMZ 70638 is identified to efficiently catalyze the regio‐selective hydroxy‐lactone oxidations to hydroxy‐lactones. Hydroxy‐lactones are common intermediates in industrial processes to cholesterol lowering (va)statin drugs. A biocatalytic aliphatic hydroxy‐lactone oxidation process is developed using pure oxygen as oxidant reaching volumetric productivities of up to 12 g L−1 h−1, product concentrations of almost 50 g L−1 and 95% reaction yield. For co‐factor recycling a previously engineered, water‐forming NAD(P)H‐oxidase from Streptococcus mutans is used. The process is scaled up to industrial pilot plant scale and it could be demonstrated that ADH catalyzed oxidations can be developed to efficient and safe processes. However, the ADHA wild‐type enzyme is not productive enough in chlorolactol oxidation. Therefore, enzyme engineering and multi‐parameter screening is successfully applied to optimize the enzyme for the target reaction. The optimized ADHA variant shows a 17‐fold higher oxidative activity, a 26°C increased stability and is applied to develop an efficient chlorolactol oxidation process.

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Stairway to Stereoisomers: Engineering Short‐ and Medium‐Chain Ketoreductases To Produce Chiral Alcohols

Shanbhag

2023

ChemBioChem

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The short-and medium-chain dehydrogenase/reductase superfamilies are responsible for most chiral alcohol production in laboratories and industries. In nature, they participate in diverse roles such as detoxification, housekeeping, secondary metabolite production, and catalysis of several chemicals with commercial and environmental significance. As a result, they are used in industries to create biopolymers, active pharmaceutical intermediates (APIs), and are also used as components of modular enzymes like polyketide synthases for fabricating bioactive molecules. Consequently, random, semi-rational and rational engineering have helped transform these enzymes into product-oriented efficient catalysts. The rise of newer synthetic chemicals and their enantiopure counterparts has proved challenging, and engineering them has been the subject of numerous studies. However, they are frequently limited to the synthesis of a single chiral alcohol. The study attempts to defragment and describe hotspots of engineering short-and medium-chain dehydrogenases/reductases for the production of chiral synthons.

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A green-by-design system for efficient bio-oxidation of an unnatural hexapyranose into chiral lactone for building statin side-chains

Abstract: An improved dehydrogenase LeADHI87F/N235H/P236H was co-expressed with a NADPH oxidase in E. coli for bio-oxidation of a key statin side-chain precursor.

Cited by 14 publications

References 31 publications

Biocatalysis for the Production of Pharmaceutical Intermediates

Biocatalysis for the Production of Pharmaceutical Intermediates

Optimization of Alcohol Dehydrogenase for Industrial Scale Oxidation of Lactols

Stairway to Stereoisomers: Engineering Short‐ and Medium‐Chain Ketoreductases To Produce Chiral Alcohols

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