Biocatalytic synthesis of atorvastatin intermediates

Patel, Jay

doi:10.1016/j.molcatb.2009.07.004

Cited by 59 publications

(27 citation statements)

References 32 publications

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“…The synthetic activity of the DERA immobilised on MCFs was maintained at acetaldehyde concentrations of up to 600 mM, which is a higher tolerance than that reported in a previous study [14]. Due to the reversible nature of aldol reactions, very long reaction times are [4]. However, high acetaldehyde concentrations would shift the reaction equilibrium towards the product, promoting the DR5P synthesis reaction and accelerating the reaction velocity.…”

Section: Synthesis Of Dr5p With Immobilised and Free Deramentioning

confidence: 70%

“…Among the biocatalytic synthesis methods for preparing chiral intermediates of atorvastatin (Lipitor), the DERA catalytic sequential reaction is of particular interest because easily available bulk chemicals can be used as substrates in a one-pot, two-step aldol addition reaction of two molecules of acetaldehyde with an acceptor aldehyde [1]. Unfortunately, aldolase enzymes often suffer from substrate inhibition and are easily inactivated at the required aldehyde concentrations used during the biocatalytic synthesis of chiral atorvastatin intermediates [4,5].…”

Section: Introductionmentioning

confidence: 99%

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Amino acid-mediated aldolase immobilisation for enhanced catalysis and thermostability

Wang

Gao

Zhang

et al. 2012

Bioprocess Biosyst Eng

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To improve the properties of the immobilised 2-deoxy-D-ribose-5-phosphate aldolase (DERA), unreacted functional groups on support surface were blocked with amino acids. The relative activities of the immobilised enzyme were 144.7 and 141.9% when the post-immobilisation modification was done with Arg and Phe, respectively. The residual activity of immobilised DERA after heating at 60 °C for 120 min was 65.1% when Phe and Val were used as the blocking amino acids, a 2.0- and 2.87-fold increase over that of the immobilised (no post-immobilisation blocking) and free DERA. Immobilised DERA maintained maximal activity in 2-deoxyribose-5-phosphate (DR5P) synthesis up to 600 mM of acetaldehyde, which was much higher than the amount of acetaldehyde tolerated by free enzyme (300 mM). This superior resistance to high acetaldehyde concentrations would accelerate the DR5P reaction by shifting the reaction equilibrium towards the product. The results from this study suggest that the novel immobilised DERA may be useful for industrial applications.

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Section: Synthesis Of Dr5p With Immobilised and Free Deramentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Amino acid-mediated aldolase immobilisation for enhanced catalysis and thermostability

Wang

Gao

Zhang

et al. 2012

Bioprocess Biosyst Eng

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“…The stereochemical purity of the two chiral centers belonging to the pharmacophore of statins is critical to their bioactivity, as exemplified by atorvastatin and rosuvastatin (see Scheme 1), which are top-selling cholesterol-lowering drugs throughout the world with Bblockbusterŝ tatus. Considerable research efforts have been devoted to the development of novel strategies for the stereoselective synthesis of the chiral side chain of statins (Liljeblad et al 2009;Muller 2005;Patel 2009). tert-Butyl (S)-6-chloro-5-hydroxy-3-Electronic supplementary material The online version of this article (doi:10.1007/s00253-015-6675-1) contains supplementary material, which is available to authorized users.…”

Section: Introductionmentioning

confidence: 99%

Highly efficient enzymatic synthesis of tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate with a mutant alcohol dehydrogenase of Lactobacillus kefir

Chen

et al. 2015

Appl Microbiol Biotechnol

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tert-Butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH) is a valuable chiral synthon, which is used for the synthesis of the cholesterol-lowering drugs atorvastatin and rosuvastatin. To date, only the alcohol dehydrogenases from Lactobacillus brevis (LbADH) and Lactobacillus kefir (LkADH) have demonstrated catalytic activity toward the asymmetric reduction of tert-butyl 6-chloro-3,5-dioxohexanoate (CDOH) to (S)-CHOH. Herein, a tetrad mutant of LkADH (LkTADH), A94T/F147L/L199H/A202L, was screened to be more efficient in this bioreduction process, exhibiting a 3.7- and 42-fold improvement in specific activity toward CDOH (1.27 U/mg) over LbADH (0.34 U/mg) and wild-type LkADH (0.03 U/mg), respectively. The molecular basis for the improved catalytic activity of LkTADH toward CDOH was investigated using homology modeling and docking analysis. Two major issues had a significant impact on the biocatalytic efficiency of this process, including (i) the poor aqueous stability of the substrate and (ii) partial substrate inhibition. A fed-batch strategy was successfully developed to address these issues and maintain a suitably low substrate concentration throughout the entire process. Several other parameters were also optimized, including the pH, temperature, NADP(+) concentration and cell loading. A final CDOH concentration of 427 mM (100 g/L) gave (S)-CHOH in 94 % yield and 99.5 % e.e. after a reaction time of 38 h with whole cells expressing LkTADH. The space-time yield and turnover number of NADP(+) in this process were 10.6 mmol/L/h and 16,060 mol/mol, respectively, which were the highest values ever reported. This new approach therefore represents a promising alternative for the efficient synthesis of (S)-CHOH.

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“…Since Wong [1,2] reported that a one-pot tandem reaction catalyzed by 2-deoxy-D-ribose-5-phosphate aldolase (DERA) could be used to synthesize six membered lactol derivatives, aldolases have attracted the interest of researchers because of their ability to efficiently catalyze the formation of CeC bonds with stereospecific control to yield a single product [3e5]. In recent years, DERA has been used for the synthesis of the side chain of atorvastatin, providing an attractive alternative to traditional chemical methodologies [6].…”

Section: Introductionmentioning

confidence: 99%

“…NMR spectrum (DMSO-d6 ) d 161.91, 149.47, 146.25, 145.19, 141.53, 138.93, 138.93, 128.81, 123.09, 123.09, 115.40, 115.80, 114.33, 112.33, 110.27, 102.85, 57.23. ESI-MS: m/z % ¼ 307.0 [MÀH], 309.2 [MþH].…”

mentioning

confidence: 99%

An improved flurogenic probe for high-throughput screening of 2-deoxyribose aldolases

Fang

et al. 2015

Biochemical and Biophysical Research Communications

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Biocatalytic synthesis of atorvastatin intermediates

Cited by 59 publications

References 32 publications

Amino acid-mediated aldolase immobilisation for enhanced catalysis and thermostability

Amino acid-mediated aldolase immobilisation for enhanced catalysis and thermostability

Highly efficient enzymatic synthesis of tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate with a mutant alcohol dehydrogenase of Lactobacillus kefir

An improved flurogenic probe for high-throughput screening of 2-deoxyribose aldolases

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