Isopropylamine as Amine Donor in Transaminase‐Catalyzed Reactions: Better Acceptance through Reaction and Enzyme Engineering

Dawood, Ayad W. H.; Weiss, M.S.; Schulz, Christian; Pavlidis, Ioannis V.; Iding, Hans; Souza, Rodrigo O. M. A. de; Bornscheuer, Uwe T.

doi:10.1002/cctc.201800936

Cited by 46 publications

(29 citation statements)

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“…The breakthrough for synthetic application came with Celgenes discovery of the particular advantages of isopropylamine as amine donor. [51] Celgene showed preparative usefulness of the transaminase technology for enantiopure l-alanine (from pyruvate) and (S)-Moipa ((S)-1-methoxy-isopropylamine, 28; Scheme 8) and (S)-2-amino-3-methylbutane from the respective ketones.T he latter amines serve as precursors for herbizides.Several thousand tons of (S)-Moipa are produced annually as building block for (S)-Dimethenamide 29 and could potentially serve for (S)-Metolachlor 30 (Scheme 9). A particularly remarkable achievement of Celgenesd evelopment was to overcome product inhibition by enzyme engineering.…”

Section: Chiral Alcohols Produced By Enzymatic Hydroxylationsmentioning

confidence: 99%

Biocatalysis: Enzymatic Synthesis for Industrial Applications

et al. 2020

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in 2007, followed by postdoctoral studies at York University (UK) and Greifswald University (Germany). In 2010, she transitionedto industry applying and developing biocatalytic technologies at Novacta in the UK, prior to joining Chemical Process Development at GSK, with responsibility for the development and implementation of new biocatalytic technologyi nboth pre-and post-commercialization routes. Since Dec. 2016, Radka is leading the Bioreactions group in GDC at the Novartis Institute for Biomedical Research in Basel, Switzerland. Jeffrey Moore obtained his PhD in Chemical Engineeringf rom the California Institute of Technology in 1996 as Frances Arnold's first Directed Evolution graduate student. His foundational work led to an evolved p-nitrobenzyl esterase and the Lonza Centenary Prize (1997). In 1996, he joined the Biocatalysis Group of Merck & Co.in Rahway NJ, spending two decades inventing new enzymes and new enzymatic processes. In 2018, he transitionedtothe Merck Protein EngineeringG roup responsible for evolving enzymes for the discovery,d evelopmenta nd commercials cale manufacture of medicines. He has been awarded aUS Presidential Green Chemistry Award (2010), the BioCat2012 Award (2012) and the Thomas Edison Inventorship Award (2014). Kai Baldenius studied chemistry in Hamburg and Southampton. He received his PhD for research in asymmetric organometallic catalysis, supervised by H. tom Dieck and H. B. Kagan. After his postdoc on natural product synthesis with K. C. Nicolaou at the Scripps Research Institute he joined BASF in 1993. Kai served BASF in various functions (R&D, production, marketing, sales) before he took the lead of BASF'sbiocatalysis research for almost ad efcade. He left BASF to become afree-lancing consultanti n2019 and in 2020 he has founded Baldenius Biotech Consulting. Uwe T. Bornscheuer studied chemistry and received his PhD in 1993 at Hannover University followed by apostdoc at Nagoya University (Japan). In 1998, he completed his Habilitation at Stuttgart University about the use of lipases and esterasesi n organic synthesis. He has been Professor at the Institute of Biochemistry at Greifswald University since 1999. Beside other awards, he received in 2008 the BioCat2008 Award. He was just recognized as "Chemistry Europe Fellow". His current research interest focuses on the discovery and engineering of enzymes from various classes for applications in organic synthesis, lipid modification, degradation of plastics or complex marine polysaccharides.

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Section: Chiral Alcohols Produced By Enzymatic Hydroxylationsmentioning

confidence: 99%

Biocatalysis: Enzymatic Synthesis for Industrial Applications

et al. 2020

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“…Moreover, the same steric consideration explains the drastic activity loss for A8 , A11 and ( S )‐ D3 . Although the substrate structure would not undergo rejection in the S pocket, A1 shows a very low reactivity for most ω‐TAs as also observed with 0.07% activity of OATA for A1 relative to that for A6

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D8 is regarded as an ideal amino donor for amination of ketones . However, not many ω‐TAs display a significant activity for D8 .…”

Section: Resultsmentioning

confidence: 83%

Combinatorial Mutation Analysis of ω‐Transaminase to Create an Engineered Variant Capable of Asymmetric Amination of Isobutyrophenone

2019

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ω-Transaminase (ω-TA) is an important enzyme for asymmetric synthesis of chiral amines. Rapid creation of a desirable ω-TA variant, readily available for scalable process operation, is demanded and has attracted intense research efforts. In this study, we aimed to develop a quantitative mutational analysis (i. e., Ranalysis) that enables prediction of combinatorial mutation outcomes and thereby provides reliable guidance of enzyme engineering through combination of already characterized mutations. To this end, we determined three mutatable active-site residues of ω-TA from Ochrobactrum anthropi (i. e., leucine 57, tryptophan 58 and valine 154) by examining activities of nine alanine-scanning mutants for seven substrate pairs. The R-analysis of the mutatable residues is based on assessment of changes in relative activities for a series of structurally analogous substrates. Using three sets of substrates (five α-keto acids, six arylalkylamines and three arylalkyl ketones), we found that combination of two point mutations display additive effects of each mutational outcome such as steric relaxation for bulky substrates or catalytic enhancement for amination of ketones. Consistent with the Ranalysis-based prediction, the ω-TA variant harboring triple alanine mutations, i. e. L57A, W58A and V154A, showed high activity improvements for bulky substrates, e. g. a 3.2 × 10 4 -fold activity increase for 1phenylbutylamine. The triple mutant even enabled asymmetric amination of isobutyrophenone, carrying a branched-chain alkyl substituent to be accepted in a small binding pocket that normally shows a steric limit up to an ethyl group, with > 99% ee of a resulting (S)-amine.

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“…Isopropylamine (11) and racemic sec-butylamine (12) and the corresponding ketones are low boiling-compounds that can be easily removed by vacuum. 8,49,50 Although the pool of TAs which accept isopropylamine (11) as amine donor is limited, in case of acceptance industrial use of 11 is preferred compared to L-alanine, as the forming acetone can be easily removed. 51 However, due to its unfavoured K eq , 11 has to be used in high excess and the forming acetone shows severe inhibitory effect.…”

Section: Resultsmentioning

confidence: 99%