Asymmetric Construction of Alkaloids by Employing a Key ω‐Transaminase Cascade

Taday, Freya; Ryan, James P.; Argent, Stephen P.; Caprio, Vittorio; Maciá, Beatriz; O’Reilly, Elaine

doi:10.1002/chem.202000067

Cited by 21 publications

(16 citation statements)

References 44 publications

(31 reference statements)

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“…This methodology has recently seen expansion to alkyne equivalents, generating exo-cyclic enamines. 42 In the follow-up manuscript to this work, O'Reilly and coworkers again demonstrate how enzyme selectivity may be exploited to perform this challenging retrosynthetic disconnection through the use of an ADH to deliver a range of tetrahydropyrans and tetrahydrofurans, moieties that are both challenging to incorporate into synthesis and readily present in bioactive molecules. 41 Analysis of the products described across the two manuscripts resulting from this biocatalytic methodology reveals that the heterocycles obtained present an opportunity to cover a wide region of chemical space.…”

Section: Biocatalysis For Fragment Synthesismentioning

confidence: 96%

Is it time for biocatalysis in fragment-based drug discovery?

2020

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Section: Biocatalysis For Fragment Synthesismentioning

confidence: 96%

Is it time for biocatalysis in fragment-based drug discovery?

2020

View full text Add to dashboard Cite

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“…In addition, the use of an excess of an amino donor is perhaps the easiest way to shift the equilibrium toward product formation [ 12 , 13 , 14 ]. In the last few decades, a number of academic and industrial examples using ATAs for chiral amine production have been reported in the literature [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Computer Modeling Explains the Structural Reasons for the Difference in Reactivity of Amine Transaminases Regarding Prochiral Methylketones

Teixeira

Farias

Horta

et al. 2022

IJMS

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Amine transaminases (ATAs) are pyridoxal-5′-phosphate (PLP)-dependent enzymes that catalyze the transfer of an amino group from an amino donor to an aldehyde and/or ketone. In the past decade, the enzymatic reductive amination of prochiral ketones catalyzed by ATAs has attracted the attention of researchers, and more traditional chemical routes were replaced by enzymatic ones in industrial manufacturing. In the present work, the influence of the presence of an α,β-unsaturated system in a methylketone model substrate was investigated, using a set of five wild-type ATAs, the (R)-selective from Aspergillus terreus (Atr-TA) and Mycobacterium vanbaalenii (Mva-TA), the (S)-selective from Chromobacterium violaceum (Cvi-TA), Ruegeria pomeroyi (Rpo-TA), V. fluvialis (Vfl-TA) and an engineered variant of V. fluvialis (ATA-256 from Codexis). The high conversion rate (80 to 99%) and optical purity (78 to 99% ee) of both (R)- and (S)-ATAs for the substrate 1-phenyl-3-butanone, using isopropylamine (IPA) as an amino donor, were observed. However, the double bond in the α,β-position of 4-phenylbut-3-en-2-one dramatically reduced wild-type ATA reactivity, leading to conversions of <10% (without affecting the enantioselectivity). In contrast, the commercially engineered V. fluvialis variant, ATA-256, still enabled an 87% conversion, yielding a corresponding amine with >99% ee. Computational docking simulations showed the differences in orientation and intermolecular interactions in the active sites, providing insights to rationalize the observed experimental results.

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“…In the TD and OATA cascade reaction, the reaction catalyzed by TD was much faster than that of OATA. Asymmetric synthesis of chiral amines using OATA has suffered from an unfavorable reaction equilibrium when a high concentration of substrate was used [ 13 – 15 ]. Therefore, OATA determines the conversion yield of the whole process.…”

Section: Introductionmentioning

confidence: 99%

Active-site engineering of ω-transaminase from Ochrobactrum anthropi for preparation of L-2-aminobutyric acid

et al. 2021

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Background The unnatural amino acid, L-2-aminobutyric acid (L-ABA) is an essential chiral building block for various pharmaceutical drugs, such as the antiepileptic drug levetiracetam and the antituberculosis drug ethambutol. The present study aims at obtaining variants of ω-transaminase from Ochrobactrum anthropi (OATA) with high catalytic activity to α-ketobutyric acid through protein engineering. Results Based on the docking model using α-ketobutyric acid as the ligand, 6 amino acid residues, consisting of Y20, L57, W58, G229, A230 and M419, were chosen for saturation mutagenesis. The results indicated that L57C, M419I, and A230S substitutions demonstrated the highest elevation of enzymatic activity among 114 variants. Subsequently, double substitutions combining L57C and M419I caused a further increase of the catalytic efficiency to 3.2-fold. This variant was applied for threonine deaminase/OATA coupled reaction in a 50-mL reaction system with 300 mM L-threonine as the substrate. The reaction was finished in 12 h and the conversion efficiency of L-threonine into L-ABA was 94%. The purity of L-ABA is 75%, > 99% ee. The yield of L-ABA was 1.15 g. Conclusion This study provides a basis for further engineering of ω-transaminase for producing chiral amines from keto acids substrates.

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Asymmetric Construction of Alkaloids by Employing a Key ω‐Transaminase Cascade

Cited by 21 publications

References 44 publications

Is it time for biocatalysis in fragment-based drug discovery?

Is it time for biocatalysis in fragment-based drug discovery?

Computer Modeling Explains the Structural Reasons for the Difference in Reactivity of Amine Transaminases Regarding Prochiral Methylketones

Active-site engineering of ω-transaminase from Ochrobactrum anthropi for preparation of L-2-aminobutyric acid

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