Amine dehydrogenases: efficient biocatalysts for the reductive amination of carbonyl compounds

Abstract

Amines constitute the major targets for the production of a plethora of chemical compounds that have applications in the pharmaceutical, agrochemical and bulk chemical industries. However, the asymmetric synthesis of α-chiral amines with elevated catalytic efficiency and atom economy is still a very challenging synthetic problem. Here, we investigated the biocatalytic reductive amination of carbonyl compounds employing a rising class of enzymes for amine synthesis: amine dehydrogenases (AmDHs). The three AmDHs from this study – operating in tandem with a formate dehydrogenase from Candida boidinii (Cb-FDH) for the recycling of the nicotinamide coenzyme – performed the efficient amination of a range of diverse aromatic and aliphatic ketones and aldehydes with up to quantitative conversion and elevated turnover numbers (TONs). Moreover, the reductive amination of prochiral ketones proceeded with perfect stereoselectivity, always affording the (R)-configured amines with more than 99% enantiomeric excess. The most suitable amine dehydrogenase, the optimised catalyst loading and the required reaction time were determined for each substrate. The biocatalytic reductive amination with this dual-enzyme system (AmDH–Cb-FDH) possesses elevated atom efficiency as it utilizes the ammonium formate buffer as the source of both nitrogen and reducing equivalents. Inorganic carbonate is the sole by-product.

Biocatalytic Production of Amino Carbohydrates through Oxidoreductase and Transaminase Cascades

“…[32] Briefly,t ransaminases operate through ap ing-pong, bi-bi reaction in which the first half-reaction involves the transfer of the amino group from the amine donor to the PLP cofactor.T he deaminated amine donor (i.e.,t he respective ketone/aldehyde product) is then released, leaving the cofactor as pyridoxamine 5'-phosphate (PMP). [35][36][37] So-called sugar transaminases have been shownt oa ccept nucleotide sugars as amine donors and acceptors; [19,20] however,t hese are not suitable for direct amination of biomass-derived carbohydrates. Transaminases have been functionally classified as a-transaminases (a-TAs) and w-transaminases (w-TAs), on the basis of amine donor anda cceptor specificity.W hereas a-TAs transfer amino groupsf rom the a-carbon atom of amino acids to aketo acids, w-TAs are more versatile as they do not requirea carboxylate group in the amine acceptor andc an donate the amino group to a-keto acids as well as other ketones and aldehydes.…”

The Kinetic Resolution of Racemic Amines Using a Whole-Cell Biocatalyst Co-Expressing Amine Dehydrogenase and NADH Oxidase

“…Among them, as AmDH catalyzes the asymmetric reductive amination of ketones, and uses cheap ammonia as the reagent and generates only water as by product, with high atom efficiency and enantioselectivity [14], AmDH is highly attractive and possesses tremendous potential for the synthesis of chiral amines [13]. Until now, only one NAD + -dependent AmDH found in nature has been reported, in Streptomyces virginiae, but it showed poor enantioselectivity and its DNA information is not available [15].…”

“…M4, Exiguobacterium sibiricum, and Caldalkalibacillus thermarum [14,19,20]. A systematic investigation of substrate acceptance, optimal reaction conditions, and the chemo-and stereoselectivity of AmDHs has been carried out [13,20]. In addition, AmDHs have been used in elegant hydrogen borrowing dual-enzyme cascade reactions for the synthesis of chiral amines from alcohols with "closed-loop" recycling of the cofactor [19,21].…”

“…Recently, many biocatalytic methods for the production of chiral amines have been developed using biocatalysts, such as lipase [5], amine oxidase [6], imine reductase [7], transaminase [8], ammonia lyases [9], Pictet-Spenglerase [10], barberine bridge enzyme [11], engineered P450 monooxygenase [12], and amine dehydrogenase (AmDH) [3]. Each enzyme has its own advantages and disadvantages for the synthesis of chiral amines ( [13] and references therein for more details).…”

Direct Alkylation of Amines with Primary and Secondary Alcohols through Biocatalytic Hydrogen Borrowing

“…[12] Only ah andful of examples have been reported involving enantioselective transformations with modest enantiomeric excess. [16][17][18][19][20][21][22][23][24] These enzymes have also been combined in cascades to carry out multiple transformations in one pot, often with the oxidation and reduction steps taking place concurrently. [16][17][18][19][20][21][22][23][24] These enzymes have also been combined in cascades to carry out multiple transformations in one pot, often with the oxidation and reduction steps taking place concurrently.…”