NAD(P)H‐Dependent Dehydrogenases for the Asymmetric Reductive Amination of Ketones: Structure, Mechanism, Evolution and Application

Abstract

Asymmetric reductive aminations are some of the most important reactions in the preparation of active pharmaceuticals, as chiral amines feature in many of the world's most important drugs. Although many enzymes have been applied to the synthesis of chiral amines, the development of reductive amination reactions that use enzymes is attractive, as it would permit the one‐step transformation of readily available prochiral ketones into chiral amines of high optical purity. However, as most natural “reductive aminase” activities operate on keto acids, and many are able to use only ammonia as the amine donor, there is considerable scope for the engineering of natural enzymes for the reductive amination of ketones, and also for the preparation of secondary amines using alkylamines as donors. This review summarises research into the development of NAD(P)H‐dependent dehydrogenases for the reductive amination of ketones, including amino acid dehydrogenases (AADHs), natural amine dehydrogenases (AmDHs), opine dehydrogenases (OpDHs) and imine reductases (IREDs). In each case knowledge of the structure and mechanism of the enzyme class is addressed, with a further description of the engineering of those enzymes for the reductive amination of ketones towards primary and also secondary amine products.

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

“…Among them, the chiral amines are of great interest to the pharmaceutical and fine-chemical industries, since enantiopure amines are important building blocks for pharmaceutical manufacturing [1]. Given the significance of chiral amines, their efficient synthesis in enantiopure form has become an attractive challenge to organic chemists and biologists in recent years [2][3][4]. 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].…”

“…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]. Due to the importance of the reductive amination of ketones by AmDH, an extensive and detailed review on relevant studies has recently been published [3].…”

Deracemization of Racemic Amines to Enantiopure (R)‐ and (S)‐amines by Biocatalytic Cascade Employing ω‐Transaminase and Amine Dehydrogenase

“…Although ω‐TAs have been well documented in deracemization;, the utility of AmDHs in deracemization protocols to produce enantiopure amines is still unexplored. Although, the synthesis of ( R )‐amines have been successfully carried out by easier strategies such as AmDH‐catalyzed reductive amination of ketones ,. Also, recent years have evidenced the improved array of new ( R )‐selective ω‐TAs for the scalable synthetic applications .…”

Identification of Novel Bacterial Members of the Imine Reductase Enzyme Family that Perform Reductive Amination

“…These reductive aminases (RedAms) from fungi are able to utilize stoichiometric or near‐stoichiometric ketone/amine equivalents to achieve high conversions (Figure b) . Other enzyme classes that catalyze reductive amination include amino acid dehydrogenases (AADHs) and the engineered amine dehydrogenases (AmDHs) as well as N ‐methylamino acid dehydrogenases (NMAADHs), although the latter are limited to ammonia or methylamine as the amine coupling partner . Opine dehydrogenases (OpDHs) catalyze reductive amination between an amino acid and keto acid and have been engineered to broaden their substrate scope and application by Codexis…”