Abstract
NADPH-dependent imine reductases (IREDs) are enzymes capable of enantioselectively reducing imines to chiral secondary amines, which represent important building blocks in the chemical and pharmaceutical industry. Since their discovery in 2011, many previously unknown IREDs have been identified, biochemically and structurally characterized and categorized into families. However, the catalytic mechanism and guiding principles for substrate specificity and stereoselectivity remain disputed. Herein, we describe the crystal structure of S-IRED-Ms from Mycobacterium smegmatis together with its cofactor NADPH. S-IRED-Ms belongs to the S-enantioselective superfamily 3 (SFam3) and is the first IRED from SFam3 to be structurally described. The data presented provide further evidence for the overall high degree of structural conservation between different IREDs of various superfamilies. We discuss the role of Asp170 in catalysis and the importance of hydrophobic amino acids in the active site for stereospecificity. Moreover, a separate entrance to the active site, potentially functioning according to a gatekeeping mechanism regulating access and, therefore, substrate specificity is described.
Highlights
IntroductionEver since the U.S Food and Drug Administration (FDA) issued regulatory guidelines for the development of stereoisomeric drugs in 1992 [1], the search for a cost-effective (and in recent history preferably ecologically sustainable) way to generate enantiomerically pure compounds has become a primary concern for the pharmaceutical industry
Ever since the U.S Food and Drug Administration (FDA) issued regulatory guidelines for the development of stereoisomeric drugs in 1992 [1], the search for a cost-effective way to generate enantiomerically pure compounds has become a primary concern for the pharmaceutical industry
In the last ten years, imine reductases (IREDs) have become a promising target for the development of a biocatalytic approach to the enantioselective generation of chiral amines via asymmetric reduction of prochiral imines
Summary
Ever since the U.S Food and Drug Administration (FDA) issued regulatory guidelines for the development of stereoisomeric drugs in 1992 [1], the search for a cost-effective (and in recent history preferably ecologically sustainable) way to generate enantiomerically pure compounds has become a primary concern for the pharmaceutical industry. The asymmetric synthesis of chiral secondary amines has become one major focus of the industry and many chemical methods to achieve this goal based on the reduction of the C=N bond exist, for example the asymmetric hydrogenation of prochiral imines with transition metal catalysts or stable organic hydrogen donors [5,6]. These methods often suffer from major drawbacks like high costs due to the need for higher amounts of expensive catalysts and hazardous reaction conditions. 3-thiazolidines proved to be all but inaccessible by established reduction technologies as of yet, those failing because of catalyst-poisoning, low reactivity, undesired ring-opening of the product or low enantioselectivity and yields [7,8]
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