Unlocking New Reactivities in Enzymes by Iminium Catalysis

Abstract

The application of biocatalysis in conquering challenging synthesis requires the constant input of new enzymes. Developing novel biocatalysts by absorbing catalysis modes from synthetic chemistry has yielded fruitful new-to-nature enzymes. Organocatalysis was originally bio-inspired and has become the third pillar of asymmetric catalysis. Transferring organocatalytic reactions back to enzyme platforms is a promising approach for biocatalyst creation. Herein, we summarize recent developments in the design of novel biocatalysts that adopt iminium catalysis, a fundamental branch in organocatalysis. By repurposing existing enzymes or constructing artificial enzymes, various biocatalysts for iminium catalysis have been created and optimized via protein engineering to promote valuable abiological transformations. Recent advances in iminium biocatalysis illustrate the power of combining chemomimetic biocatalyst design and directed evolution to generate useful new-to-nature enzymes.

Keywords: Biocatalysis; Chemomimetic Catalysis; Iminium Ions; Organocatalysis.

Figure 1

A) Typical reaction pathways of iminium catalysis, enamine catalysis, and carbonyl catalysis. B) Example of common organocatalysts used for iminium catalysis. C) Current approaches for the development of enzymes for iminium biocatalysis.

Figure 2

Repurposing 4‐OT for iminium biocatalysis. A) The native reaction of 4‐OT. B) Michael addition catalyzed by 4‐OT(F50A). C) Cycloaddition‐type reactions (epoxidation and cyclopropanation) catalyzed by 4‐OT mutant enzymes.

Figure 3

The natural aldol reaction and repurposed Michael reaction catalyzed by DERA‐WT and DERA‐MA, respectively.

Figure 4

The design and evolution of RA95.0 enzyme variants. RA95.5‐8 was redirected for various iminium catalysis reactions. FADS: fluorescence‐activated droplet sorting.

Figure 5

A) Artificial enzyme LmrR_V15pAF with a catalytic aniline side‐chain, constructed using genetic‐code expansion technology. B) LmrR_V15pAF catalyzed reactions proceed via iminium ion intermediates.

Figure 6

A) Hybrid catalyst based on the streptavidin–biotin technology; the biotin was functionalized with an amine to accommodate iminium catalysis. B) Michael addition and ene reduction catalyzed by artificial hybrid catalysts.

Figure 7

Future perspectives of iminium biocatalysis. KRED (ketoreductase), ADH (alcohol dehydrogenase), AlDH (aldehyde dehydrogenase), IRED (imine reductase), RedAm (reductive aminase), EnelRED (multifunctional imine reductase), SOMO (singly occupied molecular orbital).