State-of-the-Art Biocatalysis

Abstract

The use of enzyme-mediated reactions has transcended ancient food production to the laboratory synthesis of complex molecules. This evolution has been accelerated by developments in sequencing and DNA synthesis technology, bioinformatic and protein engineering tools, and the increasingly interdisciplinary nature of scientific research. Biocatalysis has become an indispensable tool applied in academic and industrial spheres, enabling synthetic strategies that leverage the exquisite selectivity of enzymes to access target molecules. In this Outlook, we outline the technological advances that have led to the field's current state. Integration of biocatalysis into mainstream synthetic chemistry hinges on increased access to well-characterized enzymes and the permeation of biocatalysis into retrosynthetic logic. Ultimately, we anticipate that biocatalysis is poised to enable the synthesis of increasingly complex molecules at new levels of efficiency and throughput.

Figure 1

(A) Early uses of enzyme-mediated transformations, such as fermentation, chiral resolutions, and functional group interconversions. (B) Recent advances in genome sequencing, gene synthesis, and bioinformatics increase the accessibility of obtaining enzymes. (C) Select strategies in modern biocatalysis include cascades, chemoenzymatic synthesis, and enzyme evolution.

Figure 2

(A) Dynamic kinetic resolution of racemic N-acylhemiaminals by a lipase. (B) NAD(P)H recycling system developed by Wong and Whitesides. (C) Cascade system for construction of chiral amines using an ω-transaminase. Abbreviations: G6PDH glucose-6-phosphate dehydrogenase, DH dehydrogenase, TA transaminase, L-AADH l-α-amino acid dehydrogenase.

Figure 3

(A) Conceptual phylogenetic tree depicting locations of calculated ancestral sequences. (B) Conceptual SSN demonstrating nodes, edges, and clusters. (C) Workflow for a traditional cloning procedure.

Figure 4

Biocatalysis in complex molecule synthesis: (A) selected C–H functionalization reactions. (B) Selected C–C bond forming reactions.

Figure 5

Chemoenzymatic sequences to complex molecules. (A) Amino-acid C–H hydroxylation in the synthesis of manzacidin C. (B) Hydroxylative dearomatization in the synthesis of azaphilone natural products. (C) Benzylic hydroxylation en route to xyloketal D synthesis. (D) Alpha deuteration of amino acids in the formation of deutero safinamide.

Figure 6

Multienzyme biocatalytic sequences: (A) Merck’s biocatalytic synthesis of islatravir. (B) Multienzyme synthesis of napyradiomycin A1 and B1. (C) Multienzyme sequence toward the synthesis of tropolone stipitatic aldehyde.