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Abstract Billions of years of evolution have led to the selection of (hyper)thermophiles capable of flourishing at elevated temperatures. The corresponding native (hyper)thermophilic enzymes retain their tertiary and quaternary structures at near‐boiling water temperatures and naturally retain catalytically competent conformational dynamics under these conditions. And yet, while hyper/thermophilic enzymes offer special opportunities in biocatalysis and in hybrid bio/chemocatalytic approaches to modern synthesis in both academia and industry, these enzymes remain underexplored in biocatalysis. Among the strategic advantages that can be leveraged in running biocatalytic transformations at higher temperatures are included more favorable kinetics, removal of volatile byproducts to drive reactions forward, improved substrate solubility and product separation, and accelerated stereodynamics for dynamic kinetic resolutions. These topics are discussed and illustrated with contemporary examples of note, in sections organized by stratagem. Finally, the reader is alerted in particular to archaeal enzymes that have proven useful in non‐natural synthetic chemistry ventures, and at the same time is referred to a rich area of archaea whose genomes have been sequenced but whose enzymatic activities of interest have not yet been mined. Though hyperthermophilic archaea are among the most ancient of organisms, their enzymes may hold the key to many future innovations in biocatalytic chemistry–perhaps we really do need to go ‘back to the future’. 

Abstract These studies reveal the first structure ofClostridium acetobutylicumalcohol dehydrogenase (CaADH), a protein exhibiting remarkable substrate promiscuity and stereochemical fidelity. The CaADH enzyme is utilized here for synthesizing 20 potential aryl isoserine side chains for the Taxotere family of tubulin‐binding chemotherapeutics. The approach involves dynamic reductive kinetic resolution (DYRKR) upon the corresponding α‐chloro‐β‐keto esters, showing high D‐synstereoselectivity, including those leading to the clinically relevant milataxel (Ar = 2‐furyl) and simotaxel (Ar = 2‐thienyl) side chains. Furthermore, various cross‐coupling chemistries performed on thep‐bromophenyl isoserine side chain significantly enhance the structural diversity of the taxoid side chain library obtained (16 additional taxoid side chains). The CaADH structure is notable: (i) the nicotinamide cofactor is bound in ananti‐conformation, with the amide carbonyl occupying the ketone binding pocket, and (ii) a flexible loop near the active site likely contributes to the remarkable substrate promiscuity observed in CaADH. We present our perspective on the dynamic nature of the CaADH active site through molecular dynamics simulation, proposing a halogen bonding model as a potential mechanism for the remarkable selectivity for an (S)‐configured C─Cl bond, in addition to the D‐facial selectivity, demonstrated across 20 diverse substrates by this remarkable short‐chain dehydrogenase enzyme.