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Industrial biocatalysis Aleksey Zaks
The number of industrial processes for the synthesis of fine and commodity chemicals, pharmaceutical and agrochemical intermediates and drug substances utilizing biological catalysts continues to grow. The combination of new molecular biology techniques, such as directed evolution and pathway engineering, with new and efficient high-throughputscreening methods is poised to bolster this field and further advance the contribution of biocatalysis to the chemical and the pharmaceutical industries.
Addresses Schering-Plough Research Institute, 1011 Morris Avenue, Union, New Jersey 07083, USA; e-mail: Current Opinion in Chemical Biology 2001, 5:130–136 1367-5931/01/$ — see front matter © 2001 Elsevier Science Ltd. All rightsreserved. Abbreviations DEAE diethylaminoethyl ee enantiomeric excess

Pharmaceutical industry
The use of biological catalysts in the synthesis of pharmaceutical intermediates, drug metabolites and drug products is now common. The growing list of compounds synthesized with the assistance of enzymes now includes anti-cancer, anti-viral, anti-infective, antipsychotic, anti-arrhythmic, andcholesterol-lowering agents, calcium channel blockers, ACE inhibitors and many others [3••,6•]. Although it is well accepted that enzymes are extremely versatile and capable of catalyzing a wide variety of chemical reactions, their practical use is often curtailed by their limited commercial availability. Among the approaches utilized in the search for new catalytic activities, high-throughput microbialscreening and the selective enrichment technique are considered to be the most reliable. The latter approach was efficiently utilized by a Bristol–Myers Squibb team for the synthesis of Omapatrilat, a vasopeptidase inhibitor targeted for the treatment of hypertension (Figure 1) [23••]. By using the selective enrichment technique, the authors have isolated a novel L -lysine ε-aminotransferase capableof oxidizing the ε-amino group of L-lysine. The 81 kD enzyme, consisting of two subunits, was purified to homogeneity and characterized. It was then cloned, overexpressed in Escherichia coli and produced by large-scale fermentation. The isolated enzyme was used in the oxidation of the dipeptide 1 to the aldehyde intermediate 2 (Figure 1). The glutamate by-product was recycled back toα-ketoglutarate with glutamate oxidase, obtained by fermentation of Streptomyces lividans. The conversion of 1 to 3 proceeded with the overall yield of 65–70%. Two alternative enzymatic approaches were also used to establish the sidechain chirality of Omapatrilat. In the approach based on allysine ethylene acetal 5 [24••], the proper stereochemistry of the amino group was established by enantioselectivereductive amination of 4 with phenylalanine dehydrogenase. The NADH cofactor consumed in this transformation was efficiently recycled with formate and formate dehydrogenase. By using heat-dried cells of recombinant E. coli and Candida boidinii as the source of phenylalanine and formate dehydrogenases, respectively, 197 kg of 5 were produced in three batches with an average yield of 91% and enantiomericexcess (ee) >98%. 8 The approach, based on L-6-hydroxynorleucine (8) utilized a D-amino acid oxidase to convert racemic 6 6-hydroxynorleucine (6) to 2-keto-6-hydroxyhexanoic acid 7 (7) leaving behind the unreactive enantiomerically pure L-isomer [25]. The ketoacid 7 was then converted to 8 by reductive amination with glutamate dehydrogenase. This two-step process proceeded in 91% yield and >97%ee.

Interest in industrial biocatalysis continues to grow, as judged by the impressive number of books and reviews published in the past two years [1,2,3••,4,5,6•,7–9,10••,11–14]. This trend is hardly surprising considering the increased integration of biological catalysts into a variety of industrial processes ranging from the manufacture of commodity chemicals, such as...
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