Microbial penicillin acylase

Penicillin acylases - [ANTIBIOTICS - BETA-LACTAMS - PENICILLINS AND OTHERS] (Vol 3) -use m synthesis [MICROBIAL TRANSFORMATIONS] (Vol 16)... 

Chemferm is one of among several companies which apply penicillin acylase for the kinetically controlled industrial synthesis of semisynthetic antibiotics in aqueous environments (Scheme 37) [109-111]. Ampicillin (119) and amoxicillin (120) can be obtained by the enzyme-catalyzed condensation of 6-aminopenicillic acid (6-APA, 117) with the amide or ester of D-(-)-4-hydrox-yphenylglycine and D-(-)-phenylglycine, respectively. In a similar way, cephalexin (121) can be obtained by reaction of D-(-)-phenylglycine with 7-aminodesacetoxycephalosporanic acid (7-ADCA, 118). Penicillin acylase from diverse microbial strains such as E. colU Klyveromyces citrophiluy and Bacillus megabacterium was successfully applied for this transformation and was used in its immobilized form based on a gelatin carrier. The immobilization allows an easy separation from the reaction medium and the reuse of the enzyme for at least 50 cycles. Impressive characteristics of this transformation are yields >90%, a selectivity of >95%, and an optical purity of >99% ee. The industrial manufacture takes place in repetitive batch reactors at many locations worldwide with an annual production volume of 2,000 t. 

The use of microbial amidases (acylases) for the production of 6-aminopenicillanic acid was revie% ed.33 An eunidase from coli shotted comparable efficacy in deacylating penicillins and cephalosporins containing the sterically similar phenylacetyl and thienylacetyl components. 

The above two processes employ isolated enzymes - penicillin G acylase and thermolysin, respectively - and the key to their success was an efficient production of the enzyme. In the past this was often an insurmountable obstacle to commercialization, but the advent of recombinant DNA technology has changed this situation dramatically. Using this workhorse of modern biotechnology most enzymes can be expressed in a suitable microbial host, which enables their efficient production. As with chemical catalysts another key to success often is the development of a suitable immobilization method, which allows for efficient recovery and recycling of the biocatalyst. 

The microbial sources of penicillin amidases/acylases required for side-chain removal were found and were quickly commercialised as whole-cell biocatalysts. 

E. Baldaro, C. Fuganti, S. Servi, A. Tagliani, M. Terreni, The Use of Immobilized Penicillin G Acylase in Organic Synthesis, in Microbial reagents in organic synthesis (Ed. S. Servi), Kluwer Academic Publishers, 1992, pp. 175-188. 

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