Cephalosporin enzymatic conversion

Examples of this, in addition to the above acrylamide example and the related enzymatic conversion of 3-cyanopyridine to nicotinamide, are die amidase cleavage of penicillins to produce 6-aminopenicillanic acid (6-APA) and the corresponding (more complex) process for converting cephalosporin C to 7-aminocephalosporanic acid (7-ACA) (see Chapter 9, footnote 8.)... 

An innovative approach to cephalosporin C and 7ACA recovery involves the enzymatic conversion of cephalosporin C to solvent extractable intermediates and ultimately to 7ACA. The first step involves microbial deamination or chemical transamination to the a-ketoadipyl or, after spontaneous decarboxylation, glutaryl cephalosporin C derivatives (51-54). These derivatives then—unlike cephalosporin C itself--can be enzymatically cleaved to 7ACA (55-60). These reactions are shown in Figure IS. 

Figure 13. Enzymatic or chemical deamination of cephalosporin C and enzymatic conversion to 7ACA.

The biosynthesis of cephalosporins is analogous to that of the penicillins. It is derived from the peptide 5-(a-aminoadipoyl)cysteinylvaline (see p 160). First, the P-lactam ring is formed. This is followed by a C-H bond fission, not at the p-position but at the y-position of the valine building-block. However, enzymatic conversion of the penam system into the ceph-3-em system cannot be excluded. 

Parmar A, Knmar H, Marwaha S S, Kennedy J F (1998). Recent trends in enzymatic conversion of cephalosporin C to 7-aminocephalosporanic acid (7-ACA). Cri. Rev. Biotechnol. 18 1-12. 

Sarkar P, Bhatacharya P, Mukherjea R (1987) Isolation and purification of protease from human placenta by foam fractionation. Biotechnol Bioeng 29 934-940 Savidge T (1984) Enzymatic conversions used in the production of penidUins and cephalosporins. In Vandamme E (ed). Biotechnology of industrial antibiotics. Marcel Dekker, New York, pp 171-224... 

II. ENZYMES CONVERTING CEPHALOSPORIN C TO 7-ACA A. Enzymatic Conversion of Cephalosporin C to 7-ACA... 

Various methods are known to produce 7-ACA from cephalosporin C (Ceph C) by removing the a-aminoadipyl side-chain. They can be classified into three types, the chemical process, a two-step enzymatic process and an enzymatic process in which the side-chain is directly removed from Ceph C. Today two processes are running commercially on an industrial scale, the classical chemical process and the modern two-step biocatalytic process (Fig. 2). Until now the favorable direct process is less effective, because of low conversion. 

Kim MG, Lee SB (1996) Penicillin acylase-catalyzed synthesis of P-lactam antibiotics in water-methanol mixtures effect of cosolvent content and chemical nature of substrate on reaction rates and yields. J Mol Catal B Enzym 1 201-211 Kohsaka M, Domain AL (1976) Conversion of penicDlin N to cephalosporin(s) by ceU-free extracts of Cephalosporium acremonium. Biochem Biophys Res Commun 70(2) 465-473 Koreishi M, Tani K, Ise Y et al. (2007) Enzymatic synthesis of P-lactam antibiotics and /V-fatty-acylated amino compounds by the acyl transfer reaction catalyzed by peniciUin V acylase from Streptomyces mobaraensis. Biosci Biotechnol Biochem 71(6) 1582-1586 Kupka JY, Shen, YQ, Wolfe S et al. (1983) Partial purification and properties of the alpha-ketoglutarate-linked ring expansion enzyme of beta-lactam biosynthesis of Cephalosporium acremonium. FEMS Microbiol Lett 16 1-6... 

The multistep chemical conversion of penicillin G to 7-ADCA (Fig. 16) has recently been replaced by a 2-step biosynthesis (Fig. 18). This is a major step forward to shorten the industrial synthesis of cephalosporins and this has already been implemented. The 7-N-adipoyl-ADCA is obtained directly through fermentation with a modified Penicilium chrysogenum followed by a simple enzymatic removal of the amino substituent. Again, various reagents such as silylat-ing agents, phosphor halides, pyridine and DMF, and some halogenated solvents have been replaced by biocatalysts in aqueous medium. 

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