Cephalosporins and cephamycins

Fig. 1. Biosynthesis of cephalosporins and cephamycins. a, Cephalosporium acremonium, b, Penicillium chjsogenum, c, Streptomjces clavuligerus-, d, Streptomjces lipmanir, e, Streptomjces wadajamensis, REX is a ring expansion en2yme (deacetoxycephalosporin C synthethase).

In organisms which produce cephalosporin and cephamycins, the configuration of the O -aminoadipyl side chain of (30) is D, while penicillin producers yield the l isomer. The exact point at which the configuration is inverted is unknown. Subsequent steps in cephalosporin biosynthesis are believed to involve ring expansion to deacetoxycephalosporin C (31), which may proceed by a mechanism analogous to the chemical pathway (see Section 5.10.4.2), followed by hydroxylation and acetylation at C-3 to produce cephalosporin C (32). 

Martin JF, Liras P (1989) Enzymes involved in penicillin, cephalosporin and cephamycin biosynthesis. In Fiechter A (ed) Advin Biochem Eng Biotech. Springer, Berlin Heidelberg New York... 

Cephalosporins and cephamycins are similar to penicillins chemically, in mechanism of action, and in toxicity. Cephalosporins are more stable than penicillins to many bacterial G-lactamases and therefore usually have a broader spectrum of activity. Cephalosporins are not active against enterococci and Listeria monocytogenes. 

Based on the identified homology of the cefD and cefDZ proteins with known eukaryotic enzymes, a mechanism for the A. chrysogenum two-component epimerization system which is different from the epimerization found in prokaryotes has been established <2002JBC46216>. Therefore, it was suggested that the cephalosporin biosynthesis pathway begins with the activation of the substrate isopenicillin N to its CoA, followed by an epimerization to the D-enantiomer, namely penicillinyl-CoA. Next, the required hydrolysis of the CoA-thioesters seems to occur in a nonstereoselective manner by different thioesterases. The resulting product, penicillin N, is the direct precursor of all cephalosporins and cephamycins. 

The second major group of P-lactam antibiotics includes cephalosporins and cephamycins. The analog X is H are cephalosporins, and those X is OCH3 are called cephamycins. 

Table 1 Some cephalosporins and cephamycins (all rINNs except where stated)...

Cephalosporins and cephamycins Carbacephems and carbapenems Monocyclic beta-lactams... 

Cephalosporins and cephamycins inhibit bacterial cell wall synthesis in a manner similar to that of penicillin. 

Penicillins Cephalosporins and Cephamycins Tetracyclines Aminoglycosides Sulfonamides Erythromycin, Its Salts, and Esters Other Antimicrobial Agents. 

Figuic I The common pathway for biosynthesis of penicillins, cephalosporins, and cephamycins in bacteria and fungi. Abbreviations ACV, 5-(L a aminoadipyl) L CYsteinyl l>valine IPN, isopeni-cillin N 6-APA 6-aminopenicillanic add DAC, deacetylcephalosporin C DAOC. deacetoxy cephalosporin C OCDAC, o-carbamoyl-deacetoxycephalosiwrin C. The genes ate indicated in parentheses. 

The reaction rate of (3-lactam hydrolysis for a number of cephalosporins and cephamycins, as expressed by the (Table VIII), indicates the greater stability of cephamycins to enzymatic degradation by (3-lactamase from Aerohacter cloacae 18410/62. 

TABLE XIV Kinetics of Hydrolysis of Various Cephalosporins and Cephamycins by the P-Lactamase from Proteus morganii 1510 ... 

TABLE XIX In Vitro Activities of 7-Trifluoromethylthioacetamido Derivatives of Cephalosporins and Cephamycins" ... 

Martin, J. F., and Liras, P., Enzymes Involved in Penicillin, Cephalosporin and Cephamycin Biosynthesis, Advances in Biochemical Engineering/Biotechnology, 39, 153 (1989). 

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