Cephalosporin biosynthesis

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). 

Queener S.W. (1990) Molecular biology of penicillin and cephalosporin biosynthesis. Antimicrob Agents Chemother, 34, 943-948. 

G Banko, S Wolfe, AL Demain. Cell-free synthesis of delta-(L-alpha-aminoadipyl)-L-cysteine, the first intermediate of penicillin and cephalosporin biosynthesis. Biochem Biophys Res Commun 137 528-535, 1986. 

A Khetan, LH Malmberg, DH Sherman, WS Hu. Metabolic engineering of cephalosporin biosynthesis in Streptomyces clavuligerus. Ann NY Acad Sci 782 17-24, 1996. 

SM Samson, JE Dotzlaf, ML Slisz, GW Becker, RM Van Frank, LE Veal, WK Yeh, JR Miller, SW Queener, TD Ingolia. Cloning and expression of the fungal expandase/hydroxylase gene involved in cephalosporin biosynthesis. Bio/Technol-ogy 5 1207-1214, 1987. 

S Gutierrez, J Velasco, AT Marcos, FJ Fernandez, F Fierro, JL Barredo, B Diez, JF Martin. Expression of the cefG gene is limiting for cephalosporin biosynthesis in Acremonium chrysogenum. Appl Microbiol Biotechnol 48 606-614, 1997. 

H Kimura, M Izawa, Y Sumino. Molecular analysis of the gene cluster involved in cephalosporin biosynthesis from Lysobacter lactamgenus. Appl Microbiol Bio-technol 44 589-596, 1996. 

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 Rules Governing Medicinal Products in the European Community, Vol. IV, Guide to Good Manufacturing Practice for the Manufacture of Medicinal Products. Queener, S. W. (1990) Molecular biology of penicillin and cephalosporin biosynthesis. Antimicrobial Agents and Chemotherapy, 34,943—948. 

Operation of hydrolases in the reverse direction to effect acylation is also viable, as shown by the preparation of 26 from 25.46 Hog kidney acylase has been used to resolve (2RS,3RS)-valine-[ H]3 for cephalosporin biosynthesis.47... 

Huddleston JA, Abraham EP. The stereochemistry of heta-lactam formation in cephalosporin biosynthesis. Biochem J 169(3) 705-707, 1978. 

The intracellular levels of ammonium ions, in S. noursei, are also influenced by the action of alanine dehydrogenase [102]. Ammonium liberated by alanine oxidation is available for the biosynthesis of glutamine via glutamine synthetase. 0-aminobenzoic acid represses both enzymes while stimulating formation of glutamate dehydrogenase and the antibiotic. Cephalosporin biosynthesis appears to be regulated by the same mechanism [103]. 

The second step of the penicillin and cephalosporin biosynthesis is the cycliza-tion of the linear ACV tripeptide to the bicyclic IPN, catalyzed by IPNS (cyclase), a nonheme-Fe(II)-dependent oxidase. The enzyme has a molecular mass of about 38 kDa and formally catalyzes a reaction which is exceptional in that a densely functionalized bicyclic ring is formed in a single four-electron oxidation step from a simple tripeptide through the removal of four hydrogen equivalents of the ACV tripeptide in a desaturative ring closure with concomitant reduction of dioxygen to water [162]. 

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