419 Thiophenes, Imidazoles, Thiazoles, Isoxazoles 



attachment of side-chains by the methods of organic 

 chemistry. 



HOOC— CH N C=0 HOOC— CH N C=0 



CH3 I I I CH3 I I I O 



C CH CH— NH. C CH CH— NH— C— R 



CH3 ^ CH3 ^ 



6-Aminopenicillanic Acid Penicillins 



Since 6-aminopenicillanic acid can be isolated from 

 penicillin fermentations in good yields, it is probably an 

 intermediate. Also, the fact that side-chain precursors 

 are so readily incorporated into the molecule indicates 

 attachment of the side-chain to be the final step in peni- 

 cillin biosynthesis. This is also known to be the rate-lim- 

 iting step, and, even in commercial fermentations, side- 

 chain precursors are added routinely. 



The precursors of the 6-aminopenicillanic acid nucleus 

 have been show^n to be (stereospecifically) L-cysteine- and 

 L-valine,'^ although additions of these amino acids to fer- 

 mentations do not cause dramatic improvements in yields 

 or in rates of synthesis. Degradation studies have shown 

 that L-cysteine occurs in the same configuration after in- 

 corporation into the penicillin molecule, while valine has 

 been converted to the o-form. Aside from the change in 

 configuration of valine, both amino acids are incorporated 

 intact. 



Other substances have been considered as penicillin 

 precursors and intermediates. Among them are peni- 

 cillamine,^ y8-hydroxy valine,^ serine,- glycine,- homocys- 



2H. R. V. Arnsteln and P. T. Grant, Biochem. J. 57 353, 360 

 (1954); H. R. V. Arnsteln and J. C. Crawhall, ibid. 67 180 (1957); 

 Carl M. Stevens, Edward Inamine and Chester W. Belong, /. Biol. 

 Chem. 219 405 (1956); H. R. V. Arnsteln and H. Margreiter, Bio- 

 chem. J. 68 339 (1958); F. H. Grau and W. J. Halliday, ibid. 69 205 

 (1957). 



^H. R. V. Arnsteln and Margaret E. Clubb, ibid. 65 618 (1957); 

 Carl M. Stevens and Chester W. Belong, /. Biol. Chem. 230 991 

 (1958). 



* Carl M. Stevens, Pran Vohra, Edward Inamine and Oliver A. 

 Rohoh, Jr., ibid. 205 1001 (1953). 



