36. BIOSYNTHESIS OF PYRIMIDINE NUCLEOTIDES 



325 



NH3 + C02 



ATP 



(acetylglutamate) 



NH 2 COOP03H2 

 carbamyl- 

 phosphate 



aspartic acid 



aspartate 



corbomy/ 



transferase. 



caH 



NH 2 CH 2 

 I I 



CO QH 

 ^NK XO,H 

 H 2 



carbamyl- 

 aspartate 



d/ hydro - 

 orotase 



HgOaPOCH^O 



O O 



11 11 

 0-P-O-P-OH 



OH OH OH . OH 



5-phosphoribosyl- 

 pyrophosphate 



pyrophosphate 



FAD. 2H 

 ^. 



FAD 



C0 2 H d/hydroorotote 



dehydrogenase 



NH CH 2 



V ■ 



Y orot/d/ne - 5 -phosphate 

 1 pyrophosphory/ase 



1 



CO CH 



H c ^2' 



dihydroorot'ic 

 acid 



CO,H 



HoO,POCH 2 



'2^3 



CO, 



orot/d/ne-5-phosphate I2 3 +] 

 C0 2 H decarboxy/ase <y^\r 



H 2 3 POCH^O 



)H OH 



orotidine-5'- 



phosphate 



OH OH 

 uridine -5- 

 phosphate 



Fig. 1. The pathway of de novo synthesis of uridine-5'-phosphate. 



b. Biosynthesis in Cell- Free Systems 



In organisms capable of de novo pyrimidine synthesis the operation of 

 the sequence of reactions shown in Fig. 1 has been generally confirmed in 

 those cases investigated. 



The first reaction, the formation of carbamylaspartic acid from aspartic 

 acid is formally analogous to citrulline formation from ornithine. Grisolia 

 and Cohen 19 have demonstrated a requirement for adenosine-5'-triphos- 

 phate (ATP), Mg++, and acetylglutamate in the formation of the activated 

 derivative of NH 3 and CO2 (compound X) involved in citrulline synthesis. 

 The involvement of compound X in carbamylaspartic acid synthesis in an 

 isolated mammalian enzyme system has also been demonstrated. 1911 Jones 

 et al. 20 have made the important discovery that carbamyl phosphate is 



19 S. Grisolia and P. P. Cohen, J. Biol. Chem. 198, 561 (1952). 



19a P. Reichard and G. Hanshoff, Acta Chem. Scand. 8, 1102 (1954); 9, 519 (1955). 



20 M. E. Jones, L. Spector, and F. Lipmann, J. Am. Chem. Soc. 77, 819 (1955). 



