I04 



INTERMEDIARY METABOLISM AND GROWTH 



as cofactors in the transfer of the ''one carbon groups" to the methyl group of 

 DNA-T. Incorporation of formate-'^'C or q-^^'C uracil deoxyriboside into DNA- 

 thymine is inhibited by aminopterin and the inhibition is partially reversed by 

 leucovorin (Friedkin and Roberts, 1955, 1956; Pvusoffetal., 1956; Totter and Best, 

 1955). Incorporation of radioactive thymidine into DNA-thymine is not inhibited 

 by aminopterin. In the synthesis of the methyl group of DNA-thymine from 

 ^H'^^COONa or L-serine-3-''*C-H20H, 0.9 and i .5 atoms of deuterium, respectively, 

 accompany the labelled carbon. On the other hand, during the conversion of the 

 j3-carbon of serine and of formate to carbon atoms 2 and 8 of purines, an 

 extensive labilization of deuterium takes place. These differences are probably 

 attributable to the fact that a hydroxymethylfolic acid derivative is required for 

 thymine biosynthesis and ayo/'w^/-folic acid derivative for purine synthesis. 



— CDrP- 



CR ^CDr- 



-MeCDr- 



U-— =-UR-— UDr- 

 Pi 



N^^-CHjOH-THFA 



-^TDr- 



Pi 



■MeCDrP- 



-TDrP- 



Fig. 46. Deoxyribonucleoside metabolism and DNA-thymine synthesis. 



Uracil deoxyriboside and cytosine deoxyriboside are acceptors of the [^-carbon 

 of serine or of formate (Fig. 46). 2-''*C uracil deoxyriboside is converted to thy- 

 midine and to DNA-thymine by bone marrow cells and by the tissues of the rat 

 (Friedkin and Roberts, 1955, 1956; Reichard, 1955). Deoxyuridine is not, how- 

 ever, a precursor of DNA-cytosine or of RNA pyrimidines. Likewise, in the rat, 

 deoxycytidine-'^N is converted to DNA thymine and cytosine but not to RNA 

 pyrimidines. (Reichard and Estborn, 1951). The presence of non-labelled de- 

 oxyuridine or deoxycytidine stimulates the incorporation of formate-^'*C or of 

 serine-3-^'*C into free thymidine and in some cases DNA-thymine by normal 

 lymphatic tissues and tumors (Kit, 1957) and into the DNA-thymine of bone 

 marrow and Ehrlich ascites tumor cells {Prusoff et al., 1956; Frusoff and Lajtha, 

 1956). On the other hand, free uracil, uridine, cytosine, or thymine do not stim- 

 ulate the formation of thymidine or DNA-thymine by normal and malignant 

 lymphatic tissues (Kit, 1957), although uridine does stimulate the conversion of 

 formate ^■*G to DNA thymine by Ehrlich tumor cells (Frusoff and Lajtha, 1956). 

 Free uracil-2-'''C is a DNA-thymine precursor in the Ehrlich tumor cells (Kit, 

 1957; Lagerkvist et al, 1955). 



It is unlikely that 5-methyluridine and free thymine are direct precursors of 

 DNA-thymine in the rat. The administration of labelled thymine or 5-methyluri- 

 dine to the rat residted in very little labelling of the DNA-thymine (Reichard, 

 1955). Deoxyuridine may be an intermediate in the conversion of deoxycytidine 

 to thvmidine. However, to a minor desrree, deoxvcvtidine mav also react directly 



