518 R. E. HANDSCHUMACHER AND A. D. WELCH 



whereas the incorporation of preformed thymidine was essentially unaffected. 607 

 However, using slices of regenerating livers, other workers have reported some effects 

 of uracil methylsulfone on the incorporation of orotic acid into the pyrimidines of 

 the RNA. 608 The high reactivity of this compound, apparently with sulfhydryl sites 

 on several enzymes concerned with pyrimidine metabolism, may make it a useful 

 tool in studying the nature of certain of the reactive centers on these enzymes, and 

 in providing a specific blocking agent for these reactions. 



The inhibitory effects of 2-thiouracil (XVIII) on the growth of L. casei and E. 

 coli were noted as early as 1945 and the specific reversal of these effects by uracil 

 encouraged further study of this analog in other systems. 509 Examples of its effect 

 on the rate of growth of seedlings, 510 protozoa, 511 viruses, 512513 and experimental 

 tumors 514 • 515 have been added. Although this compound (and its 6-propyl derivative) 

 is considered primarily as an antithyroid drug, its action in most of the systems re- 

 ferred to above appears to be mediated by an effect on nucleic acid metabolism. In- 

 corporation of this analog into the RNA of (a) tobacco mosaic virus, 512, 516, 6n (b) 

 Bacillus megaterium, il8 and (c) livers of rats treated with acetylaminofluorene 519, 620 

 has been described. More complete studies with the first two types of RNA have 

 clearly indicated that the compound was present in normal ribonucleotide form, and 

 that it replaced up to 20% of the normal uracil component. 517, 518 Liberation of this 

 analog from the RNA of tobacco mosaic virus indicated that a large percentage of 

 the compound was present as 2-thiouridine and its 3',5'-diphosphate. 517 Such a re- 

 sult would suggest that the analog is present in higher concentrations in oligonucleo- 

 tides or that it may be found primarily at the ends of RNA molecules. It has been 

 proposed that the decrease in growth rate of tobacco mosaic virus exposed to thio- 

 uracil, but lack of effect on the total number of infectious particles, is the result of 

 inactivation of some but not all subunits of RNA within the virus; however, this 

 remains only an hypothesis. 516 As with many of the other agents discussed, incorpora- 

 tion into nucleic acids may bear little relationship to inhibition, since 2-thiothymine 

 is a potent inhibitor of E. coli, but is not incorporated to any significant degree into 

 its DNA. 432 Although thiouracil is a substrate for the nucleoside phosphorylase from 

 horse liver and yields the corresponding ribonucleoside or deoxyribonucleoside, de- 

 pending upon the pentose phosphate supplied, 521 little more has been done on the 



507 W. H. Prusoff, Cancer Research 18, 603 (1958). 



508 K. Ogata, T. Shimizu, and K. Togashi, Biochim. ct Biophys. Acta 29, 656 (1958). 



509 F. Strandskov and O. Wyss, J. Baeteriol. 50, 237 (1945); ,/. Bacteriol. 52, 575 

 (1946). 



510 \V. R. Trotter, Nature 164, 63 (1949). 



511 G. W. Kidder and V. C. Dewey, J. Biol. Chem. 178, 382 (1949). 



512 R. Jeener and J. Rosseels, Biochim. el Biophys. Acta 11, 438 (1953). 



513 B. Commoner and F. Mercer, Nature 168, 113 (1951); Arch. Biochem. Biophys. 35, 

 278 (1952). 



514 K. E. Paschkis, A. Cantarow, and J. Stasney, Science 114, 264 (1951). 



515 J. Meites, Cancer Research 18, 176 (1958). 



516 R. Jeener, Biochim. et Biophys. Acta 23, 351 (1957). 



517 H. G. Mandel, R. Markham, and R. E. F. Matthews, Biochim. et Biophys. Acta 

 24, 205 (1957). 



518 R. Hamers, Biochim. et Biophys. Acta 21, 170 (1956). 



519 R. J. Rutman, A. Cantarow, and K. E. Paschkis, Federation Proc. 12, 122 (1953). 



520 A. Cantarow, K. E. Paschkis, and R. J. Rutman, J. Natl. Cancer Inst. 15, 1615 

 (1955). 



521 D. B. Strominger and M. Friedkin, /. Biol. Chem. 208, 663 (1954). 



