694 THE BIOCHEMISTRY OF B VITAMINS 



The interaction of thioformamide with 3-chloro-5-hydroxy-2-pentanone, 

 which forms the thiazole portion of the thiamine molecule in vitro, also 

 occurs in pea root cells. 5-Hydroxy-2-pentanone (CH 3 — CO— CH 2 — CH 2 

 — CH 2 OH) is also utilized by the root cells for the thiazole synthesis, but 

 4-hydroxy-2-pentanone did not allow formation of 4-methyl-5- (a-hy- 

 droxyethyl) thiazole which has appreciable activity for pea roots. 67a 



Inhibitory Analogues of Thiamine 



The first report of an analogue of thiamine which may interfere with 

 the utilization of this vitamin is that of Abderhalden, 70 who observed in 

 1939 that the administration of 2-methyl-4-amino-5-bromomethylpyrimi- 

 dine (as well as the 5-bromoethyl homologue) to rats maintained on a diet 

 which appeared to be adequate for growth led to acute cramps and death 

 of the animals. It was found that this effect could be prevented by the 

 addition of corn sprouts or more dried yeast to the diet. These results 

 were confirmed by Morii, 30 who showed that the 5-hydroxy, 5-bromo, 

 and 5-chloro analogues, but not the 5-amino analogue, also produced 

 spasms in mice as well as in rats. 



In 1940, Buchman, et al. 71 showed that the thiazole pyrophosphate 

 portion of cocarboxylase (thiamine pyrophosphate) inhibited the car- 



N C— CH 3 



HC C— CH 2 CH 2 — O— PO— O— PO— OH 



\/ II 



S OH OH 



Jf.-methyl-5-^-hydroxyeihylthiazole pyrophosphate 



boxylase system of yeast, in which cocarboxylase is the coenzyme. Later, 

 Sevag, et al. 12 reported that sulfathiazole specifically inhibits the cocar- 

 boxylase system of yeast. This effect can be overcome by the addition 

 of cocarboxylase, one mole of cocarboxylase being able to prevent the 

 union of 322 moles of sulfathiazole with the carboxylase protein. Subse- 

 quently, it was shown that p-aminobenzoic acid, although itself slightly 

 inhibitory, largely overcame the inhibitory effect of sulfathiazole on the 

 carboxylase system of Staphylococcus aureus and Escherichia coli. More- 

 over, these carboxylase systems are also inhibited (although to a lesser 

 extent) by sulanilamide, sulfapyridine, sulfadiazine, 2-sulfanilamido- 

 5-ethyl-4-thiazolone, 2-aminopyridine, 2-aminothiazole and 2-amino- 

 pyrimidine, 72 some of which possess very little structural similarity to 

 thiamine. These results suggest that the relationship between thiamine 

 and sulfathiazole may be more obscure than it appeared initially. 



Robbins 60 reported that pyrithiamine (heteroaneurine), l-(2'-methyl- 

 4'- amino - 5'-pyrimidylmethyl) - 2-methyl- 3 - (/?- hydroxyethyl) pyridinium 



