ANALOGS OF THIAMINE 523 



difference in inhibitory activity between these two analogs possibly indi- 

 cates the importance of the pyrimidyl 4 '-amino group. This was substan- 

 tiated in the demonstration by Cerecedo and Eich (1955) that oxypyri- 

 thiamine, in which the 4'-amino group is replaced by hydroxyl group, does 

 not inhibit rat liver thiamine kinase. 



Mano and Tanaka (1960) studied a large series of thiamine analogs with 

 respect to their abilities to be phosphorylated by a rat liver thiamine kinase 

 system and their inhibitory potencies on thiamine phosphorylation (see ac- 

 companying tabulation). The analogs and thiamine were all at 0.1 milf. 



Relative activity % Inhibition of 



(thiamine — 100) thiamine kinase 



The inhibitions by pyrithiamine and the 2'-alkylthiamines are competitive 

 and the following values of K^ were calculated: pyrithiamine 0.033 m.M, 

 2'-ethylthiamine 0.041 mM, and 2'-butylthiamine 0.043 mM. The inability 

 of the enzyme to catalyze the phosphorylation of oxythiamine and pyri- 

 thiamine is noteworthy in view of the theory that these analogs may exert 

 their effects in the diphosphate form. It may be recalled that Woolley (1951 ) 

 failed to demonstrate the synthesis of pyrithiamine-PP in chicken blood. 

 There has been surprisingly little attention to this important problem of 

 analog phosphorylation in organisms. 



Inhibition of Thiaminase 



The importance of this enzyme in the mammalian metabolism of thiamine 

 is not known. The only evidence for its possible function is the appearance 

 in the urine of the pyrimidine and thiazole moieties of thiamine following 

 administration of thiamine. It would seem unlikely that inhibition of this 

 enzyme is an important factor in the toxicity of thiamine analogs, but it 

 could be of some significance in determining the effects on tissue levels of 

 thiamine-PP. It was stated by Soodak and Cerecedo (1944) that oxythia- 

 mine inhibits carp thiaminase but no data were given. Pyrithiamine inhibits 



