524 2. ANALOGS OF ENZYME REACTION COMPONENTS 



this enzyme around 40% when analog and thiamine are both 0.5 mM (Sea- 

 lock and White, 1949). Pyrithiamine is split by the enzyme but at a slower 

 rate than is thiamine. Apparently it is bound more tightly than thiamine, 

 but reacts more slowly, since in mixtures of the two only the splitting of 

 thiamine is depressed. Thus too little is known of the effects of these analogs 

 on thiaminase to evaluate the importance of the inhibitions. 



Sealock examined the effects of a series of substituted methylthiazolium 

 ions on fish thiaminase and found that 3-o-aminobenzyl-4-methylthiazole 

 (ABMT) is a particularly potent inhibitor (see tabulation) (Sealock and 

 Goodland, 1944). The inhibition is competitive, with K^^ = 0.0831 mM and 

 Ki = 0.00197 mM, possibly indicating that ABMT is bound 2.3 kcal/mole 



Analog 



3-o-Aminobenzyl-4-methylthiazole 



3-^-Aminoethyl-4-methylthiazole 



3-/3-Phthalimidoethyl-4-methylthiazole 



3-o-Nitrobenzyl-4-methy]thiazole 



3-Ethyl-4-methylthiazole 



3-Phenyl-4-methylthiazole 



3-Phenyl-2-methyl-4-methylthiazole 



3-Ethyl-2-methyl-4-methylthiazole 



more tightly than thiamine. The amino group is probably quite important, 

 since the replacement with a nitro group reduces the inhibition so markedly. 

 The aminobenzylthiazoles were later studied in greater detail (Sealock and 

 Livermore, 1949) and the position of the amino group was shown to be 

 critical, only the ortho compound being inhibitory (see accompanying ta- 

 bulation). On the other hand, the position of the thiazole methyl group is 

 not critical. Thiamine was 0.5 mM in these experiments. Kenten (1958) has 



Amino position in Methyl position in Concentration „, ^ i -i • • 



, , . XI,- 1 • / jiT\ /o Inhibition 



benzyl ring thiazole ring (mM) 



ortho 

 meta 

 para 

 ortho 

 meta 

 para 

 ortho 



