578 2. ANALOGS OF ENZYME REACTION COMPONENTS 



ficiency, there appears to be no really good evidence for any of these reac- 

 tions being unassociated with pyridoxal function. We have discussed (p. 567) 

 various possible reasons for different effects of deoxypyridoxol and dietary 

 deficiency on tissue Bg vitamer levels and, hence, on metabolic disturbances 

 in the tissues. 



Toxopyrimidine 



This substance (4-amino-5-hydroxymethyl-2-methylpyrimidine), which is 

 essentially the pyrimidine portion of thiamine, has been known for many 

 years to produce abnormal motor behavior and convulsions, and a search 

 for antidotes led to the discovery that the pyridoxine group is specific in 

 preventing the toxic reactions. It was then realized that toxopyrimidine 

 bears a structural resemblance to pyridoxal. Makino and Koike (1954 a,b) 

 believed that toxopyrimidine acts in the phosphorylated form since tyrosine 

 decarboxylase is not inhibited by toxopyrimidine up to 1 mM, whereas to- 

 xopyrimidine-P exerted some inhibition at 0.001 mM and almost complete 

 inhibition at 0.1 mM. The inhibition is competitive with respect to pyridox- 

 al-P. Haughton and King (1958) confirmed this inhibition but stated that 

 it required an (I)/(C) ratio of 1000 to get 50% inhibition, whereas Makino 

 and Koike found around 50% inhibition with a ratio near 3. No inhibition 

 of tryptophanase, transaminase, glutamate decarboxylase, or arginine de- 

 carboxylase was observed, and they concluded that toxopyrimidine is not 

 of much value in the study of pyridoxal-P enzymes. The failure to inhibit 

 significantly the tryptophanase of E. coli was also reported by Wada et 

 al. (1958). McCormick and Snell (1961) found no inhibition of pyridoxal 

 kinase at concentrations of 0.01-0.1 mM toxopyrimidine. Rindi and Fer- 

 rari (1959) found that 90-120 min after the intraperitoneal injection of 

 125 mg/kg of toxopyrimidine in pyridoxine-deficient rats, convulsions hav- 

 ing been produced, the y-aminobutyrate levels in the brain have fallen 

 some 23%, although glutamate is unchanged. Administration of pyridoxa- 

 mine stops the convulsions and increases brain y-aminobutyrate. This dose 

 of toxopyrimidine reduces brain glutamate decarboxylase 20% but does 

 not significantly alter transaminase activity (Rindi et al., 1959). Again pyri- 

 doxamine restores activity. We have already noted (Table 2-37) that toxo- 

 pyrimidine can reduce brain glutamate decarboxylase at high doses, but at 

 lower convulsive doses in pyridoxine-deficient animals it does not. It would 

 seem that if toxopyrimidine causes convulsions by interfering with pyri- 

 doxal function, it is not mediated through a general fall in y-aminobutyrate 

 or transaminase activity, and the status of the mechanism is much the 

 same as for deoxypyridoxol, namely, uncertain. 



