572 2. ANALOGS OF ENZYME REACTION COMPONENTS 



with both deficiency and deoxypyridoxol is related to lowered transami- 

 nase activity and protein synthesis. Analyses of total brain do not, of 

 course, necessarily reflect local changes in amino acid metabolism, and the 

 site of origin of the convulsions has yet to be determined. It must be re- 

 membered that transaminase, glutamate decarboxylase, and y-aminobu- 

 tyrate levels vary in different regions of the central nervous system and, 

 furthermore, the functional dependence of various regions on pyridoxal- 

 P-dependent metabolism must also vary. The displacement of pyridoxal-P 

 from apoenzymes by deoxypyridoxol-P in vivo depends on several factors: 

 (1) rate of penetration of the analog into the cells, (2) ability of the tissue 

 to phosphorylate the analog, and (3) relative affinities of the apoenzyme 

 for the coenzyme and the phosphorylated analog. Thus one might for sev- 

 eral reasons expect the pattern of enzyme depression from deoxypyridoxol 

 to be different from that produced by simple dietary deficiency. 



Effects on Metabolism 



Kynurenate is a normal metabolite of tryptophan in the rat, but in pyri- 

 doxine-deficient animals one finds kynurenine and xanthurenate also. The 

 metabolic pathway involved here may be summarized as follows: 



kynurenate 



y 



Tryptophan -> formylkynurenine -> kynurenine -> 3-OH-kynurenine -> xanthurenate 



\ " 



anthranilate 



This is an interesting situation since the formation of all three of these 

 products involves pyridoxal-P enzymes, namely, kynurenine transaminase 

 for the formation of kynurenate and xanthurenate, and kynureninase for 

 the formation of anthranilate. The administration of deoxypyridoxal to 

 otherwise normal rats produces no particular effect, but if tryptophan is 

 given to deoxypyridoxol-treated animals there is an increase in the appear- 

 ance of kynurenine and xanthurenate, just as in dietary deficiency (Porter 

 et al., 1947). The rise in kynurenine would be expected because two of its 

 degradative pathways are depressed (including the normally most impor- 

 tant one), and the increase in xanthurenate excretion must be due to a 

 diversion of the metabolic flow through the remaining pathway. However, 

 it is difficult to understand why xanthurenate excretion should increase 

 relative to kynurenate, since both are presumably formed with the same 

 enzyme, unless a rise in kynurenine concentration increases relatively more 

 the rate of the xanthurenate pathway. It would be interesting to know 

 what happens to the level of 3-hydroxykynurenine during deoxypyridoxol 

 administration. 



Pyridoxine-deficient rats have higher blood urea than normal animals 

 and this has been attributed to an impaired utilization of amino acids, 



