TYROSINE METABOLISM 



313 



Table 2-11 (continued) 



HO 



COO" 



CH=CH-CO 



OH 



° Concentration of dopa 2 mM and pH 6.8. (Data from Hartman et al., 1955. ) 



one to speculate further about the nature of the binding to the active 

 center. Several inhibitors more potent than a-methyldopa were found. 

 The basic structure for inhibition was written as: 



HO 



(HO) 



O 



I I II 



c=c-c— X 



where X is OH, 0-alkyl, alkyl, or aryl. It is rather surprising that the 

 negatively charged carboxylate group is not necessary, esters and amides 

 being as potent as the acids, and it may be that the CO group is critical. 

 The positively charged amino group is also not necessary, since 3,4-dihy- 

 droxyhydrocinnamate is a good inhibitor, and this would make it likely 

 that the binding of the inhibitors is not too much dependent on pyridoxal 

 phosphate. The importance of the 3- and 4-hydroxyls is again evident and 

 all the potent inhibitors have phenolic groups; apparently only the sulf- 

 hydryl group can replace the hydroxyl. Halogens have the ability to aug- 

 ment binding when they are the only substituents but particularly when 

 a hydroxyl group is also present; 3,5-dibromobenzoate and 2,4-dichloro- 

 cinnamate are bound reasonably well (at least 2 kcal/mole more than the 

 unsubstituted compounds). The only unsubstituted inhibitor is phenyl- 

 pyruvate, which must be significant, although of what is not clear. The 

 interaction of the side chain must be complex and involve different types 

 of forces. If one compares all the 3,4-dihydroxy derivatives, it is seen that 



