310 



2. ANALOGS OF ENZYME REACTION COMPONENTS 



hibitor which enters into" the catalytic sequence of reactions but is not 

 able to complete the process readily. This mechanism is also suggested by 

 the results of Lovenberg et al. (1963) on kidney aromatic amino acid de- 

 carboxylase, using tryptophan as the substrate. When a-methyldopa is 

 preincubated with the enzyme in the absence of pyridoxal-P the inhibition 

 is noncompetitive and potent, but when pyridoxal-P is added during the 

 preincubation period the inhibition is competitive with respect to substrate 



0.001 



■ METHYL - OOPA 



Fig. 2-3. Inhibition of mouse brain 5-hydroxytryptophan 

 decarboxylase by a-methyldopa. The sohd curves show 

 the rate of formation of serotonin in //g/g/hr, and the 

 dashed curves show the fractional inhibition. The curves 

 X-X-X-X show the results without addition of pyridoxal-P, 

 and the curves 0-0-0-0 show the results after addition 

 of 0.008 mM pyridoxal-P. (From S. E. Smith, 1960 a.) 



and is less potent. If no preincubation is done and a-methyl dopa is added 

 with the substrate, competitive inhibition is observed. The data suggest 

 that a-methyldopa interacts specifically with the enzyme-pyridoxal-P com- 

 plex (the enzyme as isolated contains tightly bound pyridoxal-P), and the 

 protection or reversal of the inhibition by exogenous pyridoxal-P may be 

 due to the reactivation of the enzyme-bound coenzyme. The reaction of 

 the a-methyldopa with pyridoxal-P may involve the cyclization of a 

 Schiff base (Mackay and Shepherd, 1962). 



Another comprehensive study of dopa decarboxylase was made by Hart- 

 man et al. (1955), who determined the inhibitory activities of some 200 

 compounds. The results, some of which are presented in Table 2-11, enable 



