350 2. ANALOGS OF ENZYME EEACTION COMPONENTS 



1.5-2.0 g/kg. Leucocytic activity and phagocytosis are not affected by 18 

 raM kojic acid. A biochemical study was undertaken by Klein and Olsen 

 (1947), who found that the respiration of muscle and heart mince is resistant 

 to kojic acid, whereas 10 mM suppresses the respiration of liver 40%, 

 kidney 20%, and brain 15%. The convulsant dose corresponds to a tissue 

 concentration around 4-50 mM. The oxidation of both l- and D-amino 

 acids in liver homogenates is quite strongly inhibited in a competitive 

 fashion: for example, 50% inhibition is given by 0.04 niM for L-methionine 

 and by 0.12 mM for l- and D-phenylalanine. Xanthine oxidation is also 

 inhibited (50% at 0.7 mM). It was suggested that kojic acid may be an 

 inhibitor of flavin enzymes, and it is possible that some direct complexing 

 with FAD may occur. Nevertheless, FAD does not influence the inhibition 

 of D-amino acid oxidase. There is no inhibition of the oxidation of succinate, 

 tyramine, L-proline, choline, or urate at 5 mM kojic acid. Although the 

 metabolic effects are interesting, it is impossible to correlate any of these 

 inhibitions with either the central effects in animals or the bacteriostatic 

 activity. 



ANALOG INHIBITION OF THE METABOLISM 

 OF VARIOUS AMINO ACIDS 



Many reports indicate the influence of analogs on various enzymes con- 

 cerned with amino acid metabolism, but in most cases insufficient work 

 has been done to draw clear conclusions about the mechanism of the bind- 

 ing to the enzymes. It will suffice to present some of the results in Table 

 2-18. Probably many of these inhibitions are competitive but they have 

 been so indicated only when graphical analysis has shown this to be true. 

 A few of these inhibitions may be significant in feed-back control or in the 

 general regulation of amino acid metabolism. 



Generally speaking, there are certain types of amino acid analog that 

 have proved to be effective inhibitors. Mcllwain (1941) pointed out that 

 aminosulfonate analogs of amino acids are frequently bacteriostatic and 

 that this inhibition is reduced by adding the normal amino acids. If staphy- 

 lococci are trained to be independent of exogenous amino acids, the a- 

 aminosulfonates no longer inhibit. However, the exact sites of action 

 of these analogs have not been determined. Umbreit (1955 b) has discussed 

 the general inhibitory properties of the a-methylamino acids and pointed 

 out that the inhibitions are often competitive only for a short interval 

 if both substrate and inhibitor are present, whereas they are noncompetitive 

 if the inhibitor is added first. This is a matter of terminology; the inhibitions 

 are probably competitive but appear to be noncompetitive because of the 

 very high affinities of some analogs for the enzymes (an inhibition can be 

 competitive even though irreversible but the substrate must be given an 



