466 5. QUINONES 



of the simple semiquinones, has seldom been used in enzyme inhibition 

 studies unfortunately, but when it has, as in the work of Kuhn and Bei- 

 nert (1947) on pyruvate decarboxylase, it has not proved to be particularly 

 inhibitory. 



Effects of Substituent Groups on Inhibitory Activity 



The changes in activity resulting from the introduction of various groups 

 into benzo- and naphthoquinones (Table 5-2) are difficult to interpret and 

 no general theory has emerged despite the rather voluminous data. The 

 interaction of the quinone with the enzyme may be modified by introduced 

 groups in a number of ways, since these groups alter many properties 

 of the quinones (see page 1-304). Some of the more obvious and important 

 properties changed by these groups are: (1) oxidation-reduction potential, 

 (2) ionization of the hydroquinone, (3) semiquinone stability, and (4) reac- 

 tivity with SH or amino groups. In addition, these groups may exert steric 

 interference with the approach of the quinone to the enzyme surface or, 

 on the other hand, contribute to the binding energy. We shall confine 

 ourselves to a few comments on structure- action relations inasmuch as 

 failure to understand the mechanism of inhibition in most cases prevents 

 a more complete analysis. 



The introduction of successive methyl groups, or related groups, into 

 p-benzoquinone almost invariably reduces the inhibitory potency, as seen 

 by examining the data in Table 5-2 for several enzymes, mostly studied by 

 Hoffmann- Ostenhof. It is not known if this is related to the decrease in 

 Eq in such a series (Table 5-1), a decreased opportunity for the addition 

 of enzyme SH groups, steric interference by the bulky groups, or some other 

 factor. Chlorine groups, in contrast to methyl groups, generally increase 

 the inhibitory activity, and even chloranil is more potent than p-benzoqui- 

 none. Since chlorine groups do not effect E^^' markedly, the different reac- 

 tivity must be due to some other factor. Although one might expect chlor- 

 anil to be unable to add SH groups, one must remember that chlorine 

 atoms are easily displaced (see page 438). There appears to be no clear 

 rule concerning the relative activity of benzo- and naphthoquinones, some 

 enzymes being more sensitive to one and some to the other. However, in 

 ten enzymes for which adequate comparison can be made, 1,2-naphthoqui- 

 none is always more inhibitory than 1,4-naphthoquinone, which may or 

 may not be related to the difference in Eq . Masking the keto or hydroxy 

 groups of naphthoquinones usually abolishes inhibition; an example is the 

 failure of menadiol diphosphate to inhibit aldehyde oxidase (Rajagopalan 

 et al, 1962). 



If inhibition by 1,4-naphthoquinones is related to a reaction with the 

 enzyme SH groups, one would predict that the introduction of most groups 

 into the 2- and 3-positions to produce 2,3-disubstituted naphthoquinones 



