590 2. ANALOGS OF ENZYME REACTION COMPONENTS 



tamin B^g, but the inhibition by l,2-diamino-4,5-dimethylbenzene is com- 

 petitive. The only instance of the inhibition of vitamin B^g function is in 

 the synthesis of methionine from serine in E. coli where the methylamide, 

 ethylamide, and aniHde analogs of cyanocobalamin inhibit competitively 

 with respect to vitamin B^j (Guest, 1960). These analogs also inhibit the 

 growth of organisms that require methionine or vitamin B^g, but do not 

 when methionine is supplied. The inhibitions are reasonably potent, 61% 

 depression being given by 0.029 mM of the anilide derivative when cyano- 

 cobalamin is 0.000032 mM, but the analogs are obviously bound less tightly 

 than the cyanocobalamin to the enzyme involved. Hydroxocobalamin and 

 cyanocobalamin, which are analogs of cobalamin coenzyme, inhibit potent- 

 ly and competitively the diol dehydrase from Aerobacter, but once inhibition 

 occurs it cannot be reversed by either dialysis or the coenzyme (Lee and 

 Abeles, 1963). 



Lipoate functions in acyl transfer during the oxidation of keto acids and 

 this is inhibited by 6-ethyl-8-mercaptooctanoate, an analog of 6-acetyl-6,8- 

 dimercaptooctanoate (a functional form of lipoate) (Albrecht, 1957). This 

 analog does not inhibit the anaerobic decarboxylation of pyruvate in ex- 

 tracts from E. coli but inhibits pyruvate oxidation. The phosphotransacetyl- 

 ase reaction and the formation of acetyllipoate are inhibited. 



MrSCELLANEOUS ANALOG INHIBfTiONS 



There are a number of reports of inhibitions by analogs that do not readily 

 fall into any general classification. Some of these have been put into Table 

 2-38 in order to illustrate further the various types of analog, although in 

 some cases it is not quite certain whether the inhibitor should be considered 

 as an analog or not. In most instances the inhibitions are competitive, but 

 in others it may be noncompetitive or mixed, indicating that the inhibitions 

 do not all involve a simple competition between the analog and the sub- 

 strate for an enzyme site. Unfortunately, most of these inhibitions have not 

 been adequately studied with respect to mechanism. Some more important 

 examples that could not be easily summarized in the table will be discussed 

 briefly. 



Inhibition of Morphine A/-Demethylase 



The antagonistic actions of nalorphine (A'^-allylnormorphine) to the phar- 

 macological responses to morphine have been extended to the enzyme sys- 

 tem for morphine inactivation, and it appears that the configurations of 

 the tissue receptor groups and the enzyme active site are very similar 

 (Axelrod and Cochin, 1957). Several normorphine analogs were tested on 

 the A-demethylation of morphine by rat liver enzyme (see accompanying 

 tabulation) and the role of the alkyl substituent in the binding is evident. 



