586 2. ANALOGS OF ENZYME REACTION COMPONENTS 



Effects on Certain Enzymes Unrelated to Q Transfer 



Brief mention should be made of the early demonstrations that 7-methyI- 

 folate is inhibitory to dopa decarboxylase and that this is reversible with 

 folate at 10-100 times the analog concentration (Martin and Beiler, 1947). 

 Pteroylaspartate and 7-methylpteroate are less potent inhibitors, but the 

 difference is not great, so that the glutamate portion is not very important 

 for the binding (Martin and Beiler, 1948). Tyrosine decarboxylase is not 

 inhibited by 0.67 mM 7-methylfolate whereas 0.067 mM inhibits dopa de- 

 carboxylase 25%. The mechanism of this inhibition, the role of folate in 

 decarboxylase activity, and the effects of the more commonly used folate 

 analogs are all unknown. The decarboxylase inhibition prompted a study 

 of the effects of 7-methylfolate on blood pressure (Martin et al., 1947), and 

 it was found that 5 mg/kg in the dog depresses the blood pressure quite 

 significantly and for an extended period of time, but whether this is related 

 to decarboxylase inhibition is problematical. 



The inhibition of acetyl transfer by amethopterin (K, = 0.032 mM) in 

 pigeon liver extracts is interesting because it represents another possible 

 site of action for this analog, even though it is obviously much less potent 

 here than on folate reduction (Jacobson, 1960). The inhibition is not coun- 

 teracted by folate, tetrahydrofolate, or folinate, and is competitive with 

 the acetyl donor (p-nitroacetanilide) but noncompetitive with the acetyl 

 acceptor (aniline or sulfanilamide). These results do not implicate a folate 

 compound in the acetylation reaction — indeed, folate and folinate are 

 weak inhibitors, and the mechanism is more likely a simple binding to the 

 substrate site. The 10-methyl group is important since aminopterin is only 

 one-tenth, or less, as inhibitory as amethopterin. Evidence for inhibition 

 of acetylation in vivo is the higher sulfanilamide level and the lower acetyl- 

 sulfanilamide level in rabbit plasma of animals treated with amethopterin 

 (Johnson et al., 1958). 



ANALOGS OF OTHER VITAMINS, COENZYMES, 

 AND THEIR COMPONENTS 



There has been a great deal of work on the growth inhibitions produced 

 by numerous analogs of pantothenate, biotin, cobalamin, and other meta- 

 bolically necessary cofactors, but relatively few reports on enzyme inhibi- 

 tions are available. However, some of this isolated work on enzyme systems 

 is interesting in itself and perhaps some reference to it will stimulate further 

 study. 



Pantothenate is required by many microorganisms and animals because 

 it is a component of coenzyme A, the biosynthetic pathway being: 



Pantothenate -> pantothenylcysteine ->• pantetheine ->• CoA 



