ANALOGS OF PTEROYLGLUTAMATE (FOLATE) 



579 



ANALOGS OF PTEROYLGLUTAMATE (FOLATE) 



Tetrahydrofolate functions metabolically in the transfer of C^ units at 

 the oxidation level of formaldehyde or formate, and thus is important in 

 the biosynthesis of purines, pyrimidines (thymine), certain amino acids (ser- 

 ine, histidine, methionine), choline, and other biologically important sub- 

 stances. Interference with its function leads secondarily to a depression of 

 nucleic acid and protein synthesis and, because of this, to a general sup- 

 pression of cellular growth and multiplication. The possible sites of block 

 for folate analogs may be summarized as: (1) pathway for the synthesis 

 of folate, (2) reduction of folate to tetrahydrofolate, (3) reactions of C^ unit 

 transfer, and (4) degradative reactions of folate and its derivatives. The 

 transport of folate into cells should probably also be considered as a pos- 

 sible site of inhibition but little about this process is known at the present 



Folate (F) 



(1) 



dihydrofolate (FH,) 



(3) 



(2) 



S-formyl-FH^ 



(5) 

 (8) 5-formimino-FHj 



(9) (10) 



5, 10-methenyl-FH, 



(1) folate reductase 



(2) dihydrofolate reductase 



(3) glutamate-FH4 transformylase 



(4) serine hydroxymethylase 



(5) formimino transferase 



(6) 10-formyl-FH4 deacylase 



— tetrahydrofolate (FHJ — 



(4) 



-•^ lO-hydroxymethyl- FH^ 



(6y\(7) 



10-formyl-FH4 



(11) 



5, 10- methylene- FH4 



(7) tetrahydrofolate formylase 



(8) (cyclohydrolase) 



(9) formimino- FH4 cyclodeaminase 



(10) cyclohydrolase 



(11) (cyclohydrolase) 



(12) 5, 10-methylene-FH4 dehydrogenase 



time. A number of substances can inhibit the synthesis of folate in micro- 

 organisms — e.g., the sulfonamides and certain pteridines — but they will 

 not be treated in this chapter. There is no evidence that the important 

 actions of folate analogs are related to inhibition of degradative reactions. 

 We shall therefore limit the subject in this section to inhibitions of folate 

 reduction and transformylation reactions, namely, those pathways shown 

 in the accompanying diagram. 



