Principal enzymes and substrates of the folate pathway involved in formation of tetrahydrofolate (THF) and its utilisation in the thymidylate cycle. Other enzymes involved in the interconversion of tetrahydrofolate forms modified at the N5 and N10 positions of the pteroate moiety are not shown. Salvaged pre-formed folate feeds into the pathway, commonly in the form of folic acid or folinic acid (from culture medium) or 5-MeTHF (from host plasma), and modified appropriately. pABA can also be salvaged from the above sources or synthesised de novo from the shikimate pathway. Note (1), the triphosphate group is removed before the DHNA step, thought to be by non-enzymatic loss of pyrophosphate and subsequent removal of the final phosphate by a non-specific phosphatase activity. Note (2), polyglutamated forms are the preferred substrates for folate pathway enzymes and the predominant forms within the cell. It is not known whether newly synthesised folate in P. falciparum is polyglutamated at the DHF or THF stage (or both). For simplicity, it is shown here as occurring at the THF stage (large brackets), but omitted from substrate names in the thymidylate cycle. Activities targeted by the components of Fansidar, pyrimethamine (PYR) and sulfadoxine (SDX), are indicated. GTPC, GTP cyclohydrolase I (EC 3.5.4.16); DHNA, dihydroneopterin aldolase (EC 4.1.2.25); PPPK, hydroxymethyldihydropterin pyrophosphokinase (EC 2.7.6.3); DHPS, dihydropteroate synthase (EC 2.5.1.15); DHFS, dihydrofolate synthase (EC 6.3.2.12); DHFR, dihydrofolate reductase (EC 1.5.1.3); FPGS, folylpolyglutamate synthase (EC 6.3.2.17); SHMT, serine hydroxymethyltransferase (EC 2.1.2.1); TS, thymidylate synthase (EC 2.1.1.45).
