De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum.
Plasmodium falciparum was shown to synthesize pteroylpolyglutamate de novo from guanosine 5'-triphosphate (GTP), p-aminobenzoate (PABA), and L-glutamate (L-Glu). The parasite also had the capacity to synthesize pteroylpolyglutamate from both intact and degradation moieties (p-aminobenzoylglutamate and pterin-aldehyde) of exogenous folate added into the growth medium. The major product was identified as 5-methyl-tetrahydroteroylpentaglutamate following exposure to pteroylpolyglutamate hydrolase and oxidative degradation of the C9-N10 bond in the molecule and identification of products by reversed-phase high performance liquid chromatography. Inhibition of pteroylpentaglutamate synthesis from the radiolabelled metabolic precursors (GTP, PABA, L-Glu) and folate by the antifolate antimalarials, pyrimethamine and sulfadoxine at therapeutic concentrations, may suggest the existence of a unique biosynthetic pathway in the malaria parasite.
Krungkrai
J
J
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand.
Webster
H K
HK
Yuthavong
Y
Y
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000382:microbiology; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000096:biosynthesis; D006801:Humans; D010963:Plasmodium falciparum / Q000378:metabolism*; D011622:Pterins / Q000096:biosynthesis; D011624:Pteroylpolyglutamic Acids / Q000096:biosynthesis*; D011739:Pyrimethamine / Q000494:pharmacology; D013413:Sulfadoxine / Q000494:pharmacology
D011622:Pterins; D011624:Pteroylpolyglutamic Acids; C036907:pteroylpentaglutamic acid; C044774:5-methyltetrahydropteroylpentaglutamate; D013413:Sulfadoxine; D005492:Folic Acid; D011739:Pyrimethamine