De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum

Mol Biochem Parasitol. 1989 Jan 1;32(1):25-37. doi: 10.1016/0166-6851(89)90126-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid
  • Erythrocytes / microbiology
  • Folic Acid / analogs & derivatives*
  • Folic Acid / biosynthesis
  • Humans
  • Plasmodium falciparum / metabolism*
  • Pterins / biosynthesis
  • Pteroylpolyglutamic Acids / biosynthesis*
  • Pyrimethamine / pharmacology
  • Sulfadoxine / pharmacology

Substances

  • Pterins
  • Pteroylpolyglutamic Acids
  • pteroylpentaglutamic acid
  • 5-methyltetrahydropteroylpentaglutamate
  • Sulfadoxine
  • Folic Acid
  • Pyrimethamine