Transfection studies to explore essential folate metabolism and antifolate drug synergy in the human malaria parasite Plasmodium falciparum

• Published in: Molecular microbiology 2004-03, Vol.51 (5), p.1425-1438
• Main Authors: Wang, Ping, Wang, Qi, Aspinall, Tanya V., Sims, Paul F. G., Hyde, John E.
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials - metabolism; Antimalarials - pharmacology; Biological and medical sciences; Dihydropteroate Synthase - metabolism; Drug Resistance; Drug Synergism; Erythrocytes - parasitology; Folic Acid - chemistry; Folic Acid - metabolism; Folic Acid Antagonists - metabolism; Folic Acid Antagonists - pharmacology; Fundamental and applied biological sciences. Psychology; Human protozoal diseases; Humans; Infectious diseases; Malaria; Medical sciences; Microbiology; Parasitic diseases; Plasmids; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Plasmodium falciparum - metabolism; Protozoal diseases; Pyrimethamine - metabolism; Sulfadoxine - metabolism; Transfection
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/j.1365-2958.2003.03915.x

Summary Folate metabolism in Plasmodium falciparum is the target of important antimalarial agents. The biosynthetic pathway converts GTP to polyglutamated derivatives of tetrahydrofolate (THF), essential cofactors for DNA synthesis. Tetrahydrofolate can also be acquired by salvage mechanisms. Using a transfection system adapted to studying this pathway, we investigated modulation of dihydropteroate synthase (DHPS) activity on parasite phenotypes. Dihydropteroate synthase incorporates p‐aminobenzoate (pABA) into dihydropteroate, the precursor of dihydrofolate. We were unable to obtain viable parasites where the dhps gene had been truncated. However, parasites where the protein was full‐length but mutated at two key residues and having