dCTP levels are maintained in Plasmodium falciparum subjected to pyrimidine deficiency or excess.
The pyrimidine antagonists, 6-L-thiodihydroorotate (TDHO) and atovaquone, are known to induce inhibition of de-novo pyrimidine biosynthesis in Plasmodium falciparum growing in erythrocytic culture, at reactions catalysed by dihydroorotase and dihydroorotate dehydrogenase, respectively. In the present study, TDHO and atovaquone induced decreases in the levels of UTP, CTP and dTTP but not dCTP in P. falciparum. Addition of orotate with either antagonist increased UTP, CTP and dTTP but depressed GTP, ATP, dATP and dCTP, suggesting that these drugs indirectly modulate the activity of ribonucleotide reductase. The changes induced in the levels of dNTP by these pyrimidine antagonists are similar to those previously described for the antifolates, cycloguanil and WR99210.
Seymour
K K
KK
Department of Biochemistry, University of Sydney, NSW, Australia.
Yeo
A E
AE
Rieckmann
K H
KH
Christopherson
R I
RI
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone; D003845:Deoxycytosine Nucleotides / Q000378:metabolism*; D004080:Dihydroorotase / Q000037:antagonists & inhibitors; D000090722:Dihydroorotate Dehydrogenase; D009285:Naphthoquinones / Q000494:pharmacology*; D009711:Nucleotides / Q000378:metabolism; D009963:Orotic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism*
D000962:Antimalarials; D003845:Deoxycytosine Nucleotides; D000090722:Dihydroorotate Dehydrogenase; D009285:Naphthoquinones; D009711:Nucleotides; D011743:Pyrimidines; C066572:6-thiodihydroorotate; D009963:Orotic Acid; C001242:5-fluoroorotic acid; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D004080:Dihydroorotase; D053626:Atovaquone