p-Aminobenzoic acid transport by normal and Plasmodium falciparum-infected erythrocytes.
De novo folate biosynthesis is required for the growth of malarial parasites and is inhibited by several important antimalarial agents. We show here that exogenous p-aminobenzoic acid (pABA) can be utilized by malaria parasites to synthesize folates. The transport of pABA into parasite infected red cells was therefore characterized. Normal red cells transport pABA in a saturable and energy-dependent manner, with a dissociation constant of 83 nM. pABA transport in parasite-infected red cells may use the same mechanism, as demonstrated by similarities in time course, concentration-response, and dissociation constant (111 nM). The transport capacity of red cells is temperature-, energy- and pH-dependent. It is inhibited by the proton ionophore, carbonylcyanide m-chlorophenylhydrazone (CCCP), but not by the sodium ionophores nigericin and monensin. p-Aminosalicylic acid (PAS) inhibits pABA transport competitively, with a inhibition constant of 378 nM. Phloritin, flufanamic acid, and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DITS), which are inhibitors of the anion transporter (band 3), and oxalic acid, a substrate of this transporter, partially inhibit pABA transport into both normal and infected red cells. Interestingly, in both normal and infected red cells, the inhibitory effects of PAS and the anion transport inhibitors are additive, suggesting the involvement of 2 independent mechanisms.
Zhang
Y
Y
Department of Microbiology, City University of New York Medical School, City College, NY.
Merali
S
S
Meshnick
S R
SR
D010129:4-Aminobenzoic Acid / Q000097:blood / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000097:blood; D010131:Aminosalicylic Acid / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology*; D005492:Folic Acid / Q000096:biosynthesis*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007460:Iodoacetamide / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007700:Kinetics; D010963:Plasmodium falciparum / Q000378:metabolism*; D013696:Temperature
D007476:Ionophores; D010131:Aminosalicylic Acid; D000255:Adenosine Triphosphate; D005492:Folic Acid; D010129:4-Aminobenzoic Acid; D007460:Iodoacetamide