Physiology of an essential basic and neutral amino acid transporter family from Apicomplexan parasites

SJ Fairweather, E Rajendran, K Parker, S Hapuarachchi, F Lewis, A Broer, K Kirk, GG Van Dooren and S Broer

Research School of Biology, Division of Biochemistry and Biomedical Sciences, Australian National University, Canberra, ACT, 2601, Australia

Apicomplexan parasites are obligate intracellular parasites underlying many infectious diseases, including malaria, toxoplasmosis, and cryptosporidiosis. Throughout evolution they have become increasingly dependent on scavenging essential nutrients such as amino acids from host cells, due to the loss of anabolic pathways. As a result, apicomplexan membrane transporters have taken on vital roles in parasite survival and virulence. Recently, we have characterised a new family of apicomplexan transporters. Designated as the AAAT (Apicomplexan Amino Acid Transporter) family, the two most well characterised transporters, AAAT1 and AAAT6-1, are predominately basic amino acid antiporters. AAAT1 is an almost obligatory exchanger with exclusive specificity for L-arginine. In contrast, AAAT6-1 demonstrates more L-arginine uniport and a broader specificity, exchanging various neutral amino acids and L-ornithine in addition to L-arginine. AAAT1 has a higher affinity for L-arginine but is insensitive to L-lysine, while AAAT6-1 is a lower affinity L-arginine transporter but is competitively inhibited by L-lysine with high affinity. AAAT1 and AAAT6-1 harbour a puzzling electrogenic response to the membrane potential: their L-arginine-induced current/voltage response is opposite to what would be expected from the arginine Nernst potential. In addition, arginine-induced currents have a biphasic form, becoming monophasic when transporters are trans-stimulated. We hypothesise these observations may underlie an unusual voltage-gating mechnaism not often observed for membrane transporters. As both AAAT1 and AAAT6-1 are essential for parasite survival and, in the case of AAAT1, essential for virulence of Plasmodium berghei, this novel apicomplexan transporter family present themselves as excellent candidates for pharmacological targeting.