2.A.7.20.1
Chloroquine resistance transporter, PfCRT. Martin et al. (2009) have demonstrated Chloroquine transport via PfCRT. It co-transports chloroquine (CQ) or piperaquine (PPQ) and H⁺ out of the digestive vacuole (and hence away from its site of action) via a mutant form of the parasite's CRT (Lehane and Kirk, 2010).  Many mutations give rise to resistance (Tan et al. 2014; Buppan et al. 2018). The orthologue in P. vivax is 73% identical to the P. faciparum protein and has the same function (Sá et al. 2006). It is inhibited by verapamil, quinine, saquinavir and dibemethin 6a (Meier et al. 2018). TMS1 is involved in substrate selectivity and catalyzes chroroquine efflux (Antony et al. 2018). The vacuolar-half and membrane-spanning domains (especially TMS9) of PfCRT are more conserved, suggesting that its physiological substrate is expelled out of the parasite digestive vacuole. In the PfCRT occluded state, some evolutionary conserved sites, including positions related to drug resistance mutations, participate in a putative binding pocket located at the core of the PfCRT membrane-spanning domain (Coppée et al. 2020). pH-dependence of the P. falciparum chloroquine resistance transporter is linked to the transport cycle (Berger et al. 2023).  Several proteases are localized to the digestive vacuole and these proteases sequentially breakdown hemoglobin into small peptides, dipeptides, and amino acids. The peptides are exported into the host cytoplasm via the chloroquine-resistance transporter and an amino acid transporter has also been identified on the digestive vacuole membrane (Wiser 2024).