Fig. 2.

ART resistance mechanisms. In malaria parasites, hemoglobin (Hb) is endocytosed from host cell via cytostomes and transported as Hb-containing vesicles to the food vacuole (FV). Several proteins (boxed) including AP-2μ (adaptor protein-2μ), Coronin, Eps15 (epidermal growth factor receptor substrate-15 homolog), K13, UBP1 (Ubiquitin-binding protein-1), and Rab GTPases (Rabs) may participate in the endocytosis process. The symbols * and # indicate protein mutations and post-translational modification (prenylation), respectively. Hb is digested inside the FV by multiple hemoglobinases, including Falcipain 2a (FP2a), to release heme. Heme is toxic to the parasite and is converted to the inactive crystals of hemozoin (Hz). Heme is also required for ART activation. Activated ART alkylates multiple cellular targets, leading to oxidative stress response and global translation arrest eukaryotic initiation factor 2α (eIF2α) phosphorylation. Activated ART also increase reactive oxygen species (ROS) production in the parasite cytoplasm and mitochondria and cause DNA damage. In the ART-resistant parasite, mutated forms of the proteins (marked with an asterisk *) are associated with lesser Hb uptake and digestion, resulting in less heme production, lower levels of ART activation, and lower cellular stress. The resistant parasite has increased stress responses. The dashed and solid arrows indicate down-regulated and up-regulated processes, respectively, in the ART-resistant parasite. Abbreviations: M, mitochondrion; A, apicoplast; RBC, red blood cell; PV, parasitophorous vacuole. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)