TY - JOUR TI - Deconvoluting heme biosynthesis to target blood-stage malaria parasites AU - Sigala, Paul A AU - Crowley, Jan R AU - Henderson, Jeffrey P AU - Goldberg, Daniel E A2 - Clardy, Jon VL - 4 PY - 2015 DA - 2015/07/14 SP - e09143 C1 - eLife 2015;4:e09143 DO - 10.7554/eLife.09143 UR - https://doi.org/10.7554/eLife.09143 AB - Heme metabolism is central to blood-stage infection by the malaria parasite Plasmodium falciparum. Parasites retain a heme biosynthesis pathway but do not require its activity during infection of heme-rich erythrocytes, where they can scavenge host heme to meet metabolic needs. Nevertheless, heme biosynthesis in parasite-infected erythrocytes can be potently stimulated by exogenous 5-aminolevulinic acid (ALA), resulting in accumulation of the phototoxic intermediate protoporphyrin IX (PPIX). Here we use photodynamic imaging, mass spectrometry, parasite gene disruption, and chemical probes to reveal that vestigial host enzymes in the cytoplasm of Plasmodium-infected erythrocytes contribute to ALA-stimulated heme biosynthesis and that ALA uptake depends on parasite-established permeability pathways. We show that PPIX accumulation in infected erythrocytes can be harnessed for antimalarial chemotherapy using luminol-based chemiluminescence and combinatorial stimulation by low-dose artemisinin to photoactivate PPIX to produce cytotoxic reactive oxygen. This photodynamic strategy has the advantage of exploiting host enzymes refractory to resistance-conferring mutations. KW - P. falciparum KW - heme biosynthesis KW - malaria KW - metabolism KW - photodynamic therapy JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -