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Heme metabolism is central to malaria parasite biology. The parasite acquires heme from host hemoglobin in the intraerythrocytic stages and stores it as hemozoin to prevent free heme toxicity. The parasite can also synthesize heme  de novo , and all the enzymes in the pathway are characterized. To study the role of the dual heme sources in malaria parasite growth and development, we knocked out the first enzyme, δ-aminolevulinate synthase (ALAS), and the last enzyme, ferrochelatase (FC), in the heme-biosynthetic pathway of  Plasmodium berghei  ( Pb ). The wild-type and knockout (KO) parasites had similar intraerythrocytic growth patterns in mice. We carried out  in vitro  radiolabeling of heme in  Pb -infected mouse reticulocytes and  Plasmodium falciparum -infected human RBCs using [4- 14 C] aminolevulinic acid (ALA). We found that the parasites incorporated both host hemoglobin-heme and parasite-synthesized heme into hemozoin and mitochondrial cytochromes. The similar fates of the two heme sources suggest that they may serve as backup mechanisms to provide heme in the intraerythrocytic stages. Nevertheless, the  de novo  pathway is absolutely essential for parasite development in the mosquito and liver stages.  Pb KO parasites formed drastically reduced oocysts and did not form sporozoites in the salivary glands. Oocyst production in  Pb ALASKO parasites recovered when mosquitoes received an ALA supplement.  Pb ALASKO sporozoites could infect mice only when the mice received an ALA supplement. Our results indicate the potential for new therapeutic interventions targeting the heme-biosynthetic pathway in the parasite during the mosquito and liver stages.

Malaria Parasite-Synthesized Heme Is Essential in the Mosquito and Liver Stages and Complements Host Heme in the Blood Stages of Infection