Heme synthesis through the life cycle of the heme auxotrophic parasite Leishmania major

Heme is an essential molecule synthetized through a broadly conserved 8‐step route that has been lost in trypanosomatid parasites. Interestingly, Leishmania reacquired by horizontal gene transfer from γ‐proteobacteria the genes coding for the last 3 enzymes of the pathway. Here we show that intracellular amastigotes of Leishmania major can scavenge heme precursors from the host cell to fulfill their heme requirements, demonstrating the functionality of this partial pathway. To dissect its role throughout the L. major life cycle, the significance of L. major ferrochelatase (LmFeCH), the terminal enzyme of the route, was evaluated. LmFeCH expression in a heterologous system demonstrated its activity. Knockout promastigotes lacking lmfech were not able to use the ferrochelatase substrate protoporphyrin IX as a source of heme. In vivo infection of Phlebotomus perniciosus with knockout promastigotes shows that LmFeCH is not required for their development in the sandfly. In contrast, the replication of intracellular amastigotes was hampered in vitro by the deletion of lmfech. However, LmFeCH –/– parasites produced disease in a cutaneous leishmaniasis murine model in a similar way as control parasites. Therefore, although L. major can synthesize de novo heme from macrophage precursors, this activity is dispensable being an unsuited target for leishmaniasis treatment.—Orrego, L. M., Cabello‐Donayre, M., Vargas, P., Martínez‐García, M., Sánchez, C., Pineda‐Molina, E., Jiménez, M., Molina, R., Pérez‐Victoria, J. M. Heme synthesis through the life cycle of the heme auxotrophic parasite Leishmania major. FASEB J. 33, 13367–13385 (2019). www.fasebj.org