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

血红素 寄生虫寄主 利什曼原虫 营养不良 化学 微生物学 生物 生物化学 大肠杆菌 计算机科学 基因 万维网
作者
Lina M. Orrego,María Cabello‐Donayre,Paola Vargas,Marta Martínez‐García,Clara I. Sánchez,Estela Pineda‐Molina,Maribel Jiménez,Ricardo Molina,José M. Pérez‐Victoria
出处
期刊:The FASEB Journal [Wiley]
卷期号:33 (12): 13367-13385 被引量:18
标识
DOI:10.1096/fj.201901274rr
摘要

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.
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