Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites
Copyright policy )Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites
Most eukaryotic cells retain a mitochondrial fatty acid synthesis (FASII) pathway whose acyl carrier protein (mACP) and 4-phosphopantetheine (Ppant) prosthetic group provide a soluble scaffold for acyl chain synthesis and biochemically couple FASII activity to mitochondrial electron transport chain (ETC) assembly and Fe-S cluster biogenesis. In contrast, the mitochondrion of Plasmodium falciparum malaria parasites lacks FASII enzymes yet curiously retains a divergent mACP lacking a Ppant group. We report that ligand-dependent knockdown of mACP is lethal to parasites, indicating an essential FASII-independent function. Decyl-ubiquinone rescues parasites temporarily from death, suggesting a dominant dysfunction of the mitochondrial ETC. Biochemical studies reveal that Plasmodium mACP binds and stabilizes the Isd11-Nfs1 complex required for Fe-S cluster biosynthesis, despite lacking the Ppant group required for this association in other eukaryotes, and knockdown of parasite mACP causes loss of Nfs1 and the Rieske Fe-S protein in ETC complex III. This work reveals that Plasmodium parasites have evolved to decouple mitochondrial Fe-S cluster biogenesis from FASII activity, and this adaptation is a shared metabolic feature of other apicomplexan pathogens, including Toxoplasma and Babesia. This discovery unveils an evolutionary driving force to retain interaction of mitochondrial Fe-S cluster biogenesis with ACP independent of its eponymous function in FASII.
- University of Utah United States
- University of Mary United States
- University of California, Los Angeles United States
- University of Washington, Department of Biochemistry United States
- University of Melbourne Australia
Fe-S cluster synthesis, Iron (mesh), Malaria (rcdc), acyl carrier protein, Protozoan Proteins, 2.2 Factors relating to the physical environment (hrcs-rac), falciparum, 31 Biological sciences (for-2020), 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Biology (General), 32 Biomedical and Clinical Sciences (for-2020), 3 Good Health and Well Being (sdg), Organelle Biogenesis, Q, Fatty Acids, R, P, Organelle Biogenesis (mesh), Biological Sciences, mitochondria, Infection (hrcs-hc), Infectious Diseases, Medical Microbiology, Fatty Acids (mesh), Plasmodium falciparum (mesh), Medicine, Protozoan Proteins (mesh), Infection, Acyl Carrier Protein (mesh), 570, QH301-705.5, infectious disease, Science, Iron, Clinical Sciences, Plasmodium falciparum, 0601 Biochemistry and Cell Biology (for), malaria, 610, chemical biology, P. falciparum, Rare Diseases (rcdc), Rare Diseases, 42 Health sciences (for-2020), Biochemistry and Chemical Biology, Acyl Carrier Protein, biochemistry, 3207 Medical Microbiology (for-2020), Sulfur (mesh), 3202 Clinical Sciences (for-2020), 31 Biological Sciences (for-2020), Biomedical and Clinical Sciences, microbiology, Health sciences, Vector-Borne Diseases (rcdc), 2.1 Biological and endogenous factors (hrcs-rac), Malaria, 3101 Biochemistry and Cell Biology (for-2020), Vector-Borne Diseases, Good Health and Well Being, 32 Biomedical and clinical sciences (for-2020), Infectious Diseases (rcdc), organelle adaptation, Biochemistry and Cell Biology, Sulfur
Fe-S cluster synthesis, Iron (mesh), Malaria (rcdc), acyl carrier protein, Protozoan Proteins, 2.2 Factors relating to the physical environment (hrcs-rac), falciparum, 31 Biological sciences (for-2020), 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Biology (General), 32 Biomedical and Clinical Sciences (for-2020), 3 Good Health and Well Being (sdg), Organelle Biogenesis, Q, Fatty Acids, R, P, Organelle Biogenesis (mesh), Biological Sciences, mitochondria, Infection (hrcs-hc), Infectious Diseases, Medical Microbiology, Fatty Acids (mesh), Plasmodium falciparum (mesh), Medicine, Protozoan Proteins (mesh), Infection, Acyl Carrier Protein (mesh), 570, QH301-705.5, infectious disease, Science, Iron, Clinical Sciences, Plasmodium falciparum, 0601 Biochemistry and Cell Biology (for), malaria, 610, chemical biology, P. falciparum, Rare Diseases (rcdc), Rare Diseases, 42 Health sciences (for-2020), Biochemistry and Chemical Biology, Acyl Carrier Protein, biochemistry, 3207 Medical Microbiology (for-2020), Sulfur (mesh), 3202 Clinical Sciences (for-2020), 31 Biological Sciences (for-2020), Biomedical and Clinical Sciences, microbiology, Health sciences, Vector-Borne Diseases (rcdc), 2.1 Biological and endogenous factors (hrcs-rac), Malaria, 3101 Biochemistry and Cell Biology (for-2020), Vector-Borne Diseases, Good Health and Well Being, 32 Biomedical and clinical sciences (for-2020), Infectious Diseases (rcdc), organelle adaptation, Biochemistry and Cell Biology, Sulfur
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