scholarly journals Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Seyi Falekun ◽  
Jaime Sepulveda ◽  
Yasaman Jami-Alahmadi ◽  
Hahnbeom Park ◽  
James A Wohlschlegel ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Acyl Carrier Protein ◽  
Acyl Chain ◽  
Acid Synthesis ◽  
Complex Iii ◽  
Carrier Protein ◽  
Prosthetic Group ◽  
Malaria Parasites ◽  
Mitochondrial Fatty Acid

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.

scholarly journals The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Jonathan G Van Vranken ◽  
Mi-Young Jeong ◽  
Peng Wei ◽  
Yu-Chan Chen ◽  
Steven P Gygi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Acyl Carrier Protein ◽  
Acyl Chain ◽  
Acid Synthesis ◽  
Carrier Protein ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Fatty Acid

Mitochondrial fatty acid synthesis (FASII) and iron sulfur cluster (FeS) biogenesis are both vital biosynthetic processes within mitochondria. In this study, we demonstrate that the mitochondrial acyl carrier protein (ACP), which has a well-known role in FASII, plays an unexpected and evolutionarily conserved role in FeS biogenesis. ACP is a stable and essential subunit of the eukaryotic FeS biogenesis complex. In the absence of ACP, the complex is destabilized resulting in a profound depletion of FeS throughout the cell. This role of ACP depends upon its covalently bound 4’-phosphopantetheine (4-PP)-conjugated acyl chain to support maximal cysteine desulfurase activity. Thus, it is likely that ACP is not simply an obligate subunit but also exploits the 4-PP-conjugated acyl chain to coordinate mitochondrial fatty acid and FeS biogenesis.

scholarly journals Divergent Acyl Carrier Protein Mediates Mitochondrial Fe-S Cluster Biosynthesis in Malaria Parasites

2021 ◽  
Author(s):  
Seyi Falekun ◽  
Jaime Sepulveda ◽  
Yasaman Jami-Alahmadi ◽  
Hahnbeom Park ◽  
James Wohlschlegel ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Drug Targets ◽  
Fatty Acid Biosynthesis ◽  
Acyl Carrier Protein ◽  
Acid Synthesis ◽  
Complex Iii ◽  
Carrier Protein ◽  
Malaria Parasites ◽  
Cluster Biosynthesis

Plasmodium falciparum malaria parasites are early-diverging eukaryotes with many unusual metabolic adaptations. Understanding these adaptations will give insight into parasite evolution and unveil new parasite-specific drug targets. In contrast to human cells, the Plasmodium mitochondrion lacks type II fatty acid biosynthesis (FASII) enzymes yet curiously retains a divergent acyl carrier protein (mACP) incapable of modification by a 4-phosphopantetheine (Ppant) group required for canonical ACP function as the scaffold for fatty acid synthesis. We report that ligand-dependent knockdown of mACP expression is lethal to parasites, indicating an essential FASII-independent function. Decyl-ubiquinone rescues parasites temporarily from this lethal phenotype, suggesting a dominant dysfunction of the mitochondrial electron transport chain (ETC) followed by broader defects beyond the ETC. Biochemical studies reveal that Plasmodium mACP binds and stabilizes the Isd11-Nfs1 cysteine desulfurase complex required for Fe-S cluster biosynthesis, and mACP knockdown causes loss of both Nfs1 and the Rieske Fe-S cluster protein in ETC Complex III. This work identifies Ppant-independent mACP as an essential mitochondrial adaptation in Plasmodium malaria parasites that appears to be a shared metabolic feature of Apicomplexan pathogens, including Toxoplasma and Babesia. This parasite-specific adaptation highlights the ancient, fundamental role of ACP in mitochondrial Fe-S cluster biogenesis and reveals an evolutionary driving force to retain this interaction with ACP independent of its eponymous function in fatty acid synthesis.

scholarly journals Structure of the mitochondrial β-ketoacyl-[acyl carrier protein] synthase fromArabidopsisand its role in fatty acid synthesis

FEBS Letters ◽  
2004 ◽  
Vol 577 (1-2) ◽  
pp. 170-174 ◽  
Author(s):  
Johan G. Olsen ◽  
Anne V. Rasmussen ◽  
Penny von Wettstein-Knowles ◽  
Anette Henriksen
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Acyl Carrier Protein ◽  
Acid Synthesis ◽  
Carrier Protein

scholarly journals NovelXanthomonas campestrisLong-Chain-Specific 3-Oxoacyl-Acyl Carrier Protein Reductase Involved in Diffusible Signal Factor Synthesis

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Zhe Hu ◽  
Huijuan Dong ◽  
Jin-Cheng Ma ◽  
Yonghong Yu ◽  
Kai-Hui Li ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Xanthomonas Campestris ◽  
Octanoic Acid ◽  
Acyl Carrier Protein ◽  
Acid Synthesis ◽  
Carrier Protein ◽  
Content Type ◽  
Diffusible Signal Factor ◽  
Acyl Chains

ABSTRACTThe precursors of the diffusible signal factor (DSF) family signals ofXanthomonas campestrispv.campestrisare 3-hydroxyacyl-acyl carrier protein (3-hydroxyacyl-ACP) thioesters having acyl chains of 12 to 13 carbon atoms produced by the fatty acid biosynthetic pathway. We report a novel 3-oxoacyl-ACP reductase encoded by theX. campestrispv.campestrisXCC0416 gene (fabG2), which is unable to participate in the initial steps of fatty acyl synthesis. This was shown by the failure of FabG2 expression to allow growth at the nonpermissive temperature of anEscherichia colifabGtemperature-sensitive strain. However, when transformed into theE. colistrain together with a plasmid bearing theVibrio harveyiacyl-ACP synthetase gene (aasS), growth proceeded, but only when the medium contained octanoic acid.In vitroassays showed that FabG2 catalyzes the reduction of long-chain (≥C8) 3-oxoacyl-ACPs to 3-hydroxyacyl-ACPs but is only weakly active with shorter-chain (C4, C6) substrates. FabG1, the housekeeping 3-oxoacyl-ACP reductase encoded within the fatty acid synthesis gene cluster, could be deleted in a strain that overexpressedfabG2but only in octanoic acid-supplemented media. Growth of theX. campestrispv.campestrisΔfabG1strain overexpressingfabG2requiredfabHfor growth with octanoic acid, indicating that octanoyl coenzyme A is elongated byX. campestrispv.campestrisfabH. Deletion offabG2reduced DSF family signal production, whereas overproduction of either FabG1 or FabG2 in the ΔfabG2strain restored DSF family signal levels.IMPORTANCEQuorum sensing mediated by DSF signaling molecules regulates pathogenesis in several different phytopathogenic bacteria, includingXanthomonas campestrispv.campestris. DSF signaling also plays a key role in infection by the human pathogenBurkholderia cepacia. The acyl chains of the DSF molecules are diverted and remodeled from a key intermediate of the fatty acid synthesis pathway. We report aXanthomonas campestrispv.campestrisfatty acid synthesis enzyme, FabG2, of novel specificity that seems tailored to provide DSF signaling molecule precursors.

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