The interdependence of isoprenoid synthesis and apicoplast biogenesis in malaria parasites

Okada, Megan; Sigala, Paul A.

doi:10.1371/journal.ppat.1011713

Cited by 2 publications

(1 citation statement)

References 26 publications

(55 reference statements)

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“…154 Following this article's publication, the use of this chemical rescue method as a strategy to identify inhibitors for isoprenoid biosynthesis has been reported in the literature. 151,153,[155][156][157] 2.1.2 Calcium signaling.…”

Section: Isoprenoid Biosynthesismentioning

confidence: 99%

Discovery of brussonol analogs as lead candidates for malaria

Barbosa

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I became present in my own life because of this saying, and it helped me slow down and expect less from things. I also would give thanks to my Mentor, Orishas and Guardians, knowing that "I can be one person, but I am not alone" gives me strength to move forward, even when I am feeling hopeless.Second, I would like to thank my parents, Gilda and Catuta; to my brother, Diego, he was sometimes more like a father to me; to my sister-in-law, Michele; and to my nephews, Gustavo, and Vitor. Even though you do not understand what I do, and its purpose, you were always by my side, celebrating each accomplishment and having my back when things were not good. I cannot forget to thank my cat Naruto. It is going to be seven years since I have made the best decision and adopted my baby. He is always guarding, supporting, and caring for me.It is good to know that, no matter where I go, I will have him with me.Next, I would like to thank my supervisor, Rafael Guido, for the opportunity to be part of his group, and for the guidance throughout my doctorate. I also would like to thank Carol Aguiar, my co-supervisor. I came to IFSC through Carol's indication, and she taught me how to be in love with Plasmodium parasites. Thank you for the tips, emotional support, for sharing your knowledge, everything I learned is already paving a great future ahead of me. Additionally, I had an opportunity to have Adele Lehane as my supervisor for six months at the Australian National University. I would like to thank her for all her guidance, for believing in me, even when I was doubting myself. Thank you, Adele, for sharing the hood and the bench with me. It was an amazing opportunity that had a huge impact on myself, not only as a PhD student and researcher, but also as a person. I miss our morning talks. During this time, I also had the privilege to spend time in Giel van Dooren's lab. There, I saw Toxoplasma moving and learned many interesting facts about this intriguing parasite. Being around the Transporter Group opened a new area that I was not aware before, and it showed that there are many opportunities and things to learn from Apicomplexan parasites.Finally, I would like to thank my friends, and lab colleagues. I am here today because, throughout all this time, I had my chosen family with me, and I am so grateful that it is getting bigger. Every place I went I had an opportunity to meet amazing and interesting people, that hold me close when I needed, and my family was away. I will start with Gustavo Viana and Fernando Varotti. I was supervised by both researchers, and I learned a lot from them. I am fortunate to still maintain contact, even though it is not as frequent as usual. From my graduation and Master's time, I would like to thank Alessandra Gonçalves Neves, she was my first supervisor. I cannot forget Silmara, Felipe, Andressa, Simone, Matheus (China), Amanda, Karina, and Karen. I learned with each one of you, and I would like to thank you all for being part of my life. I feel grateful to realize that it does not matter how lon...

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Section: Isoprenoid Biosynthesismentioning

confidence: 99%

Discovery of brussonol analogs as lead candidates for malaria

Barbosa

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Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites

Loveridge,

Sigala

2024

Preprint

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Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. falciparum requires nutritional iron to support essential metabolic pathways, but the critical mechanisms of iron acquisition and trafficking during RBC infection have remained obscure. Parasites internalize and liberate massive amounts of heme during large-scale digestion of RBC hemoglobin within an acidic food vacuole (FV) but lack a heme oxygenase to release porphyrin-bound iron. Although most FV heme is sequestered into inert hemozoin crystals, prior studies indicate that trace heme escapes biomineralization and is susceptible to non-enzymatic degradation within the oxidizing FV environment to release labile iron. Parasites retain a homolog of divalent metal transporter 1 (DMT1), a known mammalian iron transporter. This protein localizes to the FV membrane, but its role in P. falciparum iron acquisition has not been tested. Our phylogenetic and microscopy studies indicate that P. falciparum DMT1 (PfDMT1) retains conserved molecular features critical for metal transport and is oriented on the FV membrane in an export-competent topology. Conditional knockdown of PfDMT1 expression is lethal to parasites, which display broad cellular defects in iron-dependent functions, including impaired apicoplast biogenesis and mitochondrial polarization. Parasites are selectively rescued from partial PfDMT1 knockdown by supplementation with exogenous iron, but not other metals. These results support a cellular paradigm whereby PfDMT1 is the molecular gatekeeper to essential iron acquisition by blood-stage malaria parasites and suggest that therapeutic targeting of PfDMT1 may be a potent antimalarial strategy.

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The interdependence of isoprenoid synthesis and apicoplast biogenesis in malaria parasites

Cited by 2 publications

References 26 publications

Discovery of brussonol analogs as lead candidates for malaria

Discovery of brussonol analogs as lead candidates for malaria

Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites

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