Lipoic acid biosynthesis is essential for Plasmodium falciparum transmission and influences redox response and carbon metabolism of parasite asexual blood stages

Malaria is still one of the most important global infectious diseases. Emergence of drug resistance and a shortage of new efficient anti-malarials continue to hamper a malaria eradication agenda. Malaria parasites are highly sensitive to changes in redox environment. Understanding the mechanisms reg...

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Published inbioRxiv
Main Authors Biddau, Marco, Santha Tr Kumar, Henrich, Philipp, Laine, Larissa M, Blackburn, Gavin J, Chokkathukalam, Achuthanunni, Li, Tao B, Kim Lee Sim, Hoffman, Stephen L, Barrett, Michael P, Coombs, Graham H, Mcfadden, Geoffrey I, Fidock, David A, Muller, Sylke, Sheiner, Lilach
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 17.05.2020
Subjects
Acids
Antioxidants
Biosynthesis
Cytosol
Drug development
Drug resistance
Glutathione
Glycolysis
Infectious diseases
Lipoic acid
Malaria
Metabolism
Parasites
Plasmodium falciparum
Thioredoxin
Tricarboxylic acid cycle
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Summary:Malaria is still one of the most important global infectious diseases. Emergence of drug resistance and a shortage of new efficient anti-malarials continue to hamper a malaria eradication agenda. Malaria parasites are highly sensitive to changes in redox environment. Understanding the mechanisms regulating parasite redox could contribute to the design of new drugs. Malaria parasites have a complex network of redox regulatory systems housed in their cytosol, in their mitochondrion and in their plastid (apicoplast). While the role of enzymes of the thioredoxin and glutathione pathways in parasite survival have been explored, the antioxidant role of alpha-lipoic acid (LA) produced in the apicoplast has not been tested. We analysed the effects of LA depletion on mutant Plasmodium falciparum lacking the apicoplast lipoic acid protein ligase B (lipB). Our results showed a change in expression of redox regulators in the apicoplast and the cytosol. We further detected a change in parasite central carbon metabolism, with LA depletion influencing glycolysis and tricarboxylic acid cycle activity. Importantly, abrogation of LipB impacted P. falciparum mosquito development, preventing oocyst maturation and production of infectious sporozoite stages, thus flagging LA biosynthesis as a potential target for the development of new transmission drugs. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.05.17.099630