Perturbations in fumarate levels in Plasmodium berghei leads to cysteine succination and impairs ookinete formation

Authors

Chandrashekarmath, A., Suryavanshi, A., Roy, C. S., Balaram, H.

Abstract

The TCA cycle intermediates comprise 8 carboxylic acids of which only fumarate has unsaturated carbons rendering it capable of electrophilic addition to cysteine thiols. Accumulation of fumarate due to loss of function of fumarate hydratase converts it into a powerful driver of cancer and therefore is classified as an oncometabolite. We have examined the consequences of perturbing the metabolism of fumarate and its product, malate, on Plasmodium berghei development across erythrocytic and early insect stages. Our studies on P. berghei lines lacking the genes fh and mqo, coding for the enzymes fumarate hydratase (FH) and malate quinone oxidoreductase (MQO), respectively as well as dtc and ogc coding for the transporters dicarboxylate-tricarboxylate carrier (DTC) and citrate-oxoglutarate carrier (OGC), show dramatic impairment in ookinete formation, while gametocytes and erythrocytic asexual stages remain largely unaffected. Comparative metabolomic analysis of gametocytes revealed that elevated fumarate levels in the knockouts led to succination of glutathione, possibly resulting in oxidative stress. The increased levels of the M+5 isotopologue of inosine monophosphate in the knockout gametocytes, observed in isotope tracer experiments, suggest enhanced ribose-5-phosphate and NADPH production through the pentose phosphate pathway, with the latter potentially mitigating elevated oxidative stress. The isotope tracer studies also informed that the P. berghei DTC is a transporter of malate and fumarate and OGC, a transporter of fumarate. The impaired ookinete formation arising from cysteine succination underscores the potential for developing transmission-blocking agents through selective inhibition of class I parasite FH which is distinct from its class II human counterpart.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 17 Mar 2026.

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