The transportome of the malaria parasite - PubMed (original) (raw)

Review

. 2020 Apr;95(2):305-332.

doi: 10.1111/brv.12565. Epub 2019 Nov 7.

Affiliations

Review

The transportome of the malaria parasite

Rowena E Martin. Biol Rev Camb Philos Soc. 2020 Apr.

Abstract

Membrane transport proteins, also known as transporters, control the movement of ions, nutrients, metabolites, and waste products across the membranes of a cell and are central to its biology. Proteins of this type also serve as drug targets and are key players in the phenomenon of drug resistance. The malaria parasite has a relatively reduced transportome, with only approximately 2.5% of its genes encoding transporters. Even so, assigning functions and physiological roles to these proteins, and ascertaining their contributions to drug action and drug resistance, has been very challenging. This review presents a detailed critique and synthesis of the disruption phenotypes, protein subcellular localisations, protein functions (observed or predicted), and links to antimalarial drug resistance for each of the parasite's transporter genes. The breadth and depth of the gene disruption data are particularly impressive, with at least one phenotype determined in the parasite's asexual blood stage for each transporter gene, and multiple phenotypes available for 76% of the genes. Analysis of the curated data set revealed there to be relatively little redundancy in the Plasmodium transportome; almost two-thirds of the parasite's transporter genes are essential or required for normal growth in the asexual blood stage of the parasite, and this proportion increased to 78% when the disruption phenotypes available for the other parasite life stages were included in the analysis. These observations, together with the finding that 22% of the transportome is implicated in the parasite's resistance to existing antimalarials and/or drugs within the development pipeline, indicate that transporters are likely to serve, or are already serving, as drug targets. Integration of the different biological and bioinformatic data sets also enabled the selection of candidates for transport processes known to be essential for parasite survival, but for which the underlying proteins have thus far remained undiscovered. These include potential transporters of pantothenate, isoleucine, or isopentenyl diphosphate, as well as putative anion-selective channels that may serve as the pore component of the parasite's 'new permeation pathways'. Other novel insights into the parasite's biology included the identification of transporters for the potential development of antimalarial treatments, transmission-blocking drugs, prophylactics, and genetically attenuated vaccines. The syntheses presented herein set a foundation for elucidating the functions and physiological roles of key members of the Plasmodium transportome and, ultimately, to explore and realise their potential as therapeutic targets.

Keywords: Plasmodium parasite; antimalarial drug action and resistance; carriers; channels; gene disruption phenotypes; membrane transport proteins; pumps; therapeutic targets; transportome.

© 2019 Cambridge Philosophical Society.

PubMed Disclaimer

Similar articles

Cited by

References

IX. REFERENCES

    1. *Achieng, A. O., Ingasia, L. A., Juma, D. W., Cheruiyot, A. C., Okudo, C. A., Yeda, R. A., Cheruiyot, J., Akala, H. M., Johnson, J., Andangalu, B., Eyase, F., Jura, W. G. & Kamau, E. (2014). Reduced in vitro doxycycline susceptibility in Plasmodium falciparum field isolates from Kenya is associated with PfTetQ KYNNNN sequence polymorphism. Antimicrobial Agents Chemotherapy 58, 5894-5899.
    1. *Agrawal, S., Moser, K. A., Morton, L., Cummings, M. P., Parihar, A., Dwivedi, A., Shetty, A. C., Drabek, E. F., Jacob, C. G., Henrich, P. P., Parobek, C. M., Jongsakul, K., Huy, R., Spring, M. D., Lanteri, C. A., et al. (2017). Association of a novel mutation in the Plasmodium falciparum chloroquine resistance transporter with decreased piperaquine sensitivity. Journal of Infectious Diseases 216, 468-476.
    1. *Allen, R. J. & Kirk, K. (2004). The membrane potential of the intraerythrocytic malaria parasite Plasmodium falciparum. Journal of Biological Chemistry 279, 11264-11272.
    1. Aly, A. S., Downie, M. J., Mamoun, C. B. & Kappe, S. H. (2010). Subpatent infection with nucleoside transporter 1-deficient Plasmodium blood stage parasites confers sterile protection against lethal malaria in mice. Cellular Microbiology 12, 930-938.
    1. Arnou, B., Montigny, C., Morth, J. P., Nissen, P., Jaxel, C., Moller, J. V. & Maire, M. (2011). The Plasmodium falciparum Ca2+-ATPase PfATP6: insensitive to artemisinin, but a potential drug target. Biochemical Society Transactions 39, 823-831.

Publication types

MeSH terms

LinkOut - more resources