PfATP6

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P-type calcium transporting ATPase
Identifiers
OrganismPlasmodium falciparum
SymbolPfATP6
Alt. symbolsPfATPase6
Entrez3974689

PfATP6, also known as PfSERCA or PfATPase6, is a calcium ATPase gene encoded by the malaria parasite Plasmodium falciparum.[1] The protein is thought to be a P-type ATPase involved in calcium ion transport.

Mutations in PfATP6 that had been identified in field isolates (such as S769N) and in laboratory clones (such as L263E) were shown to have decreased sensitivity to artemisinin but conversely were more susceptible to other compounds targeting SERCAs.[2] In a yeast expression system looking at mutations L263E, A623E, S769N, and A623E/S769N it was shown that there was a fitness cost to these mutations compared to the wild-type.[3]

Resistance to artemisinin antimalarials[edit]

Research in 2003 indicated that PfATP6 is a target of artemisinin (a potent antimalarial drug).[4] It was observed that single amino acid mutations in PfATP6 could abolish sensitivity to artemisinin compounds.[5] Evidence came from a Xenopus oocyte system describing specific interactions between artemisinins and PfATP6 as well as E255L-mutated mammalian SERCA and from parasites in French Guiana with mutations in PfATP6 making them less susceptible to inhibition by artemether.[6] An independent assessment using the Xenopus oocyte system reported in 2016 that while PfATP6 protein could be detected, activity was not observed.[7] In the independent oocyte work, mammalian SERCA and its E255L-mutated version were active but both were insensitive to artemisinin, again in contrast to the original claims. The authors suggested that the original results might have been affected by low ATPase signals, few experimental repeats and large standard deviations.[8] The lack of artemisinin inhibition of E255L mammalian SERCA matched results from highly purified extracts obtained after heterologous expression in yeast cells.[9][10]

More recently, research has supported the role of PfATP6 in artemisinin therapy; direct interaction of artemisinin with PfATP6 was further noted in 2016 in an in vivo screen of the malaria parasite with a tagged drug molecule in two independent studies; 124 separate Pf proteins and >60 proteins that bound to this molecule were identified.[11][12] This work was substantiated in 2022 using a functional whole cell assay after yeast heterologous expression and in vitro identifying PfATP6 as both a binding partner and capable of functional inhibition by artemisinin compounds.[13] The same system confirmed that mutated mammalian SERCA1 (E255L) is more susceptible to inhibition by artemisinins. Intraparasitic free calcium concentrations are increased after exposure to an artemisinin. In 2022 it was observed in murine neutrophils that artemisinins were inhibiting migration of these cells. Further investigation pinpointed the mechanism of neutrophil functions to inhibition of the activity of a homologue of PfATP6, SERCA3.[14] This research supports the case for artemisinin activity with malaria SERCAs.

PfATP6 mutations play no role in the reduced artemisinin susceptibility observed in southeast Asia. The consensus is that PfATP6 is a validated target for artemisinins and mammalian SERCA3, in neutrophils, has emerged as a newly identified target.

References[edit]

  1. ^ Kimura M, Yamaguchi Y, Takada S, Tanabe K (April 1993). "Cloning of a Ca(2+)-ATPase gene of Plasmodium falciparum and comparison with vertebrate Ca(2+)-ATPases". Journal of Cell Science. 104 ( Pt 4) (4): 1129–1136. doi:10.1242/jcs.104.4.1129. PMID 8314897.
  2. ^ Pulcini S, Staines HM, Pittman JK, Slavic K, Doerig C, Halbert J, et al. (August 2013). "Expression in yeast links field polymorphisms in PfATP6 to in vitro artemisinin resistance and identifies new inhibitor classes". The Journal of Infectious Diseases. 208 (3): 468–478. doi:10.1093/infdis/jit171. PMID 23599312.
  3. ^ Moore CM, Wang J, Lin Q, Ferreira P, Avery MA, Elokely K, et al. (May 2022). "Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast". Antimicrobial Agents and Chemotherapy. 66 (5): e0207921. doi:10.1128/aac.02079-21. PMC 9112895. PMID 35465707.
  4. ^ Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, Kimura M, et al. (August 2003). "Artemisinins target the SERCA of Plasmodium falciparum". Nature. 424 (6951): 957–961. Bibcode:2003Natur.424..957E. doi:10.1038/nature01813. PMID 12931192. S2CID 4408172.
  5. ^ Uhlemann AC, Cameron A, Eckstein-Ludwig U, Fischbarg J, Iserovich P, Zuniga FA, et al. (2012). "Corrigendum: A single amino acid residue can determine the sensitivity of SERCAs to artemisinins". Nature Structural & Molecular Biology. 19 (2): 264. doi:10.1038/nsmb0212-264.
  6. ^ Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, et al. (December 2005). "Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6". Lancet. 366 (9501): 1960–1963. doi:10.1016/S0140-6736(05)67787-2. PMID 16325698. S2CID 45771681.
  7. ^ David-Bosne S, Clausen MV, Poulsen H, Møller JV, Nissen P, le Maire M (January 2016). "Reappraising the effects of artemisinin on the ATPase activity of PfATP6 and SERCA1a E255L expressed in Xenopus laevis oocytes". Nature Structural & Molecular Biology. 23 (1): 1–2. doi:10.1038/nsmb.3156. PMID 26733217. S2CID 28842136.
  8. ^ Uhlemann AC, Cameron A, Eckstein-Ludwig U, Fischbarg J, Iserovich P, Zuniga FA, et al. (July 2005). "A single amino acid residue can determine the sensitivity of SERCAs to artemisinins". Nature Structural & Molecular Biology. 12 (7): 628–629. doi:10.1038/nsmb0212-264. PMID 15937493.
  9. ^ Arnou B, Montigny C, Morth JP, Nissen P, Jaxel C, Møller JV, Maire M (June 2011). "The Plasmodium falciparum Ca(2+)-ATPase PfATP6: insensitive to artemisinin, but a potential drug target". Biochemical Society Transactions. 39 (3): 823–831. doi:10.1042/BST0390823. PMID 21599655.
  10. ^ Cardi D, Pozza A, Arnou B, Marchal E, Clausen JD, Andersen JP, et al. (August 2010). "Purified E255L mutant SERCA1a and purified PfATP6 are sensitive to SERCA-type inhibitors but insensitive to artemisinins". The Journal of Biological Chemistry. 285 (34): 26406–26416. doi:10.1074/jbc.M109.090340. PMC 2924071. PMID 20530490.
  11. ^ Ismail HM, Barton V, Phanchana M, Charoensutthivarakul S, Wong MH, Hemingway J, et al. (February 2016). "Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7". Proceedings of the National Academy of Sciences of the United States of America. 113 (8): 2080–2085. Bibcode:2016PNAS..113.2080I. doi:10.1073/pnas.1600459113. PMC 4776496. PMID 26858419.
  12. ^ Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, et al. (December 2015). "Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum". Nature Communications. 6 (1): 10111. Bibcode:2015NatCo...610111W. doi:10.1038/ncomms10111. PMC 4703832. PMID 26694030.
  13. ^ Moore CM, Wang J, Lin Q, Ferreira P, Avery MA, Elokely K, et al. (May 2022). "Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast". Antimicrobial Agents and Chemotherapy. 66 (5): e0207921. doi:10.1128/aac.02079-21. PMC 9112895. PMID 35465707.
  14. ^ Morad HO, Luqman S, Pinto LG, Cunningham KP, Vilar B, Clayton G, et al. (June 2022). "Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release". Scientific Reports. 12 (1): 11078. Bibcode:2022NatSR..1211078M. doi:10.1038/s41598-022-15214-6. PMC 9245885. PMID 35773325.
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