Biology:PfATP6

From HandWiki
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

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

  1. ↑ "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. April 1993. doi:10.1242/jcs.104.4.1129. PMID 8314897. 
  2. ↑ "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. August 2013. doi:10.1093/infdis/jit171. PMID 23599312. 
  3. ↑ "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. May 2022. doi:10.1128/aac.02079-21. PMID 35465707. 
  4. ↑ "Artemisinins target the SERCA of Plasmodium falciparum". Nature 424 (6951): 957–961. August 2003. doi:10.1038/nature01813. PMID 12931192. Bibcode: 2003Natur.424..957E. 
  5. ↑ "Corrigendum: A single amino acid residue can determine the sensitivity of SERCAs to artemisinins". Nature Structural & Molecular Biology 19 (2): 264. 2012. doi:10.1038/nsmb0212-264. 
  6. ↑ "Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6". Lancet 366 (9501): 1960–1963. December 2005. doi:10.1016/S0140-6736(05)67787-2. PMID 16325698. 
  7. ↑ "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. January 2016. doi:10.1038/nsmb.3156. PMID 26733217. 
  8. ↑ "A single amino acid residue can determine the sensitivity of SERCAs to artemisinins". Nature Structural & Molecular Biology 12 (7): 628–629. July 2005. doi:10.1038/nsmb0212-264. PMID 15937493. 
  9. ↑ "The Plasmodium falciparum Ca(2+)-ATPase PfATP6: insensitive to artemisinin, but a potential drug target". Biochemical Society Transactions 39 (3): 823–831. June 2011. doi:10.1042/BST0390823. PMID 21599655. 
  10. ↑ "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. August 2010. doi:10.1074/jbc.M109.090340. PMID 20530490. 
  11. ↑ "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. February 2016. doi:10.1073/pnas.1600459113. PMID 26858419. Bibcode: 2016PNAS..113.2080I. 
  12. ↑ "Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum". Nature Communications 6 (1): 10111. December 2015. doi:10.1038/ncomms10111. PMID 26694030. Bibcode: 2015NatCo...610111W. 
  13. ↑ "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. May 2022. doi:10.1128/aac.02079-21. PMID 35465707. 
  14. ↑ "Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release". Scientific Reports 12 (1): 11078. June 2022. doi:10.1038/s41598-022-15214-6. PMID 35773325. Bibcode: 2022NatSR..1211078M. 



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