PfATP6

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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.

Resistance to artemisinin antimalarials[edit]

It was suggested in 2003 that PfATP6 is a target of artemisinin antimalarials,[2] and also that a single amino acid mutation in the enzyme can mediate resistance to this important group of compounds.[3] The main evidence came from a Xenopus oocyte system describing specific interactions between artemisinins and PfATP6 as well as E255L-mutated mammalian SERCA. However an independent reappraisal in the same system showed that while PfATP6 protein could be detected, it was inactive.[4] 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.[5] The lack of artemisinin inhibition of E255L mammalian SERCA matched results from heterologous expression in mammalian and yeast cells.[6][7]

PfATP6 mutations clearly play no role in the reduced artemisinin susceptibility observed in southeast Asia. The consensus is that PfATP6 is not directly involved in artemisinin action or resistance.[8][9]

References[edit]

  1. ^ Kimura, M.; Yamaguchi, Y.; Takada, S.; Tanabe, K. (1993). "Cloning of a Ca(2+)-ATPase gene of Plasmodium falciparum and comparison with vertebrate Ca(2+)-ATPases". Journal of Cell Science. 104 (4): 1129–1136. PMID 8314897. 
  2. ^ Eckstein-Ludwig U, Webb RJ, Van Goethem ID, et al. (August 2003). "Artemisinins target the SERCA of Plasmodium falciparum". Nature. 424 (6951): 957–61. doi:10.1038/nature01813. PMID 12931192. 
  3. ^ Uhlemann, A. C.; Cameron, A.; Fischbarg, J.; Iserovich, P.; Zuniga, F. A.; East, M.; Lee, A.; Brady, L.; Haynes, R. K.; Krishna, S. (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. 
  4. ^ David-Bosne, S; Clausen, MV; Poulsen, H; Møller, JV; Nissen, P; le Maire, M (6 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. 
  5. ^ Uhlemann, Anne-Catrin; Cameron, Angus; Eckstein-Ludwig, Ursula; Fischbarg, Jorge; Iserovich, Pavel; Zuniga, Felipe A; East, Malcolm; Lee, Anthony; Brady, Leo; Haynes, Richard K; Krishna, Sanjeev (February 2012). "A single amino acid residue can determine the sensitivity of SERCAs to artemisinins". Nature Structural & Molecular Biology. 19 (2): 264–264. doi:10.1038/nsmb0212-264. 
  6. ^ Arnou, B; Montigny, C; Morth, JP; Nissen, P; Jaxel, C; Møller, JV; Maire, Ml (June 2011). "The Plasmodium falciparum Ca(2+)-ATPase PfATP6: insensitive to artemisinin, but a potential drug target". Biochemical Society Transactions. 39 (3): 823–31. doi:10.1042/BST0390823. PMID 21599655. 
  7. ^ Cardi, D.; Pozza, A.; Arnou, B.; Marchal, E.; Clausen, J. D.; Andersen, J. P.; Krishna, S.; Moller, J. V.; le Maire, M.; Jaxel, C. (8 June 2010). "Purified E255L Mutant SERCA1a and Purified PfATP6 Are Sensitive to SERCA-type Inhibitors but Insensitive to Artemisinins". Journal of Biological Chemistry. 285 (34): 26406–26416. doi:10.1074/jbc.M109.090340. PMC 2924071Freely accessible. PMID 20530490. 
  8. ^ Winzeler, EA; Manary, MJ (2014). "Drug resistance genomics of the antimalarial drug artemisinin". Genome Biol. 15 (11): 544. doi:10.1186/s13059-014-0544-6. PMC 4283579Freely accessible. PMID 25470531. 
  9. ^ Cravo, P; Napolitano, H; Culleton, R (Aug 2015). "How genomics is contributing to the fight against artemisinin-resistant malaria parasites". Acta Trop. 148: 1–7. doi:10.1016/j.actatropica.2015.04.007. PMID 25910626.