Abstract
The ENA ATPases (from exitus natru: the exit of sodium) belonging to the P-type ATPases are structurally very similar to the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA); they exchange Na+ for H+ and, therefore, are also known as Na+-ATPases. ENA ATPases are required in alkaline milieu, as in the case for Aspergillus, where other transporters cannot mediate an uphill Na+ efflux. They are also important for salt tolerance, as described for Arabidopsis. During their life cycles, protozoan parasites might encounter a high pH environment, thus allowing consideration of ENA ATPases as possible targets for controlling certain severe parasitic diseases, such as Chagas’ Disease. Phylogenetic analysis has now shown that, besides the types IIA, IIB, IIC, and IID P-type ATPases, there exists a 5th subgroup of ATPases classified as ATP4-type ATPases, found in Plasmodium falciparum and Toxoplasma gondii. In malaria, for example, some drugs targeting PfATP4 destroy Na+ homeostasis; these drugs, which include spiroindolones, are now in clinical trials. The ENA P-type (IID P-type ATPase) and ATP4-type ATPases have no structural homologue in mammalian cells, appearing only in fungi, plants, and protozoan parasites, e.g., Trypanosoma cruzi, Leishmania sp., Toxoplasma gondii, and Plasmodium falciparum. This exclusivity makes Na+-ATPase a potential candidate for the biologically-based design of new therapeutic interventions; for this reason, Na+-ATPases deserves more attention.
Highlights
In the vast majority of cases, life has evolved in high-Na+ environments [1], which are considered inadequate for, or injurious to, proper cellular functioning [2], notably without mechanisms that can maintain low intracellular Na+ concentrations in organisms surrounded by and extracellular fluid containing ~150 mM Na+ [3]
The ENA P-type (IID P-type ATPase) and ATP4-type ATPases have no structural homologue in mammalian cells, appearing only in fungi, plants, and protozoan parasites, e.g., Trypanosoma cruzi, Leishmania sp., Toxoplasma gondii, and Plasmodium falciparum
The first evidence of a Na+ -ATPase in a trypanosomatid parasite was presented by Caruso-Neves et al [14], who showed that ouabain, the specific (Na+ + K+ )-ATPase inhibitor, did not completely abolish Na+ -stimulated ATPase activity of Trypanosoma cruzi epimastigotes, suggesting that this parasite has a Na+ -ATPase that is insensitive to ouabain
Summary
In the vast majority of cases, life has evolved in high-Na+ environments [1], which are considered inadequate for, or injurious to, proper cellular functioning [2], notably without mechanisms that can maintain low intracellular Na+ concentrations in organisms surrounded by and extracellular fluid containing ~150 mM Na+ [3]. A few years later, Proverbio et al [6] described a ouabain-resistant Na+ -ATPase activity that acts independently of K+ in isolated membranes from the outermost cortex of a guinea pig, and that was sensitive When they studied Na+ fluxes through the basolateral membranes of proximal tubule cells towards the external milieu they found two mechanisms: (i) one coupled to K+ and sensitive to ouabain, (ii) another one not coupled to K+ , resistant to ouabain and sensitive to ethacrynic acid [7]. Rocafull et al [9,12,13] purified and cloned the Na+ -ATPase from enterocytes (ATNA); its 3D structure was proposed, and the crucial amino acids of the catalytic and Na+ binding sites were identified They demonstrated the enzyme’s sensitivity to furosemide and its resistance to ouabain. Due to the emerging importance of the Na+ -ATPase for virulence and its potential as a therapeutic target, this review gives an overview of the recent findings regarding the role of Na+ -ATPase in protozoan parasites
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