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The ENA ATPases (from <i>exitus natru</i>: 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 <i>Aspergillus</i>, where other transporters cannot mediate an uphill Na⁺ efflux. They are also important for salt tolerance, as described for <i>Arabidopsis</i>. 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 <i>Plasmodium falciparum</i> and <i>Toxoplasma gondii</i>. 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., <i>Trypanosoma cruzi, Leishmania sp.</i>, <i>Toxoplasma gondii,</i> and <i>Plasmodium falciparum</i>. 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.