Characterization of P-type H-ATPase Pma1 inhibitors that extend chronological lifespan in fission yeast.

Inhibition of the activity of Pma1, a widely conserved P-type proton exporting ATPase, has been shown to extend the chronological lifespan (CLS) in fission yeast Schizosaccharomyces pombe. To develop a specific inhibitor for Pma1 of S. pombe, we focused on Si01, a candidate inhibitor of Saccharomyces cerevisiae Pma1. First, we have established a method for synthesis of Si01 and then investigated its Pma1 inhibitory activity and lifespan extension effect in fission yeast. Second, we also synthesized derivatives of Si01 and determined the minimum structure required for inhibition of S. pombe Pma1. Here we showed that the inhibitory activity of Pma1 correlates with the effect of lifespan extension. Si01 reduced the activity of purified Pma1 protein and extended the CLS of not only fission yeast but also budding yeast. These results provide a molecular basis for understanding the mechanism of Pma1 inhibition and the potential for developing molecules that regulate lifespan.