Gramicidin A directly inhibits mammalian Na(+)/K (+)-ATPase.
The linear pentadecapeptide gramicidin A forms an ion channel in the lipid bilayer to selectively transport monovalent cations. Nevertheless, we have surprisingly found that gramicidin A directly inhibits mammalian Na(+)/K(+)-ATPase. Gramicidin A inhibited ATP hydrolysis by Na(+)/K(+)-ATPase from porcine cerebral cortex at the IC(50) value of 8.1 microM, while gramicidin S was approximately fivefold less active. The synthetic gramicidin A analog lacking N-terminal formylation and C-terminal ethanolamine exhibited a weaker inhibitory effect on the ATP-hydrolyzing activity of Na(+)/K(+)-ATPase than gramicidin A, indicating that these end modifications are necessary for gramicidin A to inhibit Na(+)/K(+)-ATPase activity. Moreover, Lineweaver-Burk analysis showed that gramicidin A exhibits a mixed type of inhibition. In addition to the most well-studied ionophore activity, our present study has disclosed a novel biological function of gramicidin A as a direct inhibitor of mammalian Na(+)/K(+)-ATPase activity.
Takada
Yohei
Y
Center for Biological Resources and Informatics, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama, Japan.
Matsuo
Kentaro
K
Kataoka
Takao
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry; D002540:Cerebral Cortex / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006096:Gramicidin / Q000737:chemistry*; D006868:Hydrolysis; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013552:Swine
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D006096:Gramicidin; D000254:Sodium-Potassium-Exchanging ATPase