NA,K-ATPASE INHIBITORS FROM BOVINE HYPOTHALAMUS AND HUMAN PLASMA ARE DIFFERENT FROM OUABAIN - NANOGRAM SCALE CD STRUCTURAL-ANALYSIS

The specific, high affinity binding of plant-derived digitalis glycosi des by the mammalian sodium and potassium transporting adenosine triph osphatase (Na,K-ATPase, or sodium pump), a plasma membrane enzyme with critical physiological importance in mammalian tissues, has raised th e possibility that a mammalian analog of digitalis might exist.: We pr eviously isolated and structurally characterized from bovine hypothala mus a novel isomer of the plant glycoside, ouabain, which differs stru cturally only in the attachment site and/or the stereochemistry of the steroid moiety [Tymiak et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90 , 8189-8193]. Hamlyn and co-workers reported a molecule purified from human plasma which by mass spectrometry could not be distinguished fro m plant ouabain [Hamlyn et al. (1991) PI-oc. Natl. Acad. Sci. U.S.A. 8 8, 6259-6263]. Since rhamnoside cardiotonic steroids are not known as natural products from mammalian sources, it became important to compar e these two pure isolates to determine if the same or structurally dis tinct compounds had been found. Our results indicate that the human an d bovine Na,K-ATPase-inhibitors are identical, but different from plan t ouabain. This supports the notion that the human sodium pump may be under specific physiological regulation by a mammalian analog of the d igitalis glycosides.