Abstract
We examined the inhibitory effects of three flavonolignans and their dehydro- derivatives, taxifolin and quercetin on the activity of the Na+/K+-ATPase (NKA). The flavonolignans silychristin, dehydrosilychristin and dehydrosilydianin inhibited NKA with IC50 of 110 ± 40 μM, 38 ± 8 μM, and 36 ± 14 μM, respectively. Using the methods of molecular modeling, we identified several possible binding sites for these species on NKA and proposed the possible mechanisms of inhibition. The binding to the extracellular- or cytoplasmic C-terminal sites can block the transport of cations through the plasma membrane, while the binding on the interface of cytoplasmic domains can inhibit the enzyme allosterically. Fluorescence spectroscopy experiments confirmed the interaction of these three species with the large cytoplasmic segment connecting transmembrane helices 4 and 5 (C45). The flavonolignans are distinct from the cardiac glycosides that are currently used in NKA treatment. Because their binding sites are different, the mechanism of inhibition is different as well as the range of active concentrations, one can expect that these new NKA inhibitors would exhibit also a different biomedical actions than cardiac glycosides.
Highlights
Sodium pump (Na+/K+-ATPase, E.C. 3.6.3.9, NKA) is an enzyme of crucial importance for all animal cells
It is not surprising that an uncontrolled inhibition of NKA can result in severe diseases, e.g., renal failure, hypertension or diabetic neuropathies (Kaplan, 2002) or even death, and that the most specific NKA inhibitor cardiac glycoside ouabain was originally used as an arrow poison (Newman et al, 2008)
This study was focused on interactions of a series of phenolic compounds from silymarin with one of the most important enzymes in the animal metabolism, the NKA
Summary
Sodium pump (Na+/K+-ATPase, E.C. 3.6.3.9, NKA) is an enzyme of crucial importance for all animal cells. It is not surprising that an uncontrolled inhibition of NKA can result in severe diseases, e.g., renal failure, hypertension or diabetic neuropathies (Kaplan, 2002) or even death, and that the most specific NKA inhibitor cardiac glycoside ouabain was originally used as an arrow poison (Newman et al, 2008). Despite these risks, extracts containing cardiac glycosides were used to control heart tonics already in ancient medicine, and the extracts were prepared either from plants in Arabic medicine (Brewer, 2004) or secretions of frog Bufo bufo in Chinese medicine (Watabe et al, 1996). The use of cardiac glycosides is limited by their very
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
