Spherical Oligo-Silicic Acid SOSA Disclosed As Possible Endogenous Digitalis-Like Factor
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REVIEW ARTICLE published: 23 January 2015 doi: 10.3389/fendo.2014.00233 Spherical oligo-silicic acid SOSA disclosed as possible endogenous digitalis-like factor Franz Kerek 1* and Victor A. Voicu 2 1 SiNatur GmbH, Martinsried, Germany 2 Department of Clinical Pharmacology, Toxicology and Psychopharmacology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania Edited by: The NaC/KC-ATPase is a membrane ion-transporter protein, specifically inhibited by digi- Harvey C. Gonick, University of talis glycosides used in cardiac therapy. The existence in mammals of some endogenous California Berkeley, USA digitalis-like factors (EDLFs) as presumed ATPase ligands is generally accepted. But the Reviewed by: Ricardo Borges, University of La chemical structure of these factors remained elusive because no weighable amounts of C C Laguna, Spain pure EDLFs have been isolated. Recent high-resolution crystal structure data of Na /K - Harvey C. Gonick, University of ATPase have located the hydrophobic binding pocket of the steroid glycoside ouabain. It California Berkeley, USA remained uncertain if the EDLF are targeting this steroid-receptor or another specific bind- *Correspondence: ing site(s). Our recently disclosed spherical oligo-silicic acids (SOSA) fulfill the main criteria Franz Kerek, SiNatur GmbH, Am Klopferspitz 19, IZB, 82152 Munich, to be identified with the presumed EDL factors. SOSA was found as a very potent inhibitor C C 2C C C Germany of the Na /K -ATPase, Ca -ATPase, H /K -ATPase, and of K-dp-ATPase, with IC50 val- e-mail: [email protected] ues between 0.2 and 0.5 mg/mL. These findings are even more astonishing while so far, neither monosilicic acid nor its poly-condensed forms have been remarked biologically active. With the diameter # between 1 and 3 nm, SOSA still belong to molecular species definitely smaller than silica nano-particles with # > 5 nm. In SOSA molecules, almost all Si-OH bonds are displayed on the external shell, which facilitates the binding to hydrophilic ATPase domains. SOSA is stable for long term in solution but is sensitive to freeze-drying, which could explain the failure of countless attempts to isolate pure EDLF.There is a strong resemblance between SOSA and vanadates, the previously known general inhibitors of P- type ATPases. SOSA may be generated endogenously by spherical oligomerization of the ubiquitously present monosilicic acid in animal fluids. The structure of SOSA is sensitive to the concentration of NaC,KC, Ca2C, Mg2C, and other ions suggesting a presumably archaic mechanism for the regulation of the ATPase pumps. Keywords: oligo silicic-acid, ATPase regulation, digitalis-like factor, ouabain INTRODUCTION the membrane transport protein of the NaC and KC-ions by Skou Investigating the staircase effect on frog ventricular muscle, it was (5). This NaC/KC-ATPase (adenosine-triphosphatase) abbrevi- revealed in the early 1950s that human serum contains a factor, ated NKA or sodium pump is present in the membrane of all which improves the contractile power of the heart,similar to plant- eukaryotic cells. Every pumping cycle of the NKA moves 3 NaC derived digitalis glycosides (1). Besides the serum,this digitalis-like ions outward and 2 KC ions inward, powered by the energy of a activity was reproduced by a total extract of adrenal but, individ- phosphate bond from ATP. ual cortisol steroids were, with one exception, inactive. Referring At the beginning of the 1960s, the existence of a circulating to their finding Szent-Györgyi concluded (2) in more general natriuretic factor was postulated by De Wardener et al. (6) show- terms that “such digitalis-like factors are ubiquitously distributed ing that the blood, transfused from a saline-loaded, hypertensive in mammals” and “digitalis glycosides from plants are actually not dog, produces natriuresis in the recipient normotensive animal. It drugs but only substitutes of the body’s own digitalis-like factors.” was further observed that the plasma ultra-filtrate of saline-loaded This kind of relationship between exogenous drug-substances, dogs inhibits the sodium transport in toad bladder and the vol- which fits accidentally into the receptor of a body’s own factor ume expansion was accompanied by increasing concentrations of a has been verified by the discovery of endorphins, the endoge- sodium pump-inhibitory factor (7). Ascertaining that both effects nous counterparts of the plant-derived morphine (3). Why this were caused by the same factor the name natriuretic hormone broadly accepted rationale was not consequently applied in the was proposed. The natriuretic fraction extracted from the plasma differentiation between endogenous digitalis-like factors (EDLFs) of volume-expanded dogs inhibited the ouabain-insensitive NKA and exogenous digitalis glycosides is a subject of the present review. from rat kidney (8). A further milestone finding of the 1950s was that digitalis After the identity of the natriuretic hormone with the sodium glycosides inhibit the transport of NaC and KC ions across the pump-inhibitory factor was confirmed, the name EDLF came into erythrocyte membrane (4) and above all the seminal discovery of use (9). The initial idea that EDLF could be a natriuretic peptide www.frontiersin.org January 2015 | Volume 5 | Article 233 | 1 Kerek and Voicu Spherical oligo-silicic-acid as endogenous digitalis-like factor was rejected after disclosure of the atrial natriuretic peptide (ANP), In the next high-resolution (3.1 Å) crystal structure of the which has, contrary to EDLF no NKA-inhibitory activity (10). SERCA pump, the Toyoshima group applied the sesquiterpene Though the structure of EDLF remained obscure, some of its lactone thapsigargin, to stabilize the Ca-free E2-(TG) state (20). 2C particular characteristics were established as for instance: its non- The comparison of both crystallized forms Ca E1 and E2-(TG) peptide nature or its specific interaction with different ATPase iso- revealed further details of the ion transport mechanism. In a fol- 2C forms. But the failure of all attempts to obtain weighable amounts lowing contribution (21), the structure of the Ca -ATPase was of pure EDLF impeded for more than five decades the disclosure solved in the E1 state fixed by the ATP-analog AMPPCP. In the of its chemical structure. same year, the structure at 2.3 Å resolution of SERCA with phos- C C 2- Na /K -ATPase controls a broad spectrum of essential cel- phate analogs such as [MgF4] has been resolved (22). The studies lular functions such as ion homeostasis, membrane potential, of the Ca-pump fixed with ATP- or phosphate analogs have com- pH, temperature, and water osmosis, thereby regulating impor- pleted the structural insight into almost all important states of the tant physiological processes, e.g., muscle contraction, nervous pump turnover. signal transmission, renal sodium retention, and vascular tone. Resolving the crystal structure of the SERCA pump with the - Study data in animal models and clinical observations in human phosphate mimic [BeF3] , Olesen et al. (23) provided support beings suggest that cardiac insufficiency, essential hypertension, for the presence of an open ion pathway in the pump in which and other diseases may be caused by or connected to malfunction the transmembrane domains form a funnel-shaped geometry. or dysregulation of the sodium pump. As described later, the crystal structure data confirmed that P- The extensive research work related to the structure, characteri- type ATPases share the same architecture regardless of the size, zation, mechanism of action, and physiological implications of the charge, and number of ions that they transport. It seems that the C C Na /K -ATPase was comprehensively reviewed by Gadsby et al. differences are largely confined to the ion-binding pocket (23, 24). C C (11), Glynn (12), Kaplan (13), and Jørgensen et al. (14). Similarly, Na /K -ATPase is sensitive to inhibition by digitalis glyco- extensive reviews on the whole P-type-ATPase field have been pub- sides (e.g., digoxin, ouabain), isolated from medicinal plants used lished by Møller et al. (15), Kühlbrandt (16) and by the original over centuries to treat congestive heart failure. The term “digitalis” contributions of Axelsen and Palmgren (17, 18) with special focus designates the entire group of cardiac glycosides and aglycones on evolutionary aspects of the P-type ATPases. without regard of their structure and origin (25). Responsible for the cardiac activity is the aglycone, i.e., the steroid nucleus, ATPase RECEPTOR SITE which results after the sugar moiety from position 3 is removed. P-type ATPase is the generic designation of several ATP-driven Steroid aglycones with five-membered lactone ring in position transmembrane ion pumps found in bacteria, archaea, and 17 are named cardenolides while those with six-membered lac- eukaryotes. The prefix P refers to the ability of these proteins for tone ring bufadienolides. Both terms, cardiotonic (CTS) or cardiac phosphorylation and de-phosphorylation of their catalytic aspar- steroids (CSs), are in use but the adjective “tonic” is less rigorous tate residue (15). By the binding and removal of the phosphate as it refers to a species-dependent physiological response; thus, the group, ATPases interconvert between two conformations, denoted designation CS should be preferred over CTS. C C by E1 and E2, each with different affinity to the nucleotide ATP Since Na /K -ATPase is the target of digitalis drugs in heart (adenosine triphosphate) and the transported ions (16). A com- failure