![]() ![]() A computational study of the binding of CPA within SERCA and PfATP6 revealed differences between the two that may be exploited to develop CPA-based derivatives more specific for the parasite. As such it is a potential anti-malarial target. A closely related Ca 2+ pump, PfATP6, is also present in one of the protozoan parasites that cause malaria, Plasmodium falciparum. Crystallographic studies have suggested that CPA inhibits SERCA by blocking the calcium access channel, and that a divalent metal ion is required for binding. SERCA expends ATP to move Ca 2+ ions across the membrane. CPA is believed to act by disrupting calcium metabolism through inhibition of the sarcoplasmic reticulum Ca 2+-ATPase (SERCA). Male chickens that received CPA for 28 days showed dose-dependent decreases in the levels of Ca 2+, Mg 2+, and Fe 2+ within their sera. The major target organs are the liver, kidneys, spleen, alimentary tract, lymphoid tissue, skeletal muscle, and the myocardium. ![]() Symptoms may include weight loss, diarrhea, degeneration and necrosis of the muscles and viscera, leading to convulsions that can culminate in death. Note the indole moiety capable of absorbing light at circa 280 nm, and the presence of the tetramic acid moiety that can coordinate with metal cations.ĬPA can cause a variety of symptoms, which can vary by species. It also provides a novel way to probe the binding of CPA to metals, giving insights into CPA’s mechanism of action. The interaction of CPA with lanthanides provides a novel recognition assay for this toxin. Two cations in oxidation state one (Na +, K +) did not inhibit the interaction significantly. Inhibition was best with Cu 2+, followed by Co 2+, Al 3+, Fe 3+, Mn 2+, Au 3+, Mg 2+, and Ca 2+. With increasing cation concentration, the luminescence of the CPA/Tb 3+ complex was inhibited. Based upon the phenomenon, a competitive assay was also developed wherein terbium (Tb 3+) and a series of metal cations competed for binding with CPA. The luminescence expressed was dependent upon the type of lanthanide, its concentration, and the environment (solvent, water content, pH). This report is the first to describe the coordination of CPA with lanthanide metals, resulting in a substantial enhancement of their luminescence. Certain of the lanthanide metals undergo a dramatic increase in luminescence upon coordination with small molecules that can transfer excitation energy to the metal. The potential for CPA to act as a chelator also has implications for methods to detect this toxin. The inhibition may involve the binding of CPA with a divalent cation such as Mg 2+. CPA blocks the calcium access channel of the enzyme. Cycopiazonic acid (CPA) is a neurotoxin that acts through inhibition of the sarco(endo)plasmic reticulum Ca 2+-ATPase (SERCA). ![]()
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