Insights on the Intracellular Mechanism of Action of the Anticancer and Antiangiogenic Copper Chelator Drug: Ammonium Tetrathiomolybdate (TM)
Public DepositedThe biological antagonism between copper and molybdenum, first observed when cattle developed copper deficiencies after ingesting high levels of plant-born molybdenum, is currently being used in humans to treat two conditions: Wilson's Disease as well as several forms of metastatic cancer. There is surprisingly little known about the interaction of the biologically active tetrathiolmolybdate ion (TM) with copper-proteins. TM has been proposed to alter copper metabolism and induce copper deficiency due to its powerful ability of chelating copper ions. While the mechanism of how TM and copper interact in a physiological environment has not been clarified, preliminary results provide the molecular and structural characterization of the interaction of TM with the yeast intracellular copper chaperone, Atx1 and with the bovine superoxide dismutase, beSOD1. TM reacts quickly with Atx1 forming a robust purple trimer [TM][(Cu)(Cu-Atx1)3] complex, which represent the first detailed-structure of a [TM][Cu-protein] interaction. This complex was isolated by analytical gel filtration, and characterized by ICP-OES, Bradford assay, UV-Visible spectroscopy, Fluorescence spectroscopy, X-ray absorption spectroscopy (XAS), and X-ray protein crystallography. Moreover, we proposed a detailed in-vitro molecular characterization of the interaction of TM with beSOD1, confirming the inhibition of this protein by partial copper removal, and formation of a [CuTM]X polymeric complex, which was confirmed by XAS.
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