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Structure and Coordination Determination of Peptide-metal Complexes Using 1D and 2D 1H NMR
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Structure and Coordination Determination of Peptide-metal Complexes Using 1D and 2D 1H NMR

Published on: December 16, 2013

Inhibition of ceruloplasmin and other copper oxidases by thiomolybdate

M V Chidambaram, G Barnes, E Frieden

    Journal of Inorganic Biochemistry
    |December 1, 1984
    PubMed

    Insights

    Thiomolybdate (TM) strongly inhibits copper enzymes like ceruloplasmin by covalently binding to copper, reducing its activity. This irreversible inhibition occurs without significant protein structure changes or restoration by copper.

    Area of Science:

    • Biochemistry
    • Enzymology
    • Metalloprotein Chemistry

    Background:

    • Dietary interactions between copper and molybdate salts suggest potential enzyme inhibition.
    • Copper enzymes play crucial roles in various biological processes.

    Purpose of the Study:

    • To investigate the inhibitory mechanism of thiomolybdate (TM) on copper-dependent enzymes.
    • To elucidate the specific interactions between TM and ceruloplasmin (Cp).

    Main Methods:

    • Enzyme activity assays for multiple copper oxidases.
    • Detailed mechanistic studies on ceruloplasmin inhibition using Vmax vs. E plots.
    • Biophysical techniques including gel electrophoresis and Electron Paramagnetic Resonance (EPR).
    • Reversal and isolation experiments (dialysis, Sephadex G-10 chromatography).

    Main Results:

    • TM strongly inhibited five copper oxidases with low I50% values (1-5 microM).
    • Inhibition of ceruloplasmin by TM was found to be irreversible and did not restore activity upon copper addition or dialysis.
    • Gel electrophoresis and EPR confirmed covalent binding of TM to Cp, reducing Cu(II) to Cu(I) without altering Mo oxidation state.
    • All six copper atoms in Cp were accounted for in the TM-Cp complex, suggesting sulfide binding to copper.

    Conclusions:

    • Thiomolybdate covalently binds to copper in ceruloplasmin and other copper oxidases, leading to irreversible inhibition.
    • The mechanism involves the reduction of copper and potential binding of sulfide to the enzyme's copper centers.
    • This study provides insight into the biochemical basis of copper-molybdate dietary antagonism.

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