On the mechanism and rate of gold incorporation into thiol-dependent flavoreductases

NADPH-dependent flavoreductases are important drug targets. During their enzymatic cycle thiolates and selenolates that have high affinity for transition metals are generated. Auranofin (AF), a gold-containing compound, is classified by the World Health Organization as an antirheumatic agent and it is indicated as the scaffold for the development of new anticancer and antiparasitic drugs. AF inhibits selenocysteine-containing flavoreductases (thioredoxin reductase and thioredoxin glutathione reductase) more effectively than non Se-containing ones (glutathione reductase); this preference has been ascribed to the high affinity of selenium for gold. We solved the 3D structure of the Se-containing Thioredoxin Glutathione Reductase from the human parasite Schistosoma mansoni complexed with Au and our results challenge this view: we believe that the relative velocity of the reaction rather than the relative affinity, depends on the presence of Sec residues, which appear to dictate AF selectivity.

Gold(I) coordinated to cysteines in the active site of Schistosoma mansoni Thioredoxin Glutathione Reductase illustrates the action of gold-containing drugs.Figure optionsDownload as PowerPoint slideHighlights
► Gold inhibits flavoreductases by irreversible binding to selenocysteine or cysteine residues.
► Selenocysteine catalytically promotes gold incorporation.
► Reversible transfer of gold from selenocysteine to cysteine occurs.