Diverse biological roles of the tetrathiomolybdate anion

Biological systems use proteins as scaffolds to harbor catalytic metal centers responsible for the assimilatory and energy pathways that make life possible. Therefore, metal homeostasis is essential for life. Generally, when compared to normal cells, copper overload has negative consequences, such as radical formation, up-regulation of Cu-enzyme activity by promoting the progression of disease states and major toxic effects by substituting native metal sites in [Fe-S] and Zn proteins. So, elevated copper levels are the cause of many health problems, such as Wilson disease (WD) and cancer. One of the most important therapeutic interventions of WD is anti-copper therapy, where tetrathiomolybdate (TTM = [MoS₄]^2–, coprexa) is used as a copper-sequestering drug. The discovery of the Cu-TTM interaction in ruminant nutrition had a great impact on research in humans. Currently, TTM is also being exploited as a drug for treatment of several forms of cancer. Cu-TTM based therapy reduces excess copper, decreasing harmful and toxic effects. Therefore, high concentrations of copper, as well as several Cu-enzymes involved in WD/cancer, are promising targets for anti-copper therapy. Several TTM-treated pre-clinical models, as well as humans with WD/cancer, provide successful results. Interestingly, Cu-TTM interest expanded when a metal-cofactor, [Cu(TTM)₂]^3-, was found in the orange protein (ORP) isolated from a sulfate-reducing bacteria. This review will discuss the chemical and biological occurrence of TTM, the imbalance of Cu-trafficking leading to copper overloaded human diseases (WD and cancer), preclinical and clinical aspects of TTM as an anti-copper therapy and finally TTM as a part of the metal cofactor of ORP. The aim of this review is to promote our understanding on the role of Mo-Cu antagonism in humans as an anti-copper therapy.