Various studies in the past seem to have revealed the copper sequestering drug tetrathiomolybdate (TM) to be effective in the treatment of Wilson disease. However how the drug functions at a molecular level was not really known. Study experts from the Northwestern University now shed light on the workings of the anti-cancer drug. They seem to have uncovered additional details of the drug’s crystal structure that reveals how it disables harmful copper in cells.
Wilson disease is a condition apparently caused by an overload of copper, and certain metastatic cancers. With only that information in hand, experts through the new study gained an invaluable clue namely the three-dimensional structure of TM bound to copper-loaded metallochaperones. Preventing the chaperone and its bound copper from going about their routine functions in the cell, the drug appears to sequester them both.
“Essential metals are at the center of many emerging problems in health, medicine and the environment, and this work opens the door to new biological experiments,” mentioned Thomas V. O’Halloran, the study’s senior author and the Charles E. and Emma H. Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences at Northwestern. Along with geneticist Valeria Culotta of Johns Hopkins University, he had discovered the first copper chaperone function in 1997.
The copper chaperone protein Atx1 that offers a good model of copper metabolism in animal cells was analyzed by O’Halloran and team.
“We wondered what the drug tetrathiomolybdate did to copper chaperones — proteins charged with safely ferrying copper within the cell — and what we found was most amazing,” O’Halloran added. “The drug brings three copper chaperones into close quarters, weaving them together through an intricate metal-sulfur cluster in a manner that essentially shuts down the copper ferrying system.”
Much to their surprise, the scientists found a nest-shaped structure of the metal-sulfur.
“When we mixed TM together with copper chaperone proteins in a test tube, the color of the solution changed from light orange to deep purple,” further commented Hamsell M. Alvarez, the paper’s first author and a former doctoral student in O’Halloran’s lab, now with Merck & Co., Inc. “The sulfur atoms in the tetrathiomolybdate bound to the copper atoms to form an open cluster that bridged the chaperone proteins. In this manner, three copper proteins were jammed onto one thiomolybdate.”
With the help of protein X-ray crystallography, Alfonso Mondragon, professor of biochemistry, molecular biology and cell biology in the Weinberg College of Arts and Sciences, and graduate student Yi Xue, both co-authors of the paper, then resolved the three-dimensional crystal structure. This discovery claims to be the first example of a copper-sulfide-molybdenum metal cluster protein. With additional experiments, on the basis of the architecture scientists suggest that the drug may inhibit the traffic of copper within the cell. This could mainly be due to its ability to sequester copper chaperones and their cargo in clusters, making the copper inactive.
“We conclude that the biological activity of tetrathiomolybdate does not arise from a simple copper sequestering action but through a disruption of key protein-protein interactions important in human copper metabolism,” Alvarez said.
Inorganic elements like copper, zinc and iron contribute to the healthy functioning of all cells in living organisms. On the flip side they may need high-maintenance and an overdose could probably cause toxicity in the body. This may lead to condition such as Wilson disease which is also known to be a genetic disorder that curbs the body from removing the additional copper. It could lead to liver and neurological problems in turn. Besides, copper is also believed to be an important cofactor for tumor angiogenesis. The latter is a process of growing new blood vessels to feed the tumor and that experts believe should explain tetrathiomolybdate as promising anti-cancer drug as well.
These findings could bring in some hope for patients with Wilson disease and certain cancers whose initial growth is helped by copper-dependent angiogenesis. Scientists associated with the study are of the opinion that new classes of pharmaceutical agents that find their roots on metal trafficking pathways could be actualized in addition to further development of more efficient TM-based drugs with this knowledge.
The study has been published in Science Express.