Tetrathiomolybdate – A copper-sequestering drug:
A study has revealed that Tetrathiomolybdate, a copper-sequestering drug, plays an important role in providing a treatment for Wilson disease, which is caused by an over accumulation of copper and metastatic cancers. Small info is available, however is known about how the drug works at the molecular level.
A fresh research study conducted and guided by the Northwestern University researchers now has provided a priceless clue i.e the three-dimensional structure of TM bound to copper loaded metallochaperones. The tetrathiomolybdate sequester the chaperone and its bound copper, forbidding both from carrying out their normal functions in the cell. For those patients suffering from Wilson disease and other cancers whose primary growth is helped by copper-dependent angiogenesis, this is very promising.
The knowledge gain from the above research provides a new direction and also opens the door for the development of new classes of Pharmaceutical agents depending on metal trafficking pathways, as well as further progress of more efficient TM based drugs.
“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,” said 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. He together with geneticist – Valeria Culotta of Johns Hopkins University discovered the first copper chaperone function in 1997.
O’Halloran along with his research team studied the nature of copper chaperone protein Atx1 that offers a sound model of copper metabolism in animal cells. “We wondered what the drug tetrathiomolybdate did to copper chaperones – and what we found was amazing”, O’Halloran added. According to research, “the drug brings 3 cu chaperones into a close quarters, and weaving them together through an intricate metal-sulfur cluster such that it shuts down the copper ferrying system”. Researchers discovered a net shaped structure of the metal-surface cluster was totally unanticipated.
Hamsell M. Alvarez, the paper’s first author and a former doctoral student in O’Halloran’s lab, now with Merck & Co., Inc. has observed that, when TM is mixed together with copper chaperon proteins in a test tube, the color of the overall solution turns from light orange to deep purple. He also observed “the sulfur atoms in the TM binds with the copper atoms in order to form an open cluster that bridged the chaperone proteins. In this manner, three copper proteins were jammed onto one thiomolybdate”.
Alfonso Mondrag-n, professor of biochemistry, molecular biology and cell biology in the Weinberg College of Arts and Sciences, along with graduate student Yi Xue, solved the three-dimensional crystal structure using protein X-ray crystallography. This is the first example of a copper-sulfide-molybdenum metal cluster protein.
Depending on structure and various experiments, the scientist suggested that the drug suppresses the traffic of copper within the cell because of its ability to sequester copper chaperones and their cargo in cluster, rendering 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 added.
As we know elements such as zinc, iron, and copper are the basic requirements for the healthy functioning of cells in the living organism. But high accumulation of these elements can prove to be toxic, as is the case in Wilson disease. It is believed that copper is an important cofactor for tumor angiogenesis, the formation of new blood vessel, which accompanies the growth of malignant tissue. Researchers believe this is why tetrathiomolybdate has shown promise as an anti-cancer drug.
The use of tetrathiomolybdate as a therapeutic agent began in the 1930s when cows grazing in a certain pastures in England acquired neurological problems. This problem was then joined to other neurological problem that was with sheep grazing on certain types of soils in Australia. It was observed that molybdate, a non-toxic compound present in the grass of these pastures, when consumed in large amounts by the ruminants; produce copper deficiencies and neurological problems in the animals.
When Wilson disease was observed in humans, doctors refer molybdenum chemistry focusing on tetrathiomolybdate to solve by lowering copper levels in the body. Tetrathiomolybdate, an active pharmaceutical agent and a well-tolerated drug that has shown activity for the treatment of Wilson disease and now is in phase II clinical trials as an anti-cancer drug. In latest studies it has been examined that copper dysregulation is implicated in the pathogenesis of neurodegenerative diseases such as familial Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease, and Multiple Sclerosis as well as primary pulmonary hypertension and left ventricular hypertrophy associated with type II diabetes. Copper modulating agents including TM have been shown to be active in animal models of these diseases providing a rationale for advancing tetrathiomolybdates into clinical evaluation in these areas.