The copper sequestering drug tetrathiomolybdate (TM) has been shown in studies to be effective in the treatment of Wilson disease, a disease caused by an overload of copper, and certain metastatic cancers. That much is known. Very little, however, is known about how the drug works at the molecular level.
A new study led by Northwestern University researchers now has provided an invaluable clue: the three-dimensional structure of TM bound to copper-loaded metallochaperones. The drug sequesters the chaperone and its bound copper, preventing both from carrying out their normal functions in the cell. For patients with Wilson disease and certain cancers whose initial growth is helped by copper-dependent angiogenesis, this is very promising.
This knowledge opens the door to the development of new classes of pharmaceutical agents based on metal trafficking pathways, as well as the further development of more efficient TM-based drugs. The study will be published in Science Express Nov. 26.
"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 and geneticist Valeria Culotta of Johns Hopkins University discovered the first copper chaperone function in 1997.
O'Halloran and his research team studied the copper chaperone protein Atx1, which provides a good model of copper metabolism in animal cells. "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 said. "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."
The nest-shaped structure of the metal-sulfur cluster discovered by the researchers was completely unanticipated.
"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," said 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."
Alfonso Mondragón, 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, solved the three-dimensional crystal structure using protein X-ray crystallography. This is the first example of a copper-sulfide-molybdenum metal cluster protein.
Based on the structure and additional experiments, the scientists propose that the drug inhibits the traffic of copper within the cell because of its ability to sequester copper chaperones and their cargo in clusters, 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 said.
Inorganic elements, such as copper, zinc and iron, are vital to the healthy functioning of all cells in living organisms. But they are high-maintenance nutrients, and too much can be toxic, as is the case in Wilson disease, a genetic disorder that prevents the body from getting rid of extra copper and leads to liver and neurological problems.
Copper also is an important cofactor for tumor angiogenesis, the process of growing new blood vessels to feed the tumor. Researchers believe this is why tetrathiomolybdate has shown promise as an anti-cancer drug.
The chain of discovery that led to the use of tetrathiomolybdate as a therapeutic agent began in the 1930s when cows grazing in certain types of pastures in England developed neurological problems. This trouble was then linked to other neurological problems with sheep grazing on certain soils in Australia. It was found that molybdate, a non-toxic compound present in the grass of these pastures, when consumed in excessive amounts by the ruminants, led to copper deficiencies and neurological problems in the animals.
As copper overload disorders such as Wilson disease were discovered in humans, physicians used molybdenum chemistry focusing on tetrathiomolybdate to lower copper levels in the body. (Tetrathiomolybdate is an inorganic small molecule first synthesized by J. J. Berzelius in 1826.)
Tetrathiomolybdate is the active pharmaceutical agent in 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.
TM also has been examined in recent studies where copper dysregulation is implicated in the pathogenesis of neurodegenerative diseases such as familial amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis and Alzheimer's disease 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.
O'Halloran also is director of Northwestern's Chemistry of Life Processes Institute and serves as associate director for basic science research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Mondragón is a member and Alvarez was a Malkin Fellow of the Lurie Cancer Center.
The Science paper is titled "Tetrathiomolybdate Inhibits Copper Trafficking Proteins Through Metal Cluster Formation." In addition to O'Halloran, Alvarez, Mondragón and Xue, other authors of the paper are Chandler D. Robinson, Mónica A. Canalizo-Hernández and Rebecca G. Marvin from Northwestern, and Rebekah A. Kelly and James E. Penner-Hahn from the University of Michigan.
Megan Fellman | EurekAlert!
Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex
New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center
In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.
Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...
Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
22.06.2018 | Materials Sciences
22.06.2018 | Earth Sciences
22.06.2018 | Life Sciences