"Many drugs block the function of enzymes, essentially turning them off ," said Gary Glick, who is the Werner E. Bachmann Collegiate Professor of Chemistry at U-M. "Our compound works more like a volume control, so we’re able to dial enzyme activity down to a level that maintains normal function while simultaneously allowing for initiation of a process that selectively kills or disables disease-causing cells."
Glick and collaborators published their findings in the June 16 issue of ACS Chemical Biology.
The drug, discovered by Glick and coworkers and called benzodiazepine-423 (Bz-423), is a chemical cousin of anti-anxiety medications such as Valium and Xanax. In previous work, Glick’s group showed that Bz-423 reduces effects of arthritis and the autoimmune disease lupus in mice and may be useful in treating psoriasis. Unlike conventional drugs for these conditions, which can’t discriminate between healthy and disease-causing cells, Bz-423 is highly selective, homing in on disease-causing cells.
In an attempt to better exploit its therapeutic properties, the researchers have been studying the details of Bz-423’s activity. They learned that the compound targets an enzyme inside mitochondria, the energy factories of cells. The specific enzyme, F1F0-ATPase, is responsible for producing most of the cell’s ATP. That’s a critical role because ATP, often referred to as the cell’s energy currency, is the molecule that captures chemical energy from food and transfers it to energy-demanding processes, such as muscle contraction and the transmission of nerve signals.
"People had proposed in the past that if you could inhibit this enzyme, there might be therapeutic potential. But the problem is, if you inhibit the enzyme in the way most powerful drugs do, turning it off, you deplete the cell of ATP, and that’s fatal," Glick said. "Our new work reveals the mechanism by which Bz-423 inhibits the enzyme while still allowing it to function. This is important because it suggests principles that may be useful for targeting other bioenergetic pathways. Now we have some rules that we can apply to be able to modulate the mitochondria in new ways that could be therapeutic."
Ultimately, the findings may have applications not only for lupus, arthritis and psoriasis, but also for other conditions, Glick believes. "There are other diseases – certain cancers and a number of other immune diseases – where we think the way the cells make and utilize energy is fundamental to the disease process. Combining that knowledge with our new knowledge of how to regulate the energy of the cell could open up new avenues for treating disease and monitoring the effectiveness of treatment."
Glick collaborated on the research with Carol Fierke, who is the Jerome and Isabella Karle Collegiate Professor of Chemistry; Anthony Opipari, Jr., associate professor of obstetrics and gynecology; graduate student Kathryn Johnson and postdoctoral fellow Joanne Cleary. The researchers received funding from the National Institutes of Health.
Nancy Ross-Flanigan | EurekAlert!
What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
06.12.2016 | Materials Sciences
06.12.2016 | Medical Engineering
06.12.2016 | Power and Electrical Engineering