Researchers at the Indiana University and Stanford University schools of medicine have determined how a "chemical chaperone" does its job in the body, which could lead to a new class of drugs to help reduce the muscle damage caused by heart attacks.
Such drugs would work by restoring the activity of a mutated enzyme, rather than taking the more common approach of blocking the actions of a disease-related protein.
The team, led by Thomas Hurley, Ph.D., associate chair and professor of biochemistry and molecular biology at IU, and Daria Mochly-Rosen, Ph.D., professor of chemical and systems biology at Stanford, report in the journal Nature Structural Biology published online Jan. 10 that the compound, called Alda-1, acts much like a shim to prop up a mutated form of a key enzyme, restoring the enzyme's function.
The enzyme, called ALDH2, plays an important role in metabolizing alcohol and other toxins, including those created by a lack of oxygen in the wake of a heart attack. It also is involved in the metabolism of nitroglycerin, which is used to prevent chest pain (angina) caused by restricted blood flow and oxygen to the heart.
However some people, including about 40 percent of people of East Asian descent, carry a mutated form of the ALDH2 enzyme that does not carry out its intended functions well. People with the mutated form of the enzyme are at increased risk of cardiovascular damage.
The IU and Stanford team reported in 2008 in the journal Science that in laboratory tests Alda-1 bypassed the body's usual signaling system and activated the ALDH2 enzyme directly, reducing damage to heart muscle tissue. That finding raised the possibility of new treatments for heart attacks, methods to protect hearts during open heart surgery, organ transplants, stroke and other situations in which blood flow is interrupted.
Their current paper describes how Alda-1 activates the ALDH2 enzyme in a process that Dr. Hurley likens to a woodworking procedure in which Alda-1 attaches to the ALDH2 enzyme at a crucial spot and acts like a shim or wedge to prop it up.