Discovery of enzyme activation process could lead to new heart attack treatments (w/ Video)

Jan 10, 2010
Using a red pushpin, Thomas Hurley of the Indiana University School of Medicine demonstrates how a the compound Alda-1 works to restore functionality to a mutated form of the enzyme ALDH2, which plays an important role in metabolizing alcohol and other toxins in the body. Credit: Eric Schoch / Office of Public and Media Relations, Indiana University School of Medicine

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.

This video is not supported by your browser at this time.
Thomas Hurley of the Indiana University School of Medicine demonstrates how a the compound Alda-1 works to restore functionality to a mutated form of the enzyme ALDH2, which plays an important role in metabolizing alcohol and other toxins in the body. Credit: Eric Schoch / Office of Public and Media Relations, Indiana University School of Medicine

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 . 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 . That finding raised the possibility of new treatments for heart attacks, methods to protect hearts during , 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.

"Because of the mutation in the gene, parts of the protein structure become loose and floppy. Alda-1 reactivates the by propping up those parts of the structure so they regain normal function," said Dr. Hurley, director of the Center for Structural Biology on the Indiana University-Purdue University Indianapolis campus.

Determining how the Alda-1 compound works will enable the researchers to begin working on alternative compounds that hold more promise as potential drugs. One primary improvement needed is the ability to give the drug orally, rather than by injection, Dr. Hurley said.

"Based on the information from these studies, we're now ready to sit down with medicinal chemists and start designing new analogues by applying our understanding of what we need to leave alone and what we can modify to improve the properties of Alda-1," he said.

He predicted that alternative compounds could be available for testing by mid-2010.

Explore further: Driving cancer cells to suicide

Provided by Indiana University School of Medicine

4.7 /5 (3 votes)

Related Stories

Novel compound may lessen heart attack damage

Feb 07, 2008

A novel drug designed to lessen muscle damage from a heart attack has passed initial safety tests at the Duke Clinical Research Institute. Results of the study, available online and to be published in the February 19 issue ...

Gene predicts heart attack response and cardiac damage

Jan 30, 2008

A protein has been found that influences the response of the heart to a lack of oxygen and blood flow, such as occurs during a heart attack, a team of Yale School of Medicine researchers report today in Nature.

New therapy could preserve vessel function after heart attack

Sep 10, 2007

Scientists have identified the process that causes blood vessels to constrict during and after a heart attack. They've also demonstrated that delivering a vital molecule that is depleted during this process directly to those ...

Mitochondria send death signal to cardiac cells, study shows

Nov 08, 2007

Scientists have determined how cardiac cells die just as emergency treatments restore blood flow to a heart in distress, a paradox that has long puzzled doctors who are able to relieve pain in patients suffering from blocked ...

Mercury's link to heart disease begins in blood vessel walls

May 31, 2007

Heavy metals and other toxins have been linked to many human diseases, but determining exactly how they damage the body remains a mystery in many cases. New research focusing on a relatively obscure, misunderstood protein ...

Recommended for you

Driving cancer cells to suicide

57 minutes ago

Ludwig Maximilian University of Munich researchers report that a new class of chemical compounds makes cancer cells more sensitive to chemotherapeutic drugs. They have also pinpointed the relevant target ...

User comments : 0