Discovery of enzyme activation process could lead to new heart attack treatments

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.

"Because of the mutation in the gene, parts of the protein structure become loose and floppy. Alda-1 reactivates the enzyme 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.

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.

(Photo Credit: Eric Schoch / Office of Public and Media Relations, Indiana University School of Medicine)

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.

(Photo Credit: Eric Schoch / Office of Public and Media Relations, Indiana University School of Medicine)

Source: Indiana University School of Medicine