Molecule repairs alcohol metabolism enzyme

"We recently identified a molecule called Alda-1 that activates the defective enzyme, and in the current study, we determined how this activation is achieved," said the study's senior author, Thomas D. Hurley, Ph.D., professor and associate chairman of biochemistry and molecular biology at Indiana University School of Medicine in Indianapolis. Initial investigations of Alda-1 were led by co-author Daria Mochly-Rosen, Ph.D., professor of chemical and systems biology at Stanford University School of Medicine.

After alcohol is consumed, it is first metabolized, or broken down, into acetaldehyde, a toxic chemical that causes DNA damage. Aldehyde dehydrogenase 2 (ALDH2) is the main enzyme responsible for breaking down acetaldehyde into acetate, a nontoxic metabolite in the body. It also removes other toxic aldehydes that can accumulate in the body.

About 40 percent of the East Asian population, and many people of East Asian descent throughout the world, carry a genetic mutation that produces an inactive form of ALDH2. When individuals with the ALDH2 mutation drink alcohol, acetaldehyde accumulates in the body, resulting in facial flushing, nausea, and rapid heartbeat. In addition to its link to increased cancer risk, the inactive form of ALDH2 also reduces the effectiveness of nitroglycerin. Nitroglycerin is a drug to treat angina, chest pain that occurs when the heart doesn't get enough oxygen-rich blood.

In a series of experiments that examined the interaction between Alda-1 and the defective ALDH2 enzyme, Dr. Hurley and his colleagues found that Alda-1 restored the structure of the inactive enzyme. The normal, active form of ALDH2 creates a catalytic tunnel, a space within the enzyme in which acetaldehyde is metabolized, explained Dr. Hurley. In the defective enzyme, the tunnel does not function properly. Alda-1 binds to the defective enzyme in a way that effectively reopens the catalytic tunnel and thus allows the enzyme to metabolize acetaldehyde.

"The manner in which Alda-1 binds to the structure of ALDH2 provides us with powerful insight into the relationships between activators and inhibitors of this crucial detoxifying enzyme," says Dr. Hurley. "This insight will lead to the modification of Alda-1 to improve its potency, and also opens up the possibility of designing new analogs that can selectively affect the metabolism of other molecules that are detoxified by aldehyde dehydrogenase."