An experimental compound repaired a defective有缺陷的 alcohol metabolism新陈代谢 enzyme酶 that affects an estimated 1 billion people worldwide, according to research supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The findings, published Jan. 10, 2010 in the advance online edition of Nature Structural4 and Molecular5 Biology, suggest the possibility of a treatment to reduce the health problems associated with the enzyme3 defect. "This intriguing6 finding could have broad public health implications," said NIAAA Acting7 Director Kenneth R. Warren, Ph.D. "We look forward to further research aimed at translating these laboratory discoveries into possible treatments for people."
"We recently identified a molecule8 called Alda-1 that activates9 the defective1 enzyme, and in the current study, we determined10 how this activation11激活，活化作用 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 investigations12 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乙醛，醋醛, a toxic有毒的 chemical that causes DNA14 damage. Aldehyde dehydrogenase醛脱氢酶 2 (ALDH2) is the main enzyme responsible for breaking down acetaldehyde into acetate醋酸盐, a nontoxic无毒的 metabolite in the body. It also removes other toxic13 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 genetic15 mutation16 that produces an inactive form of ALDH2. When individuals with the ALDH2 mutation drink alcohol, acetaldehyde accumulates in the body, resulting in facial flushing, nausea17恶心，晕船, and rapid heartbeat. In addition to its link to increased cancer risk, the inactive form of ALDH2 also reduces the effectiveness of nitroglycerin硝酸甘油. Nitroglycerin is a drug to treat angina心绞痛，咽喉痛, 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 binds18 to the defective enzyme in a way that effectively reopens the catalytic催化剂，刺激因素 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净化，排毒 enzyme," says Dr. Hurley. "This insight will lead to the modification19 of Alda-1 to improve its potency20, and also opens up the possibility of designing new analogs that can selectively affect the metabolism2 of other molecules21 that are detoxified解毒 by aldehyde dehydrogenase."
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