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The compound Alda-1 repairs a common enzyme mutation. Without this repair those affected by the mutation can have a debilitating reaction to alcohol that increases their risk of certain types of cancer and may even promote some neurodegenerative diseases. Now, X-ray crystallography has revealed important details about how the compound operates and opens up its use as a novel drug lead for pharmaceutical intervention. Alda-1, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide, is an activator of the enzyme ALDH2 (aldehyde dehydrogenase 2), which as the enyzme's name would suggest is involved in converting acetaldehyde, a by-product of alcohol metabolism, into its oxidized form acetate (acetic acid, in other words). As such, ALDH2 is the second enzyme of the major oxidative pathway of alcohol metabolism. It also removes other toxic aldehydes of metabolic and environmental origin, that accumulate continuously in the body. Most Caucasians have two active versions of ALDH2 - a mitochondrial form and a cytosolic form. However, almost half of all Asians and some other people have a point mutation in the mitochondrial copy of this enzyme. This results in an accumulation of toxic and DNA-damaging acetaldehyde as the alcohol they drink is only partially metabolized. The effects include facial flushing even after consumption of a small amount of alcohol, intense nausea, drowsiness, headache, a rapid heartbeat, and other unpleasant symptoms. While such flushing effects usually discourage people with the mutation from drinking alcohol, peer pressure often overrides self-preservation. This leads to an increased risk of long-term health problems for those populations, some 1 billion people worldwide, affected by the enzyme mutation. The mutation also carries with it the problem of an increased cancer risk and reduced effectiveness of the angina drug nitroglycerin. Indeed, its wider role emerged as recent data suggested that ALDH2 is involved in cardiovascular disease through, among other things, its ability to bioactivate nitroglycerin as an anti-anginal and its role in the cardioprotective effects of ethanol before myocardial infarction. Now, Thomas Hurley of the University School of Medicine in Indianapolis and Daria Mochly-Rosen, of Stanford University School of Medicine, and colleagues have studied an experimental compound, Alda-1, which apparently remedies the defective enzyme by acting as a chaperone. Details of the study are published in the January issue of Nature Structural and Molecular Biology and point to the possibility of a treatment for reducing health problems associated with the enzyme defect. Mochly-Rosen and colleagues carried out preliminary investigations with Alda-1 and now a more detailed structural study has shed light on its activity. "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," explains Hurley. In a series of experiments that examined the interaction between Alda-1 and the defective ALDH2 enzyme, 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, Hurley explains. 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," Hurley says. "This insight will lead to the modification of Alda-1 to improve its potency, and also opens up the possibility of designing new analogues that can selectively affect the metabolism of other molecules that are detoxified by aldehyde dehydrogenase." The team adds that the study is not only pertinent to ALDH2. "It may be possible to rationally design similar molecular chaperones for other mutant enzymes by exploiting the binding of compounds to sites adjacent to the structurally disrupted regions, thus avoiding the possibility of enzymatic inhibition entirely independent of the conditions in which the enzyme operates," the team concludes. "Alda-1 would be classified as a lead compound," Hurley told SpectroscopyNOW, "ie something that we will use as the starting point for newer - hopefully more efficacious and more soluble - compounds to be designed and tested. I doubt there will anything ready for clinical application for 7-10 years, unless we get really lucky here in the next year with our analog design and testing," he added.
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