How Small Molecule Restores Aldehyde Dehydrogenase Function

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Human Aldehyde Dehydrogenase, apo form (PDB ID = 1O05)

Human Aldehyde Dehydrogenase, apo form (PDB ID = 1O05)

The lower alcohol tolerance of some Asian groups compared with people of European descent is caused, in part, by a mutant copy of the aldehyde dehydrogenase gene, ALDH2. As well as carrying out the second step in the oxidative metabolism of alcohol, the conversion of acetaldehyde to acetic acid, ALDH2 metabolises toxic species created by lack of oxygen in the wake of a heart attack and is involved in the metabolism of nitroglycerine which is used to treat angina. People with a deficiency in the activity of ALDH2 are at increased risk of cardiovascular damage and scientists at Indiana University and Stanford University reported in 2008 that a small molecule activator of ALDH2, Alda-1, could reduce infarct size in rats if administered before ischaemic damage. In vitro, Alda-1 was found to be a particularly effective activator of the inactive form of the enzyme found in some East Asian populations, suggesting that treatment with Alda-1 could be of benefit to individuals with either wild-type or mutant ALDH2 who are subjected to cardiac ischaemia by a heart attack or by procedures such as coronary bypass surgery.

Alda-1

Alda-1

Writing in Nature Structural & Molecular Biology, the team have now described mechanistic details of the activation of ALDH2 by Alda-1, a discovery which should lead to more potent and selective analogues of Alda-1 with better promise as drug candidates to minimize ischaemic heart damage. The structures of bound Alda-1 reveal how the compound activates the wild-type enzyme and how it restores the activity of the inactive form by acting as a structural chaperone.


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