Repairing Aldehyde Dehydrogenase 2 - ALDH2

Scientists have found a way to repair the activity of a defective enzyme that prevents some people breaking down alcohol and which may also hold the key to preventing heart attacks and Alzheimer's disease.

Up to 1 billion people worldwide, including 40% of east Asians, carry an altered form of a gene coding for an enzyme called aldehyde dehydrogenase 2 or ALDH2 for short.This breaks down a chemical called acetaldehyde, which is one of the substances produced when alcohol is metabolised by the liver.

Shortly after consuming alcohol, individuals with the defective form of this enzyme develop symptoms of facial flushing, a rapid heartbeat and nausea, owing to the accumulation of acetaldehyde in the bloodstream. These individuals also have an increased the risk of oesophageal cancer, Alzheimer's disease and having a worse outcome from a heart attack.

Indeed, higher levels of this enzyme in heart muscle are strongly protective against heart damage and, whilst studying this, scientists recently found a drug molecule called Alda-1 that seems to be able to boost the activity of the healthy form of the enzyme and also to repair the defective enzyme; but they didn't know how it was working.

Now, writing in the journalNature Structural and Molecular Biology, scientists at Indiana University and Stanford University, led by researcher Thomas Hurley, have found out how it works, which could lead to a whole raft of new treatments.

The team have worked out the three-dimensional structure of the enzyme, at the core of which is a tunnel-like structure that breaks down molecules like acetaldehyde. But in the defective form of the enzyme this tunnel is the wrong shape, so the enzyme cannot function.

But when the Alda-1 drug molecule locks on, which occurs on a different part of the enzyme, it bends the enzyme, prising the tunnel open so that it becomes active again.

Now that scientists have discovered how the Alda-1 drug works, it should be possible to find other molecules capable of doing the job even better and with the potential to impact on many different diseases, including reducing the damage done by heart attacks.