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Repairing Aldehyde Dehydrogenase 2 - ALDH2

Sun, 10th Jan 2010

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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. red wineThis 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 journal Nature 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.



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Oesophagectomy is also used therapeutically in this country as a way to manage oesophageal cancer. A segment of bowel can be used to bridge the excised (cancerous) section.

Unfortunately, the outcomes for patients with this type of tumour are quite poor. The 5 year survival is of the order of 5-10%; this is because the disease usually presents quite late because it tends to become quite advanced before symptoms become apparent and consequently, by the time a patient sees a doctor, they already have significant spread.

Removing the primary tumour will often help with symptoms, but metastatic disease is usually the problem and eventual cause of death, and this has invariably occurred by the time of presentation. chris, Thu, 21st Jan 2010

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