Activating Enzyme Instead of Blocking Protein

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The scientists hope that finally
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Such drugs would work by restoring the activity of a mutated enzyme, rather than taking the more common approach of blocking the actions of a disease-related protein. The research team reports that the compound, called Alda-1, acts much like a shim to prop up a mutated form of a key enzyme, restoring the enzyme's function.

The enzyme, called ALDH2, plays an important role in metabolising alcohol and other toxins, including those created by a lack of oxygen in the wake of a heart attack. It also is involved in the metabolism of nitroglycerin, which is used to prevent chest pain (angina) caused by restricted blood flow and oxygen to the heart.

However some people, including about 40 percent of people of East Asian descent, carry a mutated form of the ALDH2 enzyme that does not carry out its intended functions well. People with the mutated form of the enzyme are at increased risk of cardiovascular damage.

In 2008, researchers reported that in laboratory tests Alda-1 bypassed the body's usual signalling system and activated the ALDH2 enzyme directly, reducing damage to heart muscle tissue. The current paper describes how Alda-1 activates the ALDH2 enzyme in a process in which Alda-1 attaches to the ALDH2 enzyme at a crucial spot and acts like a shim or wedge to prop it up.

"Because of the mutation in the gene, parts of the protein structure become loose and floppy. Alda-1 reactivates the enzyme by propping up those parts of the structure so they regain normal function," said lead researcher Thomas Hurley.; Source: Indiana University School of Medicine