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Scientists reveal structural secrets of enzyme used to make popular anti-cholesterol drug
Date:5/13/2014

In pharmaceutical production, identifying enzyme catalysts that help improve the speed and efficiency of the process can be a major boon. Figuring out exactly why a particular enzyme works so well is an altogether different quest.

Take the cholesterol-lowering drug simvastatin. First marketed commercially as Zocor, the statin drug has generated billions of dollars in annual sales. In 2011, UCLA scientists and colleagues discovered that a mutated enzyme could help produce the much sought-after pharmaceutical far more efficiently than the chemical process that had been used for years and could do it better than the natural, non-mutated version of the enzyme. But no one quite knew why, until another team of UCLA researchers cracked the mystery.

Using a combination of experimental measurements and extensive computer simulations, the multidisciplinary team of researchers from three chemistry, biochemistry and chemical engineering labs at UCLA uncovered important structural features hidden in the modified enzyme that helped them unlock the secret of its efficacy. Their findings will be published in the June print edition of journal Nature Chemical Biology and are currently available online.

How the enzyme catalyst was first discovered

Simvastatin was already in widespread use when scientists found that a natural enzyme called LovD, originally harvested from a mold found in soil, could react and produce a drug similar to simvastatin. Yet as a catalyst, its rate of reaction was too low for commercial manufacturing.

So UCLA professor Yi Tang collaborated with scientists at Codexis Inc., a developer of industrial enzymes, and used a process called "directed evolution" to create a mutated version of the enzyme that was better, faster and more stable for industrial use.

"Directed evolution is a laboratory technique that mimics the natural evolution process but in a much more rapid fashion," said Tan
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Contact: Stuart Wolpert
swolpert@support.ucla.edu
310-206-0511
University of California - Los Angeles
Source:Eurekalert  

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