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

g, who holds dual appointments in the department of chemistry and biochemistry and the department of chemical and biomolecular engineering.

Tang's laboratory and the Codexis team created randomly mutated versions of LovD, each with a slightly different sequence of amino acids that altered its basic form and function. The team then selected those enzymes most capable of producing simvastatin and repeated the process to further enhance their reactivity.

After nine rounds of directed evolution, they had identified a mutated enzyme they called LovD9, which deviates from the original LovD enzyme through 29 distinct mutations and which produces simvastatin 1,000 times more efficiently than the natural enzyme.

"Simvastatin has several complicated structural features, so trying to synthesize it chemically takes time and money," said Gonzalo Jimnez-Oss, a UCLA postdoctoral scholar and the paper's first author. "If you can produce these compounds in a straightforward manner, it is a huge improvement for drug production."

Prior to the development of the LovD9 enzyme, simvastatin had been produced through a multistep process involving expensive and hazardous chemical reagents and solvents; the introduction of LovD9 into the manufacturing process in 2012 changed all this, resulting in a far more efficient and environmentally friendly alternative to the chemical manufacturing procedure.

"Because it is an enzymatic process, no toxic chemicals or excess organic solvent are used," said Tang, who received the EPA's Presidential Green Chemistry Challenge Award in 2012 for his work with Codexis.

While making simvastatin using LovD9 provided clear advantages, the reasons why the mutated enzyme worked so much better than the natural one remained unclear. So Tang turned to colleagues Kendall Houk and Todd Yeates, both professors of chemistry and biochemistry at UCLA, to see if they could combine their expertise to come up with an expla
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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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