Syndicate content

Reconstitution of Enzyme Synthesizing Lovastatin Precursor

Researchers from UCLA, and colleagues, have for the first time successfully reconstituted in the laboratory the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. "In this study, we studied the enzyme that makes a small-molecule precursor to lovastatin. And what's really different about this enzyme, compared to all other enzymes people have studied, is that this enzyme is extraordinarily large," said Dr. Yi Tang, senior author of the study. "It's one of the largest enzymes ever to be reconstituted in a test tube. It is ten times the size of most enzymes people study." The enzyme used in Dr. Tang's study has seven active sites and catalyzes more than 40 different reactions that eventually result in an important precursor to lovastatin. Dr. Tang's team has been able to recapture all of the steps needed to make the lovastatin precursor molecule. "It's like having an assembly line with seven stations, and in one round you have to go through a combination of these seven stations. Remarkably, this enzyme uses the assembly line eight times to make this small molecule—every time, it uses a different combination of the individual stations," Dr. Tang said. "So the large enzyme is programmed to utilize these stations differentially at every cycle, in different combinations, and now we can do it in a test tube." And with this, Dr. Tang hopes they will be able to disrupt, tweak, and change some of the steps to make slightly different molecules that can be just as beneficial. "It's biosynthetic engineering of an assembly line to make a molecule that nature doesn't make,” Dr. Tang said. “So our eventual goal, once we understand how the enzyme works, is to rationally manipulate the individual stations or manipulate how a set of stations is used in each iteration to generate new compounds that nature doesn't make that will result in new activities, new molecules." This report was published in the October 23 issue of Science. [Press release] [Science abstract]