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Archive - Nov 3, 2009

Date

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.

Agent Inhibits Breast Cancer Metastasis to Bone

Researchers have reduced breast cancer metastasis to bone by using an experimental agent to inhibit ROCK (Rho-associated kinase), a protein that was found to be over-expressed in metastatic breast cancer. In a study in mice, a team of researchers from Tufts University reported that inhibiting ROCK in the earliest stages of breast cancer decreased metastatic tumor mass in bone by 77 percent and overall frequency of metastasis by 36 percent. The results suggest that ROCK may be a target for new drug therapies to reduce breast cancer metastasis. "While the primary tumor causes significant illness and requires treatment, metastasis accounts for over 90 percent of breast cancer-related deaths. There are no treatments to eradicate metastasis. Establishing ROCK's role in the spread of breast cancer and identifying agents to inhibit ROCK brings us one step closer to an approach that might reduce metastasis in the future," said senior author Dr. Michael Rosenblatt. Breast cancer is the second leading fatal cancer in women, and affects just under one in eight women in the United States. Bone is the most common site of breast cancer metastasis, affected three times more often than the lungs or liver. The study was published online on November 3 in Cancer Research. [Press release] [Cancer Research abstract]