This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: A joint research group led by Ryo Tanifuji and Hiroki Oguri from the University of Tokyo and Yoshikazu Tanaka from Tohoku University has visualized SacC, an enzyme that plays a key role in building the complex five-ring core of safracin B. This core structure is shared with trabectedin, a drug used to treat soft tissue sarcoma.
While getting a clear picture of the enzyme in its working state is an achievement, the method pioneered during the project might have the widest reach. With its potential applicability to a broad range of related enzymes that produce medically useful compounds, the approach could open new avenues for research into not only optimizing existing compounds but also creating new ones. The findings are published in the Journal of the American Chemical Society.
The production line for the drug trabectedin starts with the bacterial compound safracin B, which the enzyme SacC assembles within the bacteria. The enzyme carries out a seven-step catalytic cascade, stitching together two new carbon-to-carbon bonds and producing a five-ring core scaffold in a single pass. "Synthesizing such a complex scaffold artificially," explains Tanifuji, "takes many carefully staged steps, tight control of conditions and a good deal of patience.
Yet, a bacterial enzyme can do it in a single pass, in water, at room temperature, getting every three-dimensional detail right. It would be a great step forward if we could borrow some of these tricks for ourselves." Enzymes in this family work like a factory assembly line. As they pass an unfinished molecule from one station to the next, their parts swing around considerably.
However, this motion makes them hard to photograph. When several are frozen in motion, each molecule gets caught in a slightly different pose, blurring the averaged image. Moreover, this enzyme is prone to clumping together in solution.
The researchers approached the problem from two sides, chemistry and structural biology, simultaneously. With their "chemist" hats on, they designed and synthesized small molecules that imitated the unfinished intermediates the enzyme made during its cascade reaction. On the structural biology side, they searched for a way to stabilize the enzyme and keep it from clumping together.
Extract — continue reading at the source.
