Researchers at McGill University's Faculty of Medicine have made important strides in understanding the functioning of enzymes that play an integral role in the production of antibiotics and other therapeutics.
"Many of the medicines that we rely on today are natural products, made by the Earth's flora," explains Dr. Martin Schmeing, Associate Professor in the Department of Biochemistry at McGill and the study's senior author. "This includes compounds made in microbes by massive enzymes called nonribosomal peptide synthetases, or NRPSs. NRPSs synthesize all sorts of antibiotics, which can kill dangerous fungi and bacteria, as well as compounds to help us fight off viral infections and cancers. For example, these compounds include viomycin, an antibiotic used for the treatment of multidrug-resistant tuberculosis; cyclosporin, which has been widely used as an immunosuppressant in organ transplants; and the familiar antibiotic penicillin."
In order to synthesize these drugsv, NRPSs operate similar to a factory assembly line, consisting of a series of workstations. Each station, called a "module," has multi-step workflows and moving parts that allow it to add one building block component to the growing drug.
For the first time, they were able to make high quality observations about how an individual module relates to the bigger assembly line, by visualizing a two-module portion of the NRPSs that makes the antibiotic linear gramicidin (found in Polysporin treatments). The study found a surprising lack of synchronisation between modules at all points other than when they must coordinate to pass the intermediate from one workstation to the next. Additionally, they found that the modules don't line up in a straight line or other organized fashion, but instead can line up in many different relative positions. "This level of massive flexibility was not expected," notes Dr. Schmeing, who is also Director of McGill's Centre for Structural Biology. "The enzymes are performing gymnastics."
Because the proteins are trapped in a crystal, care was taken to confirm that the results were representative of what happens in real life. Dr. Schmeing worked with his colleague, Dr. Alba Guarné, Professor in the Department of Biochemistry at McGill, to use complementary solution data, collected at the Advanced Light Source in Berkeley to validate the observations. "The structural biology community is very strong at McGill. We work together to help each other in collaborations, to obtain the biophysical equipment required for cutting-edge experiments, and to train our students" says Dr. Schmeing, noting that the experimentalists on the paper, Janice Reimer, Max Eivanskhani and Ingrid Harb, are all talented McGill graduate students. "The environment and colleagues at the McGill Centre for Structural Biology are important for the continued success of our labs."
The results could have implications for the production of new antibiotics and therapeutics in the long term.
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)