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Cornell scientists have captured an unprecedented stage in the manufacturing process of an antibiotic-producing enzyme, opening the door to future pharmaceutical development, including antibiotics, immunosuppressants and chemotherapy drugs.
The study describes the atomic structure of an enzyme – a polyketide synthase – in two different phases of its reaction cycle. This is the first time a full polyketide synthase has been visualized, said Chris Fromme ’99, one of the study’s authors and associate professor in the Department of Molecular Biology and Genetics. The main author is Saket Bagde, a PhD student in Frommes Labor. The study “Modular Polyketide Synthase Contains Two Reaction Chambers that Operate Asynchronously” was published in the November 5th issue of Science.
Many drugs used to treat humans and animals are made from natural products produced by microbes such as bacteria and fungi. Bagde used the metaphor of an automobile assembly line to describe how enzymes build these natural substances. One module would create the frame of the car, then the next add the doors, and so on. A better understanding of this assembly line process can allow scientists to modify these processes to develop new drugs.
“If you have antibiotic-resistant bacteria that can recognize a drug by its ‘door handle’ and counteract it, you can make another drug with a different door handle,” said Bagde. “By studying exactly how the reaction works, we are paving the way for other scientists to change all of these components. The potential is enormous. “
The most surprising discovery in the synthase mapping was its shape: two copies of the enzyme associate to form a complex with two reaction chambers, so the researchers expected the enzyme complex to have a symmetrical shape. Instead, they discovered that the enzyme complex takes on an asymmetrical shape, suggesting that the assembly lines only use one reaction chamber at a time.
“This has far-reaching implications for drug development because if you modify the system when you don’t know how it actually works, you can’t make it work properly and you won’t get the product you need,” said Bagde.
This could lead to drugs that aren’t as effective as they could be or that cause unnecessary side effects, Fromme said.
The study’s authors recorded two stages on the assembly line of lasalocid-A, an antibiotic widely used to treat farm animals, using two different techniques:
- X-ray crystallography, a technique scientists have used to understand proteins for more than 60 years. Researchers make proteins crystallize and then use X-rays to image them to learn more about their structure.
- Cryo-electron microscopy, a much newer method that allows researchers to freeze molecules and then use an electron beam to take high-resolution images of them.
“With these two complementary techniques, we were not only able to confirm our results, but also take pictures of the enzyme in two different stages,” says Bagde.
Cornell bought this cryo-electron microscope in 2018, and the investment “enables us to be at the forefront of world leaders in structural biology,” said Fromme.
Co-authors of the study are Bagde and Fromme, Chu-Young Kim ’96, Professor of Chemistry and Biochemistry at the University of Texas at El Paso, and Irimpan Mathews, Senior Scientist at Stanford University’s SLAC National Accelerator Laboratory. Mathews was a postdoctoral fellow at Cornell from 1996 to 2000.
This research was supported by the National Institutes of Health and the Cornell Center for Materials Research.
Krisy Gashler is a writer for the College of Agriculture and Life Sciences.
