The Natural Drug Factory

Researchers are shining a new light on how nonribosomal peptide synthetases (NRPS) work (1). Known for their ability to make “natural product peptides” – small, but potent chemical compounds – these multienzyme nanomachines have been used to develop a variety of drugs, including immunosuppressants and antibacterials.

“NRPS act as machines, with many moving parts and reaction centers that all work together,” says Martin Schmeing, Associate Professor in the Department of Biochemistry at McGill University. “They follow an elegant sort of logic in which a subsection called a module facilitates reactions that add building blocks to a growing chemical. The enzyme then passes the (now bigger) chemical to the next module, where the next building block is added, and so on.”

But the configuration of these modules has remained elusive – until now. Using ultra-intense X-ray beams, Schmeing and his colleagues were able to visualize the NRPS’ mechanism of action, by studying an NRPS called depsipeptide synthetase “We found that the modules converted keto acids into building blocks that can be added to peptide drugs,” says Schmeing. “This helps us understand how NRPS use so many building blocks to make different compounds and therapeutics. This understanding will help us build new therapeutics from new combinations of building blocks.” The researchers believe the module subsection unexpectedly acquired portions of another enzyme through evolution, enabling it to use different building blocks in chemical synthesis. 

This knowledge should help us to begin producing more potent drugs with desired properties using NRPS. But Schmeing points out that there is still much to learn before we can fully understand these nanomachines. “In our study, there was a small, but important section of the module that was not visible in some of our experiments,” he says. “We are aiming to visualize this in the future and evaluate its contributions to NRPS function.”

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