Scientists Show How Microbes Synthesize Antibiotics and Cancer Drugs
Researchers reveal how microbial enzymes assemble antibiotics and anti-cancer drugs.
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Researchers at McGill University have uncovered how microbes produce complex molecules like antibiotics and anti-cancer drugs. The team’s findings, which describe the precise mechanisms of specialized enzymes, could revolutionize drug discovery and lead to next-generation therapeutics.
The study focuses on nonribosomal peptide synthetases – large protein complexes that act like molecular “machines” to assemble small building blocks called amino acids into potent bioactive compounds. While these microbial processes have been known to exist, the exact steps remained elusive for decades.
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Subscribe for FREEVisualizing the machinery behind drug synthesis
To investigate how these enzymes operate, the team used advanced biochemical tools to capture detailed 3D images of the enzyme complexes. This approach required isolating the machines in specific configurations that revealed their working states.
“Taking 3D pictures of these massive enzymes was like solving a molecular jigsaw puzzle,”
Angelos Pistofidis
Contrary to prior assumptions, the process does not rely on general base catalysis but instead uses electrostatic stabilization in a concerted reaction pathway.
“It took years of persistence and many setbacks, but the results were worth it. For the first time, we have a smoking-gun view of how these enzymes work, and it’s not how anyone guessed.”
Dr. Martin Schmeing
Electrostatic stabilization
A chemical mechanism where interactions between charged groups stabilize a reaction, enabling specific steps in molecular assembly.Concerted reaction pathway
A type of reaction mechanism in which multiple steps occur simultaneously, rather than sequentially, leading to the desired molecular product.Implications for designing new therapeutics
Understanding how nonribosomal peptide synthetases function could significantly impact the design of novel drugs. These microbial enzymes, honed by evolution to produce bioactive molecules, could be re-engineered to create tailor-made therapies for modern medical challenges.
The findings highlight an untapped potential for harnessing these microbial systems, offering a new strategy to generate drugs with enhanced specificity or entirely novel therapeutic properties.
Advancing research on molecular machines
Beyond their immediate application in drug discovery, the methods developed during the study open new avenues for examining other complex molecular systems. The innovative techniques for imaging and analyzing these enzymes could help researchers decipher similarly intricate biological processes.
While this study provides crucial insight into the core step of antibiotic synthesis, the researchers note that their work is far from complete. Future investigations into additional 3D configurations will further illuminate the enzyme’s full potential.
Reference: Pistofidis A, Ma P, Li Z, Munro K, Houk KN, Schmeing TM. Structures and mechanism of condensation in nonribosomal peptide synthesis. Nature. 2024. doi: 10.1038/s41586-024-08417-6
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