Pathway for Bacterial Synthesis of Streptozotocin Revealed; Antibiotic Also Treatment for Pancreatic Cancer; Molecule’s Reactive “Warhead” Is Nitrosamine; Nitrosamine Reaction “Has Very Limited, If Any, Precedent in Biological or Synthetic Chemistry”

For decades, scientists and doctors have known that bacteria in soil were capable of manufacturing streptozotocin, an antibiotic compound that is also an important treatment for certain types of pancreatic cancer. What was less clear, however, was exactly how bacteria managed to do it. Led by Dr. Emily Balskus, Professor of Chemistry and Chemical Biology at Harvard University, a team of researchers has untangled that process, showing for the first time that the compound is produced through an enzymatic pathway and revealing the novel chemistry that drives the process. The study is described in an article published online on February 6, 2019 in Nature. The article is titled “An N-Nitrosating Metalloenzyme Constructs the Pharmacophore of Streptozotocin.” What makes the molecule such an effective anti-cancer agent, is a chemical structure known as a nitrosamine - what Dr. Balskus called the molecule's reactive "warhead." Known to be highly reactive, nitrosamines have been shown to be toxic in a host of other compounds, and are most commonly known outside of cancer treatment as a carcinogens found in everything from tobacco to cured meats. "This chemical motif has a great deal of biological relevance, and has been investigated thoroughly," Dr. Balskus said. "Until our work, the view of how this chemical motif was generated in biological systems involved non-enzymatic chemistry - it was just something that occurred under the right conditions." Dr. Balskus and colleagues, however, suspected the story may be more complex, and set out to explore whether bacteria evolved a natural pathway to produce nitrosamine compounds. "That's what we found in this paper," she explained.
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