The study sheds light on how nisin is made in nature and moves researchers closer to producing new antibiotics that would preclude the development and spread of antibiotic-resistant bacteria.
The scientists synthesized nisin simply in a test tube by using a single cyclase enzyme to re-create the process that normally occurs in a strain of the bacterium lactococcus lactis found naturally in milk. They demonstrated how just one protein (NisC) makes 10 new chemical bonds in a stereochemically defined fashion. Specifically, they showed that NisC is responsible for the formation of five characteristic thioether rings required for nisin’s biological activity.
“Despite all the progress in synthetic chemistry, we cannot come close to making a compound like nisin efficiently,” said professor Wilfred van der Donk of the University of Illinois at Urbana-Champaign. “Synthetic chemists in the past needed 67 steps to make it, while nature uses just two enzymes. One of these is the cyclase whose activity we have demonstrated in this paper.”
The thioether rings vary in size from four to seven amino acids and provide sturdy protease-resistant bonds at precise locations. They account for nisin’s robust resistance capability. It was theorized that one enzyme makes all five rings despite their very different sizes, but how it did so was not understood.
The new research also showed that NisC has unexpected structural similarities with mammalian farnesyl transferases, which are important for the activity of the RAS protein which when mutated is implicated in 25% of breast cancers. The researchers think that preventing farnesylation could possibly prevent the cancerous effects, because the mutant protein would no longer be localized at the membrane.