Proteins called megaenzymes play an active role in creating many common antibiotics, such as penicillin and cyclosporin.
Scientists recently took a series of 3D images of a large section from one of these enzymes in action.
They say it’s possible the images could provide a clearer picture of how antibiotics are made and perhaps pave the way for newer, more effective medications.
“This is the most complete view we’ve ever had of these enzymes in action,” says Martin Schmeing, a biochemistry professor at McGill University and senior author of a paper in Nature. “Even though megaenzymes are the second-biggest proteins known to man, they are still very small molecules and they are very mobile, so it’s difficult to see them at work.”
The enzymes the researchers are imaging are called nonribosomal peptide synthetases (or NRPSs) and act as catalysts inside specific bacteria, giving them the ability to kill all their competing bacteria.
Chemical traps
The NRPSs work like miniature assembly lines, combining building blocks through repetitive chemical reactions. Much like automobile assembly lines, these enzyme assembly lines are made up of different work stations (called modules) that each add on one section of the drug and in the process create antibiotics with new chemical features.
Because these enzymes are too small to see and constantly in motion, Schmeing and his team used chemical traps to capture the proteins in the desired position. They then used a technique called X-ray crystallography to essentially take a series of 3D pictures of the first module of an NRPS that makes the antibiotic gramicidin.
“These 3D pictures revealed the totally remarkable way the NRPS works to synthesize its product. Parts of other NRPSs have been pictured before, but there have never been so many snapshots of the different steps of synthesis, and never pictures of NRPSs that incorporate interesting chemical modifications into the antibiotic,” says Janice Reimer, PhD student and the first author on the paper.
“These pictures reveal the exquisite way these parts repurpose and recycle their limited surfaces to interact with the rest of the enzyme. Once we understand enough, we can use modern bioengineering techniques to modify NRPSs to produce all sorts of products with designer modifications, perhaps giving a veritable treasure trove of new medicines.”
Source: McGill University
