Many important natural products such as antibiotics, immunosuppressants, and cancer drugs are derived from microorganisms. They are often small proteins or peptides that are generated in the cell by non-ribosomal peptide synthetase (NRPS) enzymes. Research published today by two groups from Goethe University Frankfurt presents the structure of interactions between NRPS enzymes.
Within an NRPS, specific amino acids are taken in and then processed at each station, or module, so that in the end, peptides emerge that can be linear, cyclic, or otherwise modified. When larger peptides are synthesized, several NRPS enzymes will often operate successively—like an assembly line. The order of the “assembly line” is established by small regions called “docking domains” that connect an NRPS enzyme with the appropriate neighboring NRPS enzyme.
Although the basic principles of these NRPS interactions have been known for a long time, the structure of the docking domains has been unknown until now.
"We were able to determine the structures of individual docking domains and, for the first time, an NRPS docking domain pair as well," explains co–first author Carolin Hacker. Xiaofeng Cai, also co–first author, adds that "this made it possible to clarify the rules for the interaction of the docking domains and to change them in such a way that new natural products will be generated.”
Co–senior author Jens Wöhnert stresses that they are only at the beginning of their research. “We need structures of additional and structurally diverse docking domains so that in the end we can utilise them like building blocks,” says Wöhnert. “Our goal is to connect various biosynthesis pathways and create totally new substances."
According to co–senior author Helge Bode, "Nature has been quite inventive in this area, and there are apparently numerous different ways to mediate the interaction of these complexes.”