Proteins and nucleic acids are molecules that underlie all biological processes. They are very different in their properties, and combining them into a single hybrid molecule would create a valuable tool for genetics and medicine. Usually, “DNA-protein hybrids” are obtained through time-consuming organic synthesis, but the authors of the new paper found a much simpler way using bacteria.

All molecular biology is based on three “whales”, that is, types of biomolecules: DNA, RNA, and proteins. Each has its own important properties that you might sometimes want to combine, but hybrids based on such different molecular structures are rare in nature. Some scientists believe that half-protein-half-nucleotides may have been important in the early stages of evolution and the origin of life, but there is no evidence of this in the modern cell. At the same time, similar hybrids, such as peptide nucleic acids (PNA), are obtained by chemical synthesis.

A significant step forward was the published result. Nature Chemical BiologyThe article describes a new class of molecules (peptide-nucleobase hybrids) that combine components of nucleic acids and proteins. It contains a pyrimido structure similar to the molecule from which DNA and RNA bases are synthesized in the cell.

Initially, scientists tried to find new protein molecules capable of binding metal ions using bacteria. One of the molecules obtained had the target properties, but it turned out that it was not a protein, but a hybrid of two types of biomolecules. Later, the authors discovered the molecular mechanisms that led to such a happy coincidence. It turned out that the synthesis of the hybrid involves ribosomes, the “protein factories” found in any cell, as well as the pathway of post-translational modifications of RiPP proteins. Thanks to special enzymes, it modifies the molecule after it is formed on the ribosome.

The synthesis of hybrids consists of two stages: first, the dehydrogenase enzyme complex, which includes RRE and YcaO proteins, catalyzes the conversion of asparagine amino acid residues in the original peptide into a six-membered pyrimidine ring (heterocyclic compound whose backbone consists of carbon and nitrogen atoms). Then, the acylesterase enzyme recognizes a specific site at the end of the last synthesized peptide and cuts it. The starting compound of this reaction accelerates its course: histidine amino acid residues help to convert asparagines of the same peptide into heterocycles.

All reactions were performed in a test tube using just three components: the original polypeptide and two enzymes. The authors then performed the same transformations in Escherichia coli, a well-studied, easily cultivated bacterium. E. coli.

Obtaining such a complex and unusual compound with the help of bacterial metabolism is much easier and cheaper than organic synthesis. The new method opens up the possibility of mass production of hybrid molecules and their widespread application in practice, especially in medicine. This is possible because they can combine the properties of DNA or RNA (they can selectively bind to certain areas of nucleic acids) with the specific activity of proteins. With the help of hybrid molecules it is possible to target the molecular mechanisms of the development of many diseases.