Project Details
Projekt
Chemo-enzymatic platform for the discovery of natural and functionalized sactipeptides
Applicant
Professor Dr. Harald Kolmar
Subject Area
Biochemistry
Term
from 2017 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 379070300
Sactipeptides are members of a family of small proteins of bacterial origin. Their coding sequence is organized in gene clusters that encode enzymes required for the postsynthetic modification of these ribosomally synthesized miniproteins. Their hallmark is the presence of at least one intramolecular thioether bridge that is formed by the linkage of a cysteine thiol with the alpha carbon atom of a partner amino acid. Through this very uncommon linkage, biomolecules with only a few dozens of amino acids in length are formed that display extraordinary chemical stability and conformational rigidity. Sactipeptides often show antibacterial activity and therefore are potential candidates for their use as antibiotics. Numerous putative sactipeptides have been identified in bacterial genomes through database mining. Only for five sactipeptides the details of their thioether linkages are known. The main goal of the proposed project is the in depth characterization of up to now unexplored sactipeptides by application of a combination of methods of molecular biology, biochemistry, and peptide chemistry. This knowledge will be used for the generation of sactipeptides with novel functionalities using protein design and directed protein evolution strategies. Sactipeptides with tailor-made affinities towards disease-related target molecules have not been described to date. A prerequisite of their successful generation is a detailed knowledge about the molecular recognition of sactipeptide precursor proteins by the respective sactionine synthase enzyme that serves as tool for the chemo-enzymatic synthesis of non-natural sactipeptides. As a consequence, sequence and structure parameters of sactipeptide precursor recognition by the thioether forming enzymes will also be investigated in the frame of this project.
DFG Programme
Priority Programmes
