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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Krammer, L; Darnhofer, B; Kljajic, M; Liesinger, L; Schittmayer, M; Neshchadin, D; Gescheidt, G; Kollau, A; Mayer, B; Fischer, RC; Wallner, S; Macheroux, P; Birner-Gruenberger, R; Breinbauer, R.
A general approach for activity-based protein profiling of oxidoreductases with redox-differentiated diarylhalonium warheads
CHEM SCI. 2025;
Doi: 10.1039/d4sc08454c
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- Führende Autor*innen der Med Uni Graz
- Birner-Grünberger Ruth
- Darnhofer Barbara
- Co-Autor*innen der Med Uni Graz
- Liesinger Laura
- Schittmayer-Schantl Matthias
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- Abstract:
- Activity-based protein profiling (ABPP) is a unique proteomic tool for measuring the activity of enzymes in their cellular context, which has been well established for enzyme classes exhibiting a characteristic nucleophilic residue (e.g., hydrolases). In contrast, the enzyme class of oxidoreductases has received less attention, as its members rely mainly on cofactors instead of nucleophilic amino acid residues for catalysis. ABPP probes have been designed for specific oxidoreductase subclasses, which rely on the oxidative conversion of the probes into strong electrophiles. Here we describe the development of ABPP probes for the simultaneous labeling of various subclasses of oxidoreductases. The probe warheads are based on hypervalent diarylhalonium salts, which show unique reactivity as their activation proceeds via a reductive mechanism resulting in aryl radicals leading to covalent labeling of liver proteins at several different amino acids in close proximity to the active sites. The redox potential of the probes can be tuned by isosteric replacement varying the halonium central atom. ABPP experiments with liver using 16 probes differing in warhead, linker, and structure revealed distinct overlapping profiles and broad substrate specificities of several probes. With their capability of multi oxidoreductase subclass labeling - including rare examples for the class of reductases - and their unique design, the herein reported probes offer new opportunities for the investigation of the "oxidoreductome" of microorganisms, plants, animal and human tissues.