A5059281644- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Sirtuins and Resveratrol in Medicine
- Chemical Synthesis and Analysis
- Protein Degradation and Inhibitors
- Autophagy in Disease and Therapy
- Monoclonal and Polyclonal Antibodies Research
- Advanced Biosensing Techniques and Applications
- Advanced Proteomics Techniques and Applications
- Click Chemistry and Applications
- Biochemical and Structural Characterization
- Glycosylation and Glycoproteins Research
- Calcium signaling and nucleotide metabolism
- Ubiquitin and proteasome pathways
- Neuropeptides and Animal Physiology
- Synthesis and Catalytic Reactions
- Mass Spectrometry Techniques and Applications
- Toxin Mechanisms and Immunotoxins
- vaccines and immunoinformatics approaches
- PARP inhibition in cancer therapy
- Protein Structure and Dynamics
- Epigenetics and DNA Methylation
- Biochemical effects in animals
- HIV Research and Treatment
Martin Luther University Halle-Wittenberg
2016-2025
Stiftung des öffentlichen Rechts an der Martin-Luther-Universität Halle-Wittenberg
2024-2025
Luther University
2011-2025
Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
2018
Steinbeis Foundation
2014
JPT Peptide Technologies (Germany)
2005-2013
Charité - Universitätsmedizin Berlin
2011
University of Rostock
2009
Karolinska Institutet
2009
Swedish Institute
2009
Pin1 is an essential and conserved mitotic peptidyl-prolyl isomerase (PPIase) that distinct from members of two other families conventional PPIases, cyclophilins FKBPs (FK-506 binding proteins). In response to their phosphorylation during mitosis, binds regulates a highly set proteins overlaps with antigens recognized by the mitosis-specific monoclonal antibody MPM-2. here shown be phosphorylation-dependent PPIase specifically recognizes phosphoserine-proline or phosphothreonine-proline...
Significance Sirtuin enzymes regulate metabolism and stress responses through deacetylation of specific protein lysine residues. Sirtuins are considered attractive drug targets, but selective inhibitors rare, their mechanisms mostly unknown. We report the mechanism inhibition by Ex-527, a potent Sirt1 inhibitor widely used in physiological studies. A set Sirtuin/ligand crystal structures, together with activity binding data, reveals that compound inhibits forming trimeric complex NAD +...
In liver the mitochondrial sirtuin, SIRT5, controls ammonia detoxification by regulating CPS1, first enzyme of urea cycle. However, while SIRT5 is ubiquitously expressed, cycle and CPS1 are only present in and, to a minor extent, kidney. To address possibility that involved production also nonliver cells, clones human breast cancer cell lines MDA-MB-231 mouse myoblast C2C12, overexpressing or silenced for were produced. Our results show increased SIRT5-silenced decreased SIRT5-overexpressing...
Abstract Sirtuins are a highly conserved class of NAD + -dependent lysine deacylases. The human isotype Sirt2 has been implicated in the pathogenesis cancer, inflammation and neurodegeneration, which makes modulation activity promising strategy for pharmaceutical intervention. A rational basis development optimized inhibitors is lacking so far. Here we present high-resolution structures complex with selective drug-like that show unique inhibitory mechanism. Potency unprecedented selectivity...
A direct measure of intramolecular chain diffusion is obtained by the determination triplet–triplet energy-transfer rates between a donor and an acceptor chromophore attached at defined points on polypeptide chain. Single exponential kinetics contact formation are observed nanosecond time scale for polypeptides in which linked repeating units glycine serine residues. The depend number peptide bonds ( N ) separating show maximum shortest peptides = 3) with constant τ 1/ k 20 ns. This sets...
Histone deacetylase 11 (HDAC11) is a sole member of the class IV HDAC subfamily with negligible intrinsic deacetylation activity. Here, we report in vitro profiling HDAC11 deacylase activities, and our data unequivocally show that enzyme efficiently removes acyl moieties spanning 8–18 carbons from side chain nitrogen lysine residue peptidic substrate. Additionally, N-linked lipoic acid biotin are removed by enzyme, although lower efficacy. Catalytic efficiencies toward dodecanoylated...
Sirtuins are protein deacylases regulating metabolism and stress responses, implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 sought as chemical tools potential therapeutics, such cancer. Activators available Sirt1 exploit its unique N-terminus, whereas drug-like Sirt2-7 lacking. We synthesized screened pyrrolo[1,2-a]quinoxaline derivatives, yielding first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound...
Members of the SH2 domain family modulate signal transduction by binding to short peptides containing phosphorylated tyrosines. Each displays a distinct preference for sequence context residue. We have developed high-density peptide chip technology that allows probing affinity most domains large fraction entire complement tyrosine phosphopeptides in human proteome. Using this technique, we experimentally identified thousands putative SH2-peptide interactions more than 70 different domains....
Sirtuins are protein deacetylases used as therapeutic targets. Pharmacological Sirt1 activation has been questioned since the in vitro activator resveratrol failed to stimulate deacetylation of several physiological substrates. We tested influence substrate sequence by analyzing effects on Sirt1-dependent 6802 acetylation sites using peptide microarrays. Resveratrol stimulated a small set and inhibited another set, whereas most substrates were hardly affected. Solution assays confirmed these...
Sirtuins are evolutionary conserved NAD+-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria regulates fatty acid apoptosis. In contrast the mitochondrial deacetylase Sirt3 desuccinylase Sirt5, no prominent deacylase activity structural information available Sirt4. Here we describe acyl substrates crystal structures enzyme shows...
HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of shares low sequence identity other HDAC isoforms, which makes conventional homology modeling less reliable. AlphaFold machine learning approach that can predict the 3D proteins high accuracy even in absence similar structures. However, fact models are predicted small molecules and ions/cofactors complicates their utilization for drug design. Previously, we optimized an model by adding...
Proline residues provide a backbone switch in polypeptide chain, which is controlled by the cis/trans isomerization about peptidyl-prolyl bond. Phosphorylation of serine- and threonine-proline motifs has been shown to be critical regulatory event for many proteins. The biological significance these further highlighted discovery novel essential isomerase Pin1. Pin1 required progression through mitosis via catalyzing phosphorylated Ser/Thr-Pro specifically present mitosis-specific...
We present results on the identification and molecular characterization of conformers with secondary cis amide peptide bonds for a number oligopeptides containing tyrosine phenylalanine in aqueous solution. Employing 1H NMR techniques, adjacent to aromatic amino acid were found generate isomer population ranging from 0.1% 1% dependence chain length ionization state peptide. The rate constant trans → interconversion zwitterionic Ala-Tyr was 2.4 × 10-3 s-1 at 298 K thus range typical imidic...
Sirtuins are protein deacylases regulating metabolism and aging processes, the seven human isoforms considered attractive therapeutic targets. transfer acyl groups from lysine sidechains to ADP-ribose, formed cosubstrate NAD+ by release of nicotinamide, which in turn is assumed be a general Sirtuin inhibitor. Studies on regulation have been hampered, however, shortcomings available assays. Here, we describe mass spectrometry–based, quantitative deacylation assay not requiring any substrate...
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with pathogenesis cancer neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report design, synthesis, biological characterization first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools inhibition deacetylation. Using biochemical
The rotational barriers for cis/trans isomerization of different proline analogues have been investigated by dynamic 1H NMR spectroscopy. To this end the (S)-azetidine-2-carboxylic acid (Aze), (S)-piperidine-2-carboxylic (Pip), (R)-thiazolidine-4-carboxylic (4-Thz), (4R)-2-methylthiazolidine-4-carboxylic (2Me4-Thz), (R)-thiazolidine-2-carboxylic (2-Thz), (S)-oxazolidine-4-carboxylic (4-Oxa), (4S,5R)-5-methyloxazolidine-4-carboxylic (5Me4-Oxa), and (2S,4R)-4-hydroxypyrrolidine-2-carboxylic...
Cis−trans isomerization of proline-like oxazolidines and thiazolidines, denoted pseudo-prolines, is investigated spectrophotometrically with a chymotrypsin coupled assay by 1H NMR. A series peptides carrying substituents varying stereochemistry at the 2-C position ΨPro was prepared for evaluating kinetic thermodynamic data pertaining to imidic bond. are shown exhibit an enhanced proline effect, allowing cis content along imide bond be tailored between 5 about 100%. These Pro surrogates may...
The AGC family of protein kinases, which includes isoforms kinase B (also known as Akt), ribosomal S6 (S6K), and serum- glucocorticoid-induced (SGK) are activated in response to many extracellular signals play key roles regulating diverse cellular processes. They by the phosphorylation T loop their domain 3-phosphoinositide-dependent kinase-1 a residue located C-terminal region termed hydrophobic motif. Recent work has implicated NIMA (never mitosis, gene A)-related kinase-6 (NEK6) enzyme...
Abstract Background The mitotic exit network (MEN) is a group of proteins that form signaling cascade essential for cells to mitosis in Saccharomyces cerevisiae . MEN has also been implicated playing role cytokinesis. Two components this pathway are the protein kinase Dbf2 and its binding partner activity, Mob1. act upstream Dbf2-Mob1 have characterized, but physiological substrates yet be identified. Results Using combination peptide library selection, phosphorylation opitmal variants,...
The peptidyl prolyl cis/trans isomerase Pin1 has been implicated in the development of cancer, Alzheimer's disease and asthma, but highly specific potent inhibitors remain to be identified. Here, by screening a combinatorial peptide library, we identified series nanomolar peptidic inhibitors. Nonproteinogenic amino acids, incorporated into 5-mer 8-mer oligopeptides containing d-phosphothreonine as central template, yielded selective that blocked cell cycle progression HeLa cells...
Abstract Sirtuins are NAD + ‐dependent deacetylases acting as sensors in metabolic pathways and stress response. In mammals there seven isoforms. The mitochondrial sirtuin 5 is a weak deacetylase but very efficient demalonylase desuccinylase; however, its substrate acyl specificity has not been systematically analyzed. Herein, we investigated carbamoyl phosphate synthetase 1 derived peptide modified the lysine side chain to determine of Sirt5. From that point designed six potent...