A5041984050- Chemical Synthesis and Analysis
- Histone Deacetylase Inhibitors Research
- Sirtuins and Resveratrol in Medicine
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Biochemical and Structural Characterization
- Antimicrobial Peptides and Activities
- Autophagy in Disease and Therapy
- Calcium signaling and nucleotide metabolism
- Crystallography and molecular interactions
- Adenosine and Purinergic Signaling
- Biochemical effects in animals
- Bacterial biofilms and quorum sensing
- Biochemical and Molecular Research
- Synthesis and Catalytic Reactions
- Biochemical Acid Research Studies
- Carbohydrate Chemistry and Synthesis
- Epigenetics and DNA Methylation
- Synthetic Organic Chemistry Methods
- RNA and protein synthesis mechanisms
- Probiotics and Fermented Foods
- Polyamine Metabolism and Applications
University of Copenhagen
2016-2025
Copenhagen University Hospital
2025
Rigshospitalet
1988-2025
Brigham Young University
2024
Division of Parasitic Diseases and Malaria
2022
Center for Global Health
2022
Centers for Disease Control and Prevention
2022
Universitair Ziekenhuis Brussel
2022
Vrije Universiteit Brussel
2022
Haukeland University Hospital
2021
Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) associated with functions that are different from widely studied acetylation. While can be introduced by acetyltransferase p300, delactylases enzymes remained unknown. Here, we report systematic evaluation zinc- and nicotinamide adenine dinucleotide–dependent deacetylases (HDACs) for their ability to cleave ε- N -L-lactyllysine marks. Our...
Highlights•Fatty acid oxidation increases global histone acetylation•Lipids can provide up to 90% of acetyl-carbon for acetylation•Octanoate reprograms metabolism and becomes the major source acetyl-CoA•Lipid-derived acetyl-CoA promotes lipid-specific gene expressionSummaryCells integrate nutrient sensing coordinate proper cellular responses a particular source. For example, glucose drives expression program characterized by activating genes involved in its metabolism, part increasing...
GeneDB (http://www.genedb.org) is a genome database for prokaryotic and eukaryotic pathogens closely related organisms. The resource provides portal to sequence annotation data, which primarily generated by the Pathogen Genomics group at Wellcome Trust Sanger Institute. It combines data from completed ongoing projects with curated annotation, readily accessible web based resource. development of in recent years has focused on providing database-driven tools pipelines, as well catering...
Abstract Lysine l -lactylation (K -la ) is a novel protein posttranslational modification (PTM) driven by -lactate. This PTM has three isomers: K , N -ε-(carboxyethyl)-lysine ce and d -lactyl-lysine ), which are often confused in the context of Warburg effect nuclear presence. Here we introduce two methods to differentiate these chemical derivatization high-performance liquid chromatography analysis for efficient separation, isomer-specific antibodies high-selectivity identification. We...
Fooling enzymes with mock amides: Analogues of apicidin, a cyclic-tetrapeptide inhibitor histone deacetylase (HDAC), were designed 1,4- or 1,5-disubstituted 1,2,3-triazole in place backbone amide bond to fix the question either trans-like cis-like configuration. Thus, binding affinity distinct peptide conformations (see picture) could be probed. One analogue proved some cases superior apicidin as an HDAC inhibitor.
Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, β-peptoids (N-alkyl-β-alanines), has found use in a variety biologically compounds but been sparsely studied with respect to folding propensity. Thus, we here report an investigation effect structural variations on cis-trans amide bond rotamer equilibria selection monomer model systems. In addition various side chain effects, which...
Systematic screening of the activities eleven human zinc-dependent lysine deacylases against a series fluorogenic substrates (see scheme) as well kinetic evaluation revealed for screenings histone deacetylases HDAC10 and HDAC11 at reasonably low enzyme concentrations. Furthermore, HDAC3 in complex with nuclear receptor corepressor 1 (HDAC3–NCoR1) was shown to harbor decrotonylase activity vitro.
Protein lysine posttranslational modification by an increasing number of different acyl groups is becoming appreciated as a regulatory mechanism in cellular biology. Sirtuins are class III histone deacylases that use NAD+ co-substrate during amide bond hydrolysis. Several studies have described the sirtuins sensors NAD+/NADH ratio, but it has not been formally tested for all mammalian vitro. To address this problem, we first synthesized wide variety peptide-based probes, which were used to...
For a long time, peptides were considered unsuitable for drug development due to their inherently poor pharmacokinetic properties and proteolytic susceptibility. However, this paradigm has changed significantly in the past decade with approval of numerous antibodies proteins as drugs. In parallel, research field synthetic molecules that are able mimic or complement folding patterns exhibited by biopolymers, but not recognized proteases, have received considerable attention well. Such...
Staphylococci are associated with both humans and animals. While most non-pathogenic colonizers, Staphylococcus aureus is an opportunistic pathogen capable of causing severe infections. S. virulence controlled by the agr quorum sensing system responding to secreted auto-inducing peptides (AIPs) sensed AgrC, a two component histidine kinase. loci found also in other staphylococcal species for epidermidis, encoded AIP represses expression regulated genes aureus. In this study we aimed...
The sophistication of proteomic analysis has revealed that protein lysine residues are posttranslationally modified by a variety acyl groups. Protein acetylation regulates metabolism, gene expression, and microtubule formation been extensively studied; however, the understanding biological significance other posttranslational modifications (PTMs) is still in its infancy. acylation mediated either acyltransferase "writer" enzymes or nonenzymatic mechanisms hydrolase enzymes, termed "erasers",...
Leaving marks: The number of known posttranslational modifications for lysine has been expanded considerably. In addition to acetylation side-chain amino functionalities residues in proteins, crotonylation, succinylation, and malonylation have now identified as histone non-histone proteins.
Abstract β-Peptoids are peptidomimetics based on N -alkylated β-aminopropionic acid residues (or -alkyl-β-alanines). This type of peptide mimic has previously been incorporated in biologically active ligands and hypothesized to be able exhibit foldamer properties. Here we show, for the first time, that β-peptoids can tuned fold into stable helical structures. We provide high-resolution X-ray crystal structures homomeric β-peptoid hexamers, which reveal right-handed conformations with exactly...
The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery most potent inhibitor 5 (SIRT5) reported to date. We provide rationalization mode binding solving co-crystal structures selected inhibitors complex with both human zebrafish SIRT5, which insight for future optimization more "drug-like" properties. Importantly,...
Abstract We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence SIRT5 is genotype agnostic extends to RAS- p53-mutated AML. Results were comparable between knockdown inhibition using NRD167, potent selective inhibitor. Apoptosis induced by disruption preceded reductions oxidative phosphorylation glutamine...
Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl from post-translationally modified lysine residues. Here, we developed small peptide-based inhibitors of its activity in living cells culture.
The sirtuin enzymes are a family of lysine deacylases that regulate gene transcription and metabolism. Sirtuin 5 (SIRT5) hydrolyzes malonyl, succinyl, glutaryl ϵ-N-carboxyacyllysine posttranslational modifications has recently emerged as vulnerability in certain cancers. However, chemical probes to illuminate its potential pharmacological target have been lacking. Here we report the harnessing aryl fluorosulfate-based electrophiles an avenue furnish covalent inhibitors SIRT5. Alkyne-tagged...