A5071724648- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Glycosylation and Glycoproteins Research
- Biochemical and Molecular Research
- Glutathione Transferases and Polymorphisms
- Genetics and Neurodevelopmental Disorders
- Cytokine Signaling Pathways and Interactions
- Endoplasmic Reticulum Stress and Disease
- Cancer Research and Treatments
- Protein Degradation and Inhibitors
- Organic Chemistry Cycloaddition Reactions
- Fluorine in Organic Chemistry
- Synthesis and Reactions of Organic Compounds
- RNA modifications and cancer
- Cancer, Hypoxia, and Metabolism
- Hormonal Regulation and Hypertension
- Chronic Lymphocytic Leukemia Research
- Fungal and yeast genetics research
- RNA and protein synthesis mechanisms
- Genomics, phytochemicals, and oxidative stress
- Heat shock proteins research
- ATP Synthase and ATPases Research
- Mechanisms of cancer metastasis
- Plant biochemistry and biosynthesis
- Genomics and Chromatin Dynamics
Technical University of Munich
2015-2024
Ştefan cel Mare University of Suceava
2024
Fischer (Germany)
2021-2022
Centre universitaire de médecine générale et santé publique, Lausanne
2022
University of Lausanne
2022
University Children’s Hospital Bern
2022
Ahrens (Sweden)
2022
University Hospital of Lausanne
2022
University Children's Hospital Zurich
2022
University Hospital of Geneva
2022
Abstract Biogenesis of the 20S proteasome is tightly regulated. The N-terminal propeptides protecting active-site threonines are autocatalytically released only on completion assembly. However, trigger for self-activation and reason strict conservation threonine as active site nucleophile remain enigmatic. Here we use mutagenesis, X-ray crystallography biochemical assays to suggest that Lys33 initiates nucleophilic attack propeptide by deprotonating Thr1 hydroxyl group both residues together...
A novel, highly sensitive and specific N-Terminal-proBNP (NT-proBNP) assay based on a sandwich format has been developed. The time is below 2 hours no extraction process needed. calibration curve covers NT-proBNP concentration range from 0 pmol/L up to 600 pmol/L. analytical detection limit of the was estimated be 2.7 (3 SD). intra-assay coefficient variation 5.7% (at 50 pmol/L) 6.1% 250 pmol/L), while inter-assay CVs are 15.8% (15 8.2% (250 pmol/L). There significant interference by...
Mammalian genomes encode seven catalytic proteasome subunits, namely, β1c, β2c, β5c (assembled into constitutive 20S core particles), β1i, β2i, β5i (incorporated immunoproteasomes), and the thymoproteasome-specific subunit β5t. Extensive research in past decades has yielded numerous potent inhibitors including compounds currently used clinic to treat multiple myeloma mantle cell lymphoma. Proteasome that selectively target combinations of β1c/β1i, β2c/β2i, or β5c/β5i are available, yet...
Abstract Nature provides a rich source of compounds with diverse chemical structures and biological activities, among them, sulfur‐containing metabolites from bacteria fungi. Some these bear disulfide moiety that is indispensable for their bioactivity. Specialized oxidoreductases such as GliT, HlmI, DepH catalyze the formation this bridge in virulence factor gliotoxin, antibiotic holomycin, anticancer drug romidepsin, respectively. We have examined all three enzymes by X‐ray crystallography...
Cleavage analyses of 20S proteasomes with natural or synthetic substrates allowed to infer the substrate specificities active sites and paved way for rational design high-affinity proteasome inhibitors. However, details cleavage preferences remained enigmatic due lack appropriate structural data. In a unique approach, we here systematically examined yeast human using irreversibly acting α′,β′epoxyketone (ep) Biochemical provide insights into distinct highlight differences between types that...
The formation of glutathione (GSH) conjugates, best known from the detoxification xenobiotics, is a widespread strategy to incorporate sulfur into biomolecules. biosynthesis gliotoxin, virulence factor human pathogenic fungus Aspergillus fumigatus, involves attachment two GSH molecules and their sequential decomposition yield reactive thiol groups. degradation moieties requires activity Cys-Gly carboxypeptidase GliJ, for which we describe X-ray structure here. enzyme forms homodimer with...
Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual active sites. Whereas for β1c, β1i, β5c, β5i subunits exploit differences in substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because high structural similarity these two subunits. Here, we report development, chemical synthesis, screening a compound library that led...
Abstract Proteolytischer Abbau ist ein essenzieller zellulärer Vorgang, der hauptsächlich durch das 20S‐Proteasomkernpartikel (CP), eine Protease von 720 kDa und 28 einzelnen Untereinheiten, bewerkstelligt wird. Wegen seiner zentralen Funktion Proteasom vielversprechendes Angriffsziel für Wirkstoffe, nach intensiven Untersuchungen im letzten Jahrzehnt mit Zulassung Bortezomib die US Food and Drug Administration (FDA) auch validiert worden ist. Gegenwärtig werden mehrere verbesserte...
Abstract Clinically applied proteasome inhibitors induce cell death by concomitant blockage of constitutive and immunoproteasomes. In contrast, selective immunoproteasome inhibition is less cytotoxic has the potential to modulate chronic inflammation autoimmune diseases. this study, we rationally designed decarboxylated peptides that covalently target a non‐catalytic cysteine subunit β5i with α‐chloroacetamide‐containing sidechains. The enhanced isoform specificity decreased effects compound...
The epipolythiodioxopiperazine (ETP) gliotoxin mediates toxicity via its reactive thiol groups and thereby contributes to virulence of the human pathogenic fungus Aspergillus fumigatus. Self-intoxication mold is prevented either by reversible oxidation reduced or irreversible conversion bis(methylthio)gliotoxin. latter produced S-methyltransferase TmtA attenuates ETP biosynthesis. Here, we report crystal structure in complex with S-(5′-adenosyl)-l-homocysteine. features one substrate...
Azoles are first-line therapeutics for human and plant fungal infections, but their broad use has promoted the development of resistances. Recently, a pan-azole–resistant clinical Aspergillus fumigatus isolate was identified to carry mutation P88L in subunit HapE CCAAT-binding complex (CBC), conserved eukaryotic transcription factor. Here, we define mechanistic basis resistance this by showing that interferes with CBC’s ability bend sense CCAAT motifs. This failure leads transcriptional...
Abstract Selective inhibition of the immunoproteasome is a promising approach towards development immunomodulatory drugs. Recently, class substituted thiazole compounds that combine nonpeptidic scaffold with absence an electrophile was reported in patent. Here, we investigated mode action lead compound by using sophisticated chimeric yeast model human for structural studies. The inhibitor adopts unique orientation perpendicular to β5i substrate‐binding channel. Distinct interactions between...