A5047831492- Carbohydrate Chemistry and Synthesis
- Lysosomal Storage Disorders Research
- Trypanosoma species research and implications
- Enzyme Production and Characterization
- Glycosylation and Glycoproteins Research
- Synthesis and Catalytic Reactions
- Enzyme Catalysis and Immobilization
- Bacterial Genetics and Biotechnology
- Cellular transport and secretion
- Click Chemistry and Applications
- Calcium signaling and nucleotide metabolism
- Peptidase Inhibition and Analysis
- Bacteriophages and microbial interactions
- Ubiquitin and proteasome pathways
- Proteoglycans and glycosaminoglycans research
- Antibiotic Resistance in Bacteria
- Natural Antidiabetic Agents Studies
- Enzyme Structure and Function
- Zebrafish Biomedical Research Applications
- Studies on Chitinases and Chitosanases
- Research on Leishmaniasis Studies
- Probiotics and Fermented Foods
- Pancreatic function and diabetes
- Adenosine and Purinergic Signaling
- SARS-CoV-2 and COVID-19 Research
Leiden University
2016-2025
Universidad Complutense de Madrid
2012-2021
Scripps Research Institute
2017
Universidad Autónoma de Madrid
2015
Centre for Biomedical Network Research on Rare Diseases
2015
Consejo Superior de Investigaciones Científicas
2015
Centro de Biología Molecular Severo Ochoa
2015
Research Institute Hospital 12 de Octubre
2015
Ikerbasque
2015
Biogipuzkoa Health Research Institute
2015
Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role these tumor physio-pathology is still unknown. We analyzed CB2 receptor protein expression two series 166 and 483 breast samples operated University Hospitals Kiel, Tübingen, Freiburg between 1997 2010 mRNA previously published DNA microarray datasets. The oncogenesis was studied by generating a mouse line that expresses human V-Erb-B2 Avian...
It is increasingly clear that interindividual variability in human gut microbial composition contributes to differential drug responses. For example, gastrointestinal (GI) toxicity not observed all patients treated with the anticancer irinotecan, and it has been suggested this a result of differences types levels bacterial β-glucuronidases (GUSs). GUS enzymes promote by hydrolyzing inactive drug–glucuronide conjugate back active drug, which damages GI epithelium. Proteomics-based...
Fatty acid synthase (FASN) is a lipogenic enzyme that highly expressed in different human cancers. Here we report the development of new series polyphenolic compounds 5-30 have been evaluated for their cytotoxic capacity SK-Br3 cells, breast cancer cell line with high FASN expression. The an IC(50) < 50 μM tested ability to inhibit activity. Among them, derivative 30 blocks 90% activity at low concentration (4 μM), broad panel tumor induces apoptosis, and activation HER2, AKT, ERK pathways....
The diterpenoid ester ingenol mebutate (IngMeb) is the active ingredient in topical drug Picato, a first-in-class treatment for precancerous skin condition actinic keratosis. IngMeb proposed to exert its therapeutic effects through dual mode of action involving (i) induction cell death that associated with mitochondrial dysfunction followed by (ii) stimulation local inflammatory response, at least partially driven protein kinase C (PKC) activation. Although this model has been well...
Cell division protein FtsZ is the organizer of cytokinetic Z-ring in most bacteria and a target for new antibiotics. assembles with GTP into filaments that hydrolyze nucleotide at association interface between monomers then disassemble. We have replaced FtsZ's non-nucleotide synthetic inhibitors bacterial division. searched these small molecules among compounds from literature, virtual screening (VS), our in-house library (UCM), employing fluorescence anisotropy primary assay. From screens...
Glucocerebrosidase (GBA) is a lysosomal β-glucosidase-degrading glucosylceramide. Its deficiency causes Gaucher disease (GD), common storage disorder. Carrying genetic abnormality in GBA constitutes at present the largest risk factor for Parkinson's (PD). Conduritol B epoxide (CBE), mechanism-based irreversible inhibitor of GBA, used to generate cell and animal models investigations on GD PD. However, CBE may have additional glycosidase targets besides GBA. Here, we first vivo target...
The stabilisation of recombinant glycosidases by exogenous ligands, known as pharmacological chaperones or enzyme stabilisers, has recently garnered great clinical interest. This strategy can prevent degradation in the blood, reducing required dosages and extending IV injection intervals, thereby side effects, improving patient lifestyles treatment costs. While this therapeutic approach been successfully implemented for treating Pompe Fabry diseases, studies Gaucher disease using alone...
Macrophages are specialised cells that degrade a range of substrates during their lifetime. In inherited lysosomal storage disorders, particularly the sphingolipidoses, macrophages transform into and contribute to pathology. An appropriate cultured macrophage model is desired for fundamental research assessment considered therapeutic interventions. We compared commonly used cell lines, RAW264.7, J774A.1, THP-1 cells, with human monocyte-derived (HMDMs) isolated from peripheral blood....
The aim of the present study was to characterise a mouse model airways inflammation induced by cigarette smoke and compare it with lipopolysaccharide (LPS) regards efficacy PDE4 inhibitor (cilomilast), corticosteroid (dexamethasone) macrophage metalloelastase (MMP)-12 gene deletion. Cigarette exposure for 3 days time-dependent airway neutrophilia associated an increased level keratinocyte-derived chemokine (KC), inflammatory protein (MIP)-2, MIP-1α MMP-9 in bronchoalveolar lavage (BAL). LPS...
The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for development new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired application cyclic sulfates as electrophilic equivalents in organic synthesis, we sought test whether cyclophellitol cyclosulfates would similarly act irreversible...
The assembly switch of cell division protein FtsZ monitored with a fluorescent probe targeting the cleft between domains.
Identifying and characterizing the enzymes responsible for an observed activity within a complex eukaryotic catabolic system remains one of most significant challenges in study biomass-degrading systems. The debranching both hemicellulosic pectinaceous polysaccharides requires production α-l-arabinofuranosidases among wide variety coexpressed carbohydrate-active enzymes. To selectively detect identify produced by fungi grown on biomass, potential covalent inhibitors probes which mimic...
Essential cell division protein FtsZ is considered an attractive target in the search for antibacterials with novel mechanisms of action to overcome resistance problem. undergoes GTP-dependent assembly at midcell form Z-ring, a dynamic structure that evolves until final constriction cell. Therefore, molecules able inhibit its activity will eventually disrupt bacterial viability. In this work, we report new series small replace GTP and specifically FtsZ, blocking process. These synthesized...
Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and GBA constitutes the largest known genetic risk factor for Parkinson's disease. In past, animal models of have been generated treatment with mechanism-based inhibitors, conduritol B epoxide (CBE), cyclophellitol. Both compounds, however, also target other glycosidases, rendering generation interpretation such chemical knockout complicated. Here we demonstrate that cyclophellitol...
Amylases are key enzymes in the processing of starch many kingdoms life. They important catalysts industrial biotechnology where they applied in, among others, food and production detergents. In man amylases first digestion to glucose arguably also preferred target therapeutic strategies aimed at treatment type 2 diabetes patients through down-tuning assimilation. Efficient sensitive assays that report selectively on retaining amylase activities irrespective nature complexity biomaterial...
Deoxygenated cyclophellitol aziridines enable activity-based inter-class labeling of glycosidases including LC-MS/MS identification.
μ-glucosidases [GBA1 (glucocerebrosidase) and GBA2] are ubiquitous essential enzymes. Lysosomal GBA1 cytosol-facing GBA2 degrade glucosylceramide (GlcCer); deficiency causes Gaucher disease, a lysosomal storage disorder characterized by accumulation of GlcCer, which is partly converted to glucosylsphingosine (GlcSph). also may transfer glucose from GlcCer cholesterol, yielding glucosylated cholesterol (GlcChol). Here, we aimed clarify the role zebrafish Gba2 in glycosphingolipid metabolism...
Abstract The recent discovery of zinc‐dependent retaining glycoside hydrolases (GHs), with active sites built around a Zn(Cys) 3 (Glu) coordination complex, has presented unresolved mechanistic questions. In particular, the proposed mechanism, depending on Zn‐coordinated cysteine nucleophile and passing through thioglycosyl enzyme intermediate, remains controversial. This is primarily due to expected stability intermediate C−S bond. To facilitate study this atypical we report synthesis...
α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as new class reversible α-glucosidase that displays enzyme inhibitory activity by virtue its conformational mimicry substrate when bound in Michaelis complex. The α-d-glc-configured cyclophellitol 4 binds competitive manner human lysosomal acid (GAA), ER α-glucosidases, and, at higher concentrations, intestinal...