Prof. Dr. Christoph Arenz

Profil

• Beihilfe zur Intensivierung bilateraler Beziehungen

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 06/2009 - 05/2010 Projektleitung: Prof. Dr. Christoph Arenz

• Chemical Chaperones for an experimental therapy of Niemann-Pick Disease - investigation in a new strategy for a pharmacological treatment of an inborn metabolic disorder

  Quelle ↗

  Förderer: Volkswagen Stiftung Zeitraum: 08/2007 - 07/2010 Projektleitung: Prof. Dr. Christoph Arenz

• Chemische Werkzeuge zur Untersuchung der Rolle der sauren Sphingomyelinase unter physiologischen und pathologischen Bedingungen

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 05/2018 - 10/2021 Projektleitung: Prof. Dr. Christoph Arenz

• Chemische Werkzeuge zur Untersuchung der Rolle der Sauren Sphingomyelinase unter physiologischen und pathologischen Bedingungen

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 05/2015 - 04/2018 Projektleitung: Prof. Dr. Christoph Arenz

• Development of novel ASM inhibitors and their application to ex vivo and in vivo lung edema models

  Quelle ↗

  Zeitraum: 05/2010 - 04/2011 Projektleitung: Prof. Dr. Christoph Arenz

• Exist-Gründerstipendium SoLaGa

  Quelle ↗

  Förderer: Bundesministerium für Wirtschaft und Energie Zeitraum: 07/2015 - 06/2016 Projektleitung: Prof. Dr. Christoph Arenz

• Inhibition der mikroRNA Reifung durch kleine Moleküle

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 03/2007 - 02/2010 Projektleitung: Prof. Dr. Christoph Arenz

• Lipid-Transportproteine als pharmakologische Zielmoleküle

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 02/2026 - 01/2029 Projektleitung: Prof. Dr. Christoph Arenz

• Lipotools - Lipide im Fokus der pharmakologischen Wirkstoffentwicklung

  Quelle ↗

  Förderer: BMWE: EXIST Zeitraum: 09/2019 - 11/2020 Projektleitung: Prof. Dr. Christoph Arenz

• Neuartige Inhibitoren der sauren und neutralen Ceramidase

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 09/2010 - 08/2013 Projektleitung: Prof. Dr. Christoph Arenz

• Single molecule RNA biology - dynamics and function of RNA from transcription to degradation

  Quelle ↗

  Förderer: Einstein Stiftung Berlin Zeitraum: 12/2013 - 11/2016 Projektleitung: Prof. Dr. Christoph Arenz

• Sphingomyelinase Sonden und Inhibitoren I

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 01/2012 - 06/2013 Projektleitung: Prof. Dr. Christoph Arenz

• Sphingomyelinase Sonden und Inhibitoren II

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 02/2010 - 11/2011 Projektleitung: Prof. Dr. Christoph Arenz

• Synthese niedermolekularer Verbindungen zur Inhibition chlamydialen Wachstums

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 06/2017 - 05/2019 Projektleitung: Prof. Dr. Christoph Arenz

• Synthese und biologische Charakterisierung von potentiellen Inhibitoren der sauren Sphingomyelinase

  Quelle ↗

  Förderer: DFG Sachbeihilfe Zeitraum: 01/2006 - 12/2008 Projektleitung: Prof. Dr. Christoph Arenz

• Science & Startups Berlin

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  15 Treffer61.2%
  • Zuwendung im Rahmen des Programms „exist – Existenzgründungen aus der Wissenschaft“ aus dem Bundeshaushalt, Einzelplan 09, Kapitel 02, Titel 68607, Haushaltsjahr 2026, sowie aus Mitteln des Europäischen Strukturfonds (hier Euro-päischer Sozialfonds Plus – ESF Plus) Förderperiode 2021-2027 – Kofinanzierung für das Vorhaben: „exist Women“
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    61.2%

• ICS Maugeri SPA

  PT

  46 Treffer61.1%
  • Surface-enhanced Raman spectroscopy in liquid biopsy for breast cancer
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    61.1%

• INL - International Iberian Nanotechnology Laboratory

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  46 Treffer61.1%
  • Surface-enhanced Raman spectroscopy in liquid biopsy for breast cancer
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    61.1%

• Johannesstift Diakonie Proclusio gGmbH

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  12 Treffer57.2%
  • Professionalisierung in der Deutsch-als-Zweitsprache-Förderung für geflüchtete Menschen mit Lernschwierigkeiten
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    57.2%

• HMU Research, Development und Innovation Erfurt gGmbH

  PT

  46 Treffer55.9%
  • FOR 5187: Personalisierte Psychotherapie für Patient*innen mit fehlendem Behandlungserfolg: Mechanismen, prädiktive Marker und klinische Anwendung
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    55.9%

• Peugeot Citroen Automobiles S.A.

  PT

  75 Treffer55.3%
  • EU: Monomer Sequence Control in Polymers: Toward Next-Generation Precision Materials (EURO-SEQUENCES)
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    55.3%

• Ionera Technologies GmbH

  PT

  76 Treffer55.3%
  • EU: Monomer Sequence Control in Polymers: Toward Next-Generation Precision Materials (EURO-SEQUENCES)
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    55.3%

• TechOnYou Srl

  PT

  61 Treffer54.1%
  • EU: Hybrid Organic/Inorganic Memory Elements for Integration of Electronic and Photonic Circuitry (HYMEC)
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    54.1%

• Bernstein Center for Computational Neuroscience Berlin

  PT

  88 Treffer53.8%
  • DFG-Sachbeihilfe: Aufmerksamkeit und sensorische Integration im aktiven Sehen von bewegten Objekten
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    53.8%
  • SFB 1315/2: Mechanismen und Störungen der Gedächtniskonsolidierung: Von Synapsen zur Systemebene
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    52.4%

• BIJO-DATA Informationssysteme GmbH

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  16 Treffer53.8%
  • NutriCheck – Frühwarnsystem zur Beurteilung der Nährstoffversorgung in Milchviehbeständen mittels Erfassung und Auswertung der Fress- und Wiederkäuaktivitäten
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    53.8%

• Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology

  2010

  Nature · 516 Zitationen · DOI

• Transformation-Associated Changes in Sphingolipid Metabolism Sensitize Cells to Lysosomal Cell Death Induced by Inhibitors of Acid Sphingomyelinase

  2013

  Cancer Cell · 333 Zitationen · DOI

• Structural insights into adiponectin receptors suggest ceramidase activity

  2017

  Nature · 211 Zitationen · DOI

• Heat shock protein–based therapy as a potential candidate for treating the sphingolipidoses

  2016

  Science Translational Medicine · 179 Zitationen · DOI

  Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla(-/-)), Sandhoff disease (Hexb(-/-)), and Niemann-Pick disease type C (Npc1(-/-)) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb(-/-) and Npc1(-/-) mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.

• Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA‐induced silencing complex (RISC) components argonaute‐1, argonaute‐2, PACT, TARBP1, and TARBP2 in epithelial skin cancer

  2011

  Molecular Carcinogenesis · 114 Zitationen · DOI

  The microprocessor complex mediates intranuclear biogenesis of precursor microRNAs from the primary microRNA transcript. Extranuclear, mature microRNAs are incorporated into the RNA-induced silencing complex (RISC) before interaction with complementary target mRNA leads to transcriptional repression or cleavage. In this study, we investigated the expression profiles of the microprocessor complex subunit DiGeorge syndrome critical region gene 8 (DGCR8) and the RISC components argonaute-1 (AGO1), argonaute-2 (AGO2), as well as double-stranded RNA-binding proteins PACT, TARBP1, and TARBP2 in epithelial skin cancer and its premalignant stage. Patients with premalignant actinic keratoses (AK, n = 6), basal cell carcinomas (BCC, n = 15), and squamous cell carcinomas (SCC, n = 7) were included in the study. Punch biopsies were harvested from the center of the tumors (lesional), from healthy skin sites (intraindividual controls), and from healthy skin sites in a healthy control group (n = 16; interindividual control). The DGCR8, AGO1, AGO2, PACT, TARBP1, and TARBP2 mRNA expression levels were detected by quantitative real-time reverse transcriptase polymerase chain reaction. The DGCR8, AGO1, AGO2, PACT, and TARBP1 expression levels were significantly higher in the AK, BCC, and SCC groups than the healthy controls (P < 0.05). There was no significant difference in the TARBP2 expression levels between groups (P > 0.05). This study indicates that major components of the miRNA pathway, such as the microprocessor complex and RISC, are dysregulated in epithelial skin cancer.

• CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

  2015

  Proceedings of the National Academy of Sciences · 95 Zitationen · DOI

  Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca(2+) mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca(2+) mobilization. Ca(2+) mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.

• Potent and Selective Inhibition of Acid Sphingomyelinase by Bisphosphonates

  2009

  Angewandte Chemie International Edition · 87 Zitationen · DOI

  More than mending bones: A simple geminal aminobisphosphonate (see picture) is the most potent selective inhibitor of the acid sphingomyelinase known to date. It can be synthesized in a one-step procedure and inhibits cell death in vitro. Since the acid sphingomyelinase is a putative drug target for inflammatory lung diseases, bisphosphonates may find application in the treatment of pulmonary diseases. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

• A Homogenous Assay for Micro RNA Maturation

  2006

  Angewandte Chemie International Edition · 86 Zitationen · DOI

  Maturation process: Micro RNAs represent a recently (re-)discovered group of regulators of gene expression. Ligands of the inactive precursor RNAs (pre-miRNAs) inhibit the formation of the respective miRNAs. Such ligands could potentially be used as tools in biomedicine. A doubly labeled RNA beacon allows simple screening of potential pre-miRNA binders. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2006/z601332_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

• Lung Endothelial Ca2+ and Permeability Response to Platelet-Activating Factor Is Mediated by Acid Sphingomyelinase and Transient Receptor Potential Classical 6

  2011

  American Journal of Respiratory and Critical Care Medicine · 85 Zitationen · DOI

  The present findings outline a new signaling cascade in the induction of PAF-induced lung edema, in that stimulation of ASM causes recruitment of TRPC6 channels to caveolae, thus allowing for Ca(2+) influx and subsequent increases in endothelial permeability that are amplified in the absence of endothelial NO synthesis.

• Small Molecule Inhibitors of Acid Sphingomyelinase

  2010

  Cellular Physiology and Biochemistry · 84 Zitationen · DOI

  Despite of the importance of the acid sphingomyelinase for sphingomyelin homeostasis and sphingolipid signalling, potent and selective inhibitors for this enzyme are rare. An increasing set of data on the inhibition of acid sphingomyelinase in different disease models using indirect inhibitors has been generated and strongly implies acid sphingomyelinase as an emerging drug target. Very recently, some new and promising inhibitors from different substance classes have been developed. In this review, previous and current developments in the field are summarized.

• Subunit composition of the mammalian serine-palmitoyltransferase defines the spectrum of straight and methyl-branched long-chain bases

  2020

  Proceedings of the National Academy of Sciences · 83 Zitationen · DOI

  Sphingolipids (SLs) are chemically diverse lipids that have important structural and signaling functions within mammalian cells. SLs are commonly defined by the presence of a long-chain base (LCB) that is normally formed by the conjugation of l-serine and palmitoyl-CoA. This pyridoxal 5-phosphate (PLP)-dependent reaction is mediated by the enzyme serine-palmitoyltransferase (SPT). However, SPT can also metabolize other acyl-CoAs, in the range of C₁₄ to C₁₈, forming a variety of LCBs that differ by structure and function. Mammalian SPT consists of three core subunits: SPTLC1, SPTLC2, and SPTLC3. Whereas SPTLC1 and SPTLC2 are ubiquitously expressed, SPTLC3 expression is restricted to certain tissues only. The influence of the individual subunits on enzyme activity is not clear. Using cell models deficient in SPTLC1, SPTLC2, and SPTLC3, we investigated the role of each subunit on enzyme activity and the LCB product spectrum. We showed that SPTLC1 is essential for activity, whereas SPTLC2 and SPTLC3 are partly redundant but differ in their enzymatic properties. SPTLC1 in combination with SPTLC2 specifically formed C18, C19, and C20 LCBs while the combination of SPTLC1 and SPTLC3 yielded a broader product spectrum. We identified <i>anteiso</i>-branched-C18 SO (meC18SO) as the primary product of the SPTLC3 reaction. The meC18SO was synthesized from <i>anteiso</i>-methyl-palmitate, in turn synthesized from a precursor metabolite generated in the isoleucine catabolic pathway. The meC18SO is metabolized to ceramides and complex SLs and is a constituent of human low- and high-density lipoproteins.

• Platelet extracellular vesicles mediate transfusion-related acute lung injury by imbalancing the sphingolipid rheostat

  2020

  Blood · 81 Zitationen · DOI

  Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5% to 15%. We previously showed that stored (5 days) but not fresh platelets (1 day) cause TRALI via ceramide-mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induces TRALI. EVs formed during storage of murine platelets were enumerated, characterized for sphingolipids, and applied in a murine TRALI model in vivo and for endothelial barrier assessment in vitro. Five-day EVs were more abundant, had higher long-chain ceramide (C16:0, C18:0, C20:0), and lower sphingosine-1-phosphate (S1P) content than 1-day EVs. Transfusion of 5-day, but not 1-day, EVs induced characteristic signs of lung injury in vivo and endothelial barrier disruption in vitro. Inhibition or supplementation of ceramide-forming sphingomyelinase reduced or enhanced the formation of EVs, respectively, but did not alter the injuriousness per individual EV. Barrier failure was attenuated when EVs were abundant in or supplemented with S1P. Stored human platelet 4-day EVs were more numerous compared with 2-day EVs, contained more long-chain ceramide and less S1P, and caused more endothelial cell barrier leak. Hence, platelet-derived EVs become more numerous and more injurious (more long-chain ceramide, less S1P) during storage. Blockade of sphingomyelinase, EV elimination, or supplementation of S1P during platelet storage may present promising strategies for TRALI prevention.

• MicroRNAs—Future Drug Targets?

  2006

  Angewandte Chemie International Edition · 79 Zitationen · DOI

  Big things come in small packages: MicroRNAs (miRNAs) are small regulatory RNA molecules in eukaryotes. Altered miRNA expression patterns can be used as a diagnostic tool, for example, in patients with chronic lymphatic leukemia. Also, the inhibition of miRNA function in vivo has been recently achieved by using “antagomirs”—antisense cholesterol conjugates (see scheme; miRNP=miRNA–protein complex, RISC=RNA-induced silencing complex).

• Manumycin A and Its Analogues Are Irreversible Inhibitors of Neutral Sphingomyelinase

  2001

  ChemBioChem · 72 Zitationen · DOI

  Valuable tools for experimental anti-inflammatory therapy and for clarifying the biological role of neutral sphingomyelinase and ceramide might be represented by manumycins. The antibiotic manumycin A (1), known as a Ras farnesyltransferase inhibitor, and some of its analogues were identified as irreversible inhibitors of neutral sphingomyelinase. The simple analogue 2 is readily accessible, stable and hitherto represents the most potent irreversible inhibitor of neutral sphingomyelinase.

• Image‐Based Morphological Profiling Identifies a Lysosomotropic, Iron‐Sequestering Autophagy Inhibitor

  2019

  Angewandte Chemie International Edition · 64 Zitationen · DOI

  Chemical proteomics is widely applied in small-molecule target identification. However, in general it does not identify non-protein small-molecule targets, and thus, alternative methods for target identification are in high demand. We report the discovery of the autophagy inhibitor autoquin and the identification of its molecular mode of action using image-based morphological profiling in the cell painting assay. A compound-induced fingerprint representing changes in 579 cellular parameters revealed that autoquin accumulates in lysosomes and inhibits their fusion with autophagosomes. In addition, autoquin sequesters Fe²⁺ in lysosomes, resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. Such a mechanism of action would have been challenging to unravel by current methods. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules, warranting wider application in chemical biology.

• Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

  2016

  Journal of Lipid Research · 64 Zitationen · DOI

  The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic β-cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D.

• Development of an assay for the intermembrane transfer of cholesterol by Niemann-Pick C2 protein

  2007

  Biological Chemistry · 62 Zitationen · DOI

  Niemann-Pick type C disease is an inherited fatal disorder characterized by the accumulation of unesterified cholesterol and other lipids in the endosomal/lysosomal compartment. Two independent genes responsible for this neurodegenerative disorder have been identified, but the precise functions of the encoded Niemann-Pick C1 (NPC1) and C2 (NPC2) proteins are not yet known. We developed a cell-free assay for measuring intermembrane lipid transport and examined the ability of bovine NPC2 (bNPC2) for intermembrane cholesterol transfer. NPC2 specifically extracts cholesterol from phospholipid bilayers and catalyzes intermembrane transfer to acceptor vesicles in a dose- and time-dependent manner. This transfer activity is dependent on temperature, pH, ionic strength, lipid composition of the model membranes, and the ratio of donor to acceptor vesicles. In model membranes, the presence of the lysosomal anionic phospholipids bis(monooleoylglycero)phosphate and phosphatidyl inositol significantly stimulated cholesterol transfer by NPC2, whereas bis(monomyristoylglycero)phosphate, phosphatidyl serine, and phosphatidic acid had no effect. Moreover, ceramide stimulated cholesterol transfer slightly, whereas sphingomyelin reduced cholesterol transfer rates. With our assay system we identified for the first time the ability of other lysosomal proteins, most notably the GM2-activator protein, to mediate intermembrane cholesterol transfer. This assay system promises to be a valuable tool for further quantitative and mechanistic studies of protein-mediated lipid transfer.

• Synthesis of the First Selective Irreversible Inhibitor of Neutral Sphingomyelinase

  2000

  Angewandte Chemie International Edition · 61 Zitationen · DOI

  The sphingolipid ceramide has been discusssed for some time as a possible secondary messenger for a number of physiological and pathalogical processes, including autoimmune diseases of the central nervous system, such as multiple sclerosis. Ceramide can be activated through the action of acid or neutral sphingomyelinases. The spiroepoxide 1 is the first selective irreversible inhibitor of neutral sphingomyelinase and will, therefore, be useful in the elucidation of the biological function of ceramide.

• Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro

  2020

  Journal of Lipid Research · 60 Zitationen · DOI

  Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (<i>SMPD1/Smpd1</i>) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.

• Phosphatidylinositol-3,5-Bisphosphate Is a Potent and Selective Inhibitor of Acid Sphingomyelinase

  2003

  Biological Chemistry · 60 Zitationen · DOI

  Acid sphingomyelinase (A-SMase, EC 3.1.4.12) catalyzes the lysosomal degradation of sphingomyelin to phosphorylcholine and ceramide. Inherited deficiencies of acid sphingomyelinase activity result in various clinical forms of Niemann-Pick disease, which are characterised by massive lysosomal accumulation of sphingomyelin. Sphingomyelin hydrolysis by both, acid sphingomyelinase and membrane-associated neutral sphingomyelinase, plays also an important role in cellular signaling systems regulating proliferation, apoptosis and differentiation. Here, we present a potent and selective novel inhibitor of A-SMase, L-alpha-phosphatidyl-D-myo-inositol-3,5-bisphosphate (PtdIns3,5P2), a naturally occurring substance detected in mammalian, plant and yeast cells. The inhibition constant Ki for the new A-SMase inhibitor PtdIns3,5P2 is 0.53 microM as determined in a micellar assay system with radiolabeled sphingomyelin as substrate and recombinant human A-SMase purified from insect cells. Even at concentrations of up to 50 microM, PtdIns3,5P2 neither decreased plasma membrane-associated, magnesium-dependent neutral sphingomyelinase activity, nor was it an inhibitor of the lysosomal hydrolases beta-hexosaminidase A and acid ceramidase. Other phosphoinositides tested had no or a much weaker effect on acid sphingomyelinase. Different inositol-bisphosphates were studied to elucidate structure-activity relationships for A-SMase inhibition. Our investigations provide an insight into the structural features required for selective, efficient inhibition of acid sphingomyelinase and may also be used as starting point for the development of new potent A-SMase inhibitors optimised for diverse applications.

• A fluorescence probe for assaying micro RNA maturation

  2007

  Bioorganic & Medicinal Chemistry · 58 Zitationen · DOI

• TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

  2014

  BMC Cancer · 57 Zitationen · DOI

  Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may represent a promising new option for the future development of combination therapies. Our data also suggest that RIPK3 expression may serve as a potential predictive marker for the sensitivity of tumor cells to programmed necrosis and extend the previously established role of ceramide as a key mediator of death receptor-induced programmed necrosis (and thus as a potential target for future therapies) also to the tumor cell lines examined here.

• Elucidating the chemical structure of native 1-deoxysphingosine

  2016

  Journal of Lipid Research · 56 Zitationen · DOI

  The 1-deoxysphingolipids (1-deoxySLs) are formed by an alternate substrate usage of the enzyme, serine-palmitoyltransferase, and are devoid of the C1-OH-group present in canonical sphingolipids. Pathologically elevated 1-deoxySL levels are associated with the rare inherited neuropathy, HSAN1, and diabetes type 2 and might contribute to β cell failure and the diabetic sensory neuropathy. In analogy to canonical sphingolipids, it was assumed that 1-deoxySLs also bear a (4E) double bond, which is normally introduced by sphingolipid delta(4)-desaturase 1. This, however, was never confirmed. We therefore supplemented HEK293 cells with isotope-labeled D3-1-deoxysphinganine and compared the downstream formed D3-1-deoxysphingosine (1-deoxySO) to a commercial synthetic SPH m18:1(4E)(3OH) standard. Both compounds showed the same m/z, but differed in their RPLC retention time and atmospheric pressure chemical ionization in-source fragmentation, suggesting that the two compounds are structural isomers. Using dimethyl disulfide derivatization followed by MS(2) as well as differential-mobility spectrometry combined with ozone-induced dissociation MS, we identified the carbon-carbon double bond in native 1-deoxySO to be located at the (Δ14) position. Comparing the chromatographic behavior of native 1-deoxySO to chemically synthesized SPH m18:1(14Z) and (14E) stereoisomers assigned the native compound to be SPH m18:1(14Z). This indicates that 1-deoxySLs are metabolized differently than canonical sphingolipids.

• Amplification of a FRET Probe by Lipid–Water Partition for the Detection of Acid Sphingomyelinase in Live Cells

  2017

  Angewandte Chemie International Edition · 53 Zitationen · DOI

  Real-time monitoring of acid sphingomyelinase (ASM) activity is crucial for investigating its role in lipid-mediated signaling processes. In this study, we synthesized fluorescent phosphosphingolipids capable of FRET by phosphorodichloridate chemistry. These sphingomyelin analogues are substrates for recombinant human ASM and can be used to monitor ASM activity by fluorescence spectroscopy. Incubation with cell lysates from wild-type and knock-out mice further confirmed probe cleavage to be exclusive to ASM. We also systematically exploited the environmental sensitivity of the fluorophores to achieve significant increases in responsiveness. This concept may be transferred to other lipid probes in the future. The ASM activity in live cells was imaged by two-photon-excitation microscopy.

• Optical Nanosensing of Lipid Accumulation due to Enzyme Inhibition in Live Cells

  2019

  ACS Nano · 51 Zitationen · DOI

  Drugs that influence enzymes of lipid metabolism can cause pathological accumulation of lipids in animal cells. Here, gold nanoparticles, acting as nanosensors that deliver surface-enhanced Raman scattering (SERS) spectra from living cells provide molecular evidence of lipid accumulation in lysosomes after treatment of cultured cells with the three tricyclic antidepressants (TCA) desipramine, amitryptiline, and imipramine. The vibrational spectra elucidate to great detail and with very high sensitivity the composition of the drug-induced lipid accumulations, also observed in fixed samples by electron microscopy and X-ray nanotomography. The nanoprobes show that mostly sphingomyelin is accumulated in the lysosomes but also other lipids, in particular, cholesterol. The observation of sphingomyelin accumulation supports the impairment of the enzyme acid sphingomyelinase. The SERS data were analyzed by random forest based approaches, in particular, by minimal depth variable selection and surrogate minimal depth (SMD), shown here to be particularly useful machine learning tools for the analysis of the lipid signals that contribute only weakly to SERS spectra of cells. SMD is used for the identification of molecular colocalization and interactions of the drug molecules with lipid membranes and for discriminating between the biochemical effects of the three different TCA molecules, in agreement with their different activity. The spectra also indicate that the protein composition is significantly changed in cells treated with the drugs.

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Name

Prof. Dr. Christoph Arenz

Titel

Prof. Dr.

Fakultät

Mathematisch-Naturwissenschaftliche Fakultät

Institut

Institut für Chemie

Arbeitsgruppe

Organische Synthese

Telefon

+49 30 2093-82603

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Quelle ↗

Zuletzt gescrapt

26.4.2026, 01:02:01