Phosphatidylinositol-3,5-Bisphosphate Is a Potent and Selective Inhibitor of Acid Sphingomyelinase
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M. Kölzer
Abstract
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-?-phosphatidyl-D-myo-inositol-3,5-bisphosphate (PtdIns3,5P[2]), a naturally occurring substance detected in mammalian, plant and yeast cells. The inhibition constant Ki for the new A-SMase inhibitor PtdIns3,5P[2] is 0.53 M 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 uM, PtdIns3,5P[2] neither decreased plasma membrane associated, magnesium-dependent neutral sphingomyelinase activity, nor was it an inhibitor of the lysosomal hydrolases ?-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.
Copyright © 2003 by Walter de Gruyter GmbH & Co. KG
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Artikel in diesem Heft
- Paper of the Year 2002
- Terminal Differentiation of Epithelia
- Use of Detergents to Study Membrane Rafts: The Good, the Bad, and the Ugly
- Protein Structure Similarity as Guiding Principle for Combinatorial Library Design
- The Making of a Professional Secretory Cell: Architectural and Functional Changes in the ER during B Lymphocyte Plasma Cell Differentiation
- No Superoxide Dismutase Activity of Cellular Prion Protein in vivo
- A Nucleosome-Free dG-dC-Rich Sequence Element Promotes Constitutive Transcription of the Essential Yeast RIO1 Gene
- Phosphatidylinositol-3,5-Bisphosphate Is a Potent and Selective Inhibitor of Acid Sphingomyelinase
- Function and Structure of N-Terminal and C-Terminal Domains of Calcineurin B Subunit
- Verification of the Interaction of a Tryparedoxin Peroxidase with Tryparedoxin by ESI-MS/MS
- Kinin-B1 Receptors in Ischaemia-Induced Pancreatitis: Functional Importance and Cellular Localisation
- Bioactivatable, Membrane-Permeant Analogs of Cyclic Nucleotides as Biological Tools for Growth Control of C6 Glioma Cells
- Human Cathepsin H: Deletion of the Mini-Chain Switches Substrate Specificity from Aminopeptidase to Endopeptidase
- Nitridergic Platelet Pathway Activation by Hementerin, a Metalloprotease from the Leech Haementeria depressa
