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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


IMPACT FACTOR 2018: 3.014
5-year IMPACT FACTOR: 3.162

CiteScore 2018: 3.09

SCImago Journal Rank (SJR) 2018: 1.482
Source Normalized Impact per Paper (SNIP) 2018: 0.820

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1437-4315
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Volume 384, Issue 9

Issues

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

M. Kölzer / C. Arenz / K. Ferlinz / N. Werth / H. Schulze / R. Klingenstein / K. Sandhoff
Published Online: 2005-06-01 | DOI: https://doi.org/10.1515/BC.2003.144

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.

About the article

Published Online: 2005-06-01

Published in Print: 2003-09-28


Citation Information: Biological Chemistry, Volume 384, Issue 9, Pages 1293–1298, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2003.144.

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