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J Biol Chem, Vol. 275, Issue 2, 1128-1136, January 14, 2000
From the Cancer Research Campaign Centre for Cell and Molecular
Biology, Chester Beatty Laboratories, Fulham Road,
London SW3 6JB, United Kingdom
Activation of neutral sphingomyelinase(s) and
subsequent generation of ceramide has been implicated in a wide variety
of cellular responses. Although this enzyme(s) has not been purified
and cloned from higher organisms, one mammalian cDNA has been
previously isolated based on its similarity to the bacterial enzyme. To
further elucidate the function of this neutral sphingomyelinase, we
studied its relationship with enzymes present in mammalian cells and
tissues, its subcellular localization, and properties that could be
important for the regulation of its activity. Using specific
antibodies, it is suggested that the enzyme could represent one of
several forms of neutral sphingomyelinases present in the extract from brain particulate fraction. In PC12 cells, the enzyme is localized in
the endoplasmic reticulum and is not present in the plasma membrane.
The same result has been obtained in several cell lines transfected or
microinjected with plasmids encoding this enzyme. The molecular and
enzymatic properties of the cloned neutral
magnesium-dependent sphingomyelinase, produced using
baculovirus or bacterial expression systems, have been analyzed,
demonstrating the expected ion dependence and substrate specificity.
The enzyme activity also has a strong requirement for reducing agents
and is reversibly inhibited by reactive oxygen species and oxidized
glutathione. The studies demonstrate that the cellular localization and
some properties of this enzyme are distinct from properties previously
associated with neutral magnesium-dependent
sphingomyelinases in crude or partially purified preparations.
A Neutral Magnesium-dependent Sphingomyelinase
Isoform Associated with Intracellular Membranes and Reversibly
Inhibited by Reactive Oxygen Species*
*
This work was supported by the Cancer Research Campaign and
the Wellcome Trust.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: CRC Centre for Cell
and Molecular Biology, Chester Beatty Laboratories, Fulham Road, London
SW3 6JB, United Kingdom. Tel.: 44-171-352-8133; Fax: 44-171-352-3299;
E-mail: matilda@icr.ac.uk.
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