Acid sphingomyelinase, cell membranes and human disease: Lessons from
Edward H. Schuchman*
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, Icahn Medical Institute, Floor 14 Room 14-20A, 1425 Madison Avenue, New York, NY 10029, USA
a r t i c l ei n f o
Received 29 October 2009
Accepted 24 November 2009
Available online 26 November 2009
Edited by Sandro Sonnino
a b s t r a c t
Acid sphingomyelinase (ASM) plays an important role in normal membrane turnover through the
hydrolysis of sphingomyelin, and is one of the key enzymes responsible for the production of cera-
mide. ASM activity is deficient in the genetic disorder Types A and B Niemann–Pick disease (NPD).
ASM knockout (ASMKO) mice were originally constructed to study this disorder, and numerous
defects in ceramide-related signaling have been shown. Studies in these mice have further sug-
gested that ASM may be involved in the pathogenesis of several common diseases through the reor-
ganization of membrane microdomains. This review will focus on the role of ASM in membrane
biology, with a specific emphasis on what a rare genetic disorder (NPD) has taught us about more
? ? 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
The fluid mosaic model of the cell membrane, first proposed in
the early 1970s, suggested that membranes exist in a disorder sta-
tus without significant selectivity . This concept rapidly estab-
lished itself as dogma, although in recent years a body of
literature has shown that the cell membrane is, in fact, composed
of small ‘‘microdomains” that exist in a liquid-ordered phase .
These domains are static within the membrane, and can coalesce
and reorganize in response to various stimuli. Several laboratories
also have shown that sphingolipids and cholesterol associate with
these microdomains, and that these associations are integral to
membrane function. The sphingolipid and cholesterol-enriched
membrane microdomains have been referred to as lipid ‘‘rafts”
[3,4]. Despite a growing literature, the concept of membrane
microdomains has remained controversial, principally because
data demonstrating the existence of these domains in vivo is lim-
ited. As summarized below, studies of one sphingolipid hydrolase,
acid sphingomyelinase (ASM), specifically those using ASM knock-
out mice (ASMKO), have provided some of the strongest evidence
to date supporting the concept of membrane microdomains in
vivo. They also have highlighted the important role of this enzyme
in normal cell function and the pathogenesis of many common
Numerous reviews are available on the function of ASM in cell
signaling, as well as on its involvement in specific human diseases
(e.g. [5–7]). The purpose of this review is to summarize informa-
tion regarding the role of ASM in membrane biology. In order to
provide a biological context, a systems approach will be used.
Much of this information comes from studies using ASMKO mice,
which were originally created as a model of the human genetic dis-
order, Types A and B Niemann–Pick disease (NPD) . A brief back-
ground on ASM and NPD is provided below, followed by a
summary of studies using the ASMKO mice that reveal the function
of ASM on cell membranes. Despite the fact that NPD was de-
scribed nearly a century ago and ASM was identified over 40 years
ago, this literature has mostly emerged during the past decade. It is
therefore an evolving field, but one that has already integrated di-
verse scientific disciplines, ranging from physicians, biophysicists,
lipid biochemists and signal transduction biologists, and identified
ASM as a target for numerous, common diseases.
1.1. Acid sphingomyelinase: historical perspective
Acid sphingomyelinase (ASM; EC 220.127.116.11) is one member of a
family of enzymes that catalyzes the breakdown of sphingomyelin
by cleavage of the phosphorylcholine linkage, thereby producing
ceramide. The existence of such a ‘‘sphingomyelin cleaving en-
zyme” was first demonstrated in 1938 by the pioneering work of
Thannhauser, Reichel and colleagues . During the ensuing 25
years, several similar enzymatic activities were identified that dif-
fered mostly in their tissue distribution and pH optimum. The first
0014-5793/$36.00 ? 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
* Fax: +1 212 849 2447.
E-mail address: Edward.Schuchman@mssm.edu
FEBS Letters 584 (2010) 1895–1900
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E.H. Schuchman/FEBS Letters 584 (2010) 1895–1900