Acid Sphingomyelinase

Author: Amelia Garofalo
Date: 19/07/2011



Acid sphingomyelinase (ASM) is one member of a family of enzymes that catalyzes the breakdown of sphingomyelin by cleavage of the phosphorylcholine linkage, thereby producing ceramide. It has been identified two major forms of apparent molecular mass of 75 and 72 kDa, and a minor one with molecular mass of 57kDa. ASM is produced from a single gene SMPD1.



SMPD1 is located within the chromosomal 11 (region 11p15.4). The gene spans 6 kb and consists of six exons encoding the 629 amino acids of the full-length ASM polypeptide. Notably, the SMPD1 gene is located within an imprinted region of the human genome, and recent studies have shown that it is preferentially expressed from the maternal chromosome (i.e. paternally imprinted). Differential methylation of the paternal and maternal alleles is responsible for the imprinting, and has been mapped to several CpG dinucleotides within the SMPD1 promoter. The remaining regulatory region upstream of the SMPD1 gene resembles other housekeeping promoters, and transcriptional expression can be found in most tissues. Expression of the SMPD1 gene is carefully regulated during development. For example, in mice SMPD1 gene expression is high prior to E11, and then markedly reduced until birth. Expression is then turned back on by P1-P2. The consequence of this careful regulation is not completely understood, although it is interesting to note that altered expression of the SMPD1 gene has been found in several human cancers. (The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann–Pick disease. E. H. Schuchman. J Inherit Metab Dis)


When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

Protein Aminoacids Percentage
The Protein Aminoacids Percentage gives useful information on the local environment and the metabolic status of the cell (starvation, lack of essential AA, hypoxia)

Protein Aminoacids Percentage (Width 700 px)


mRNA synthesis
protein synthesis

post-translational modifications


Role of Acid Sphingomyelinase in biological membranes

Biological membranes primarily consist of sphingolipids, cholesterol, and other (glycero) phospholipids. The most prevalent component of the sphingolipid fraction in the cell membrane is sphingomyelin, which is composed of a highly hydrophobic ceramide moiety and a hydrophilic phosphorylcholine headgroup.

(Physiological and pathophysiological aspects of ceramide. Pin Lan Li. Am J Physiol Regul Integr Comp Physiol)

Tight interactions between the cholesterol sterol ring system and the ceramide moiety of sphingomyelin, which are mediated by hydrogen bonds and hydrophobic van der Waal interactions as well as hydrophilic interactions, promote the lateral association of sphingolipids and cholesterol and thus the separation from other phospholipids into distinct microdomains. These microdomains have been termed rafts.
Many receptors, including CD95, CD28, TNF, CD40, DR5, CD5, LFA-1, FcγRII, CD20, the interleukin-1 receptor, the platelet-activating factor (PAF) receptor, as well as infection with Pseudomonas aeruginosa, S. aureus, N. gonorrhoeae, Sindbis virus, Rhinovirus, or treatment with gamma-irradiation, UV light, doxorubicin, cisplatin trigger the release of ceramide. Most of these stimuli activate the acid sphingomyelinase, which belongs to a class of enzymes that hydrolyze sphingomyelin and thus generate ceramide. (Physiological and pathophysiological aspects of ceramide. Pin Lan Li. Am J Physiol Regul Integr Comp Physiol)

Sphingomyelinases are characterized by their pH optimum, and an acid, neutral, and alkaline sphingomyelinase were described. It has been identified two major forms of apparent molecular mass of 75 and 72 kDa and a minor one with molecular mass of 57kDa; this smaller form is generated by cleavage of the 75-kDa precursor, which is a pre-polypeptide with little if any enzymatic activity in the endoplasmic reticulum.
The 72-kDa precursor is generated into the endoplasmic reticulum/Golgi apparatus via a proteolytic cleavage of the 75-kDa pre-polypeptide and then transported to the endo/lysosomal compartments, where it is processed to its mature form.
The mature form and its precursors have six potential N-glycosylation sites, and at least five of them are important for proper folding, protection against proteolysis, and enzymatic activity. Additionally, A-SMase has a mannose 6-phosphate residue that is required for lysosomal targetting of the enzyme via the mannose 6-phosphate receptor. (Biological Roles of Acid and Neutral Sphingomyelinases and Their Regulation by Nitric Oxide. Emilio Clementi. Physiology)

Activation of the acid sphingomyelinase by receptor molecules correlates with a translocation of the enzyme from intracellular stores onto the extracellular leaflet of the cell membrane. Acid sphingomyelinase is localized within secretory vesicles, which are mobilized on stimulation to fuse with the cell membrane. This fusion brings the enzyme in close vicinity to its substrate sphingomyelin. The generation of ceramide within rafts dramatically alters the biophysical properties of these membrane domains, since ceramide molecules have the tendency to spontaneously self associate to small ceramide-enriched membrane microdomains which are involved in many cellular process. (Physiological and pathophysiological aspects of ceramide. Pin Lan Li. Am J Physiol Regul Integr Comp Physiol)

  • Enzymes
BRENDA - The Comprehensive Enzyme Information System"URL":
KEGG Pathways"URL":
Human Metabolome Database"URL":
  • Cell signaling and Ligand transport
  • Structural proteins



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