Acid sphingomyelinase is one of the enzymes that make up the

sphingomyelinase Sphingomyelin phosphodiesterase (EC 3.1.4.12, also known as neutral sphingomyelinase, sphingomyelinase, or SMase; systematic name sphingomyelin cholinephosphohydrolase) is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. ...

(SMase) family, responsible for catalyzing the breakdown of

sphingomyelin Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a ethano ...

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetylsphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up ...

and

phosphorylcholine :''Phosphorylcholine refers to the functional group derived from phosphocholine. Also not to be confused with phosphatidylcholine.'' Phosphorylcholine (abbreviated ChoP) is the hydrophilic polar head group of some phospholipids, which is compose ...

. They are organized into alkaline, neutral, and acidic SMase depending on the pH in which their enzymatic activity is optimal. Acid Sphingomyelinases (aSMases) enzymatic activity can be influenced by drugs, lipids, cations, pH, redox and other proteins in the environment. Specifically aSMases have been shown to have increased enzymatic activity in lysobisphosphatidic acid (LBPA) or

phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...

(PI) enriched environments, and inhibited activity when phosphorylated derivatives of PI are present.

Sphingomyelin phosphodiesterase 1 Sphingomyelin phosphodiesterase 1 (SMPD1), also known as acid sphingomyelinase (ASM), is an enzyme that in humans is encoded by the ''SMPD1'' gene. Sphingomyelin phosphodiesterase 1 belongs to the sphingomyelin phosphodiesterase Sphingomyelin ...

MPD1is the gene that codes for two aSMase enzymes distinct in the pools of Sphingomyelin they hydrolyse. Lysosomal sphingomyelinase (L-SMase) is found in the

lysosomal A lysosome () is a membrane-bound organelle found in many animal Cell (biology), cells. They are spherical Vesicle (biology and chemistry), vesicles that contain Hydrolysis, hydrolytic enzymes that can break down many kinds of biomolecules. A ly ...

compartment, and the secretory sphingomyelinase (S-SMase) is found extracellularly.

Structure and catalytic mechanism

The catalytic mechanism of acid sphingomyelinase is the hydrolysis of sphingomyelin to ceramide and phosphorylcholine.

Types of acid sphingomyelinases

Lysosomal acid sphingomyelinase

The lysosomal acidic SMase is considered one of the major candidates for the production of ceramide in the cellular response to stress; including environmental insults, infection with pathogens, ligation of death receptors, and chemotherapy drugs. The main mechanism of trafficking L-SMase to the lysosome is through the

mannose 6-phosphate receptor The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates. Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver th ...

mediated pathway. L-SMase acquires zinc whilst being trafficked to the lysosome, and it is thought that zinc may play a role in mediating cellular L-SMase activity.

Secreted acid sphingomyelinase

Secreted acid SMases are less well understood than their lysosomal compartmentalised counterpart. S-SMases are zinc-dependent, and have been implicated in the metabolism of lipoprotein-bound SM to Ceramide and the aggregation of LDL particles. In circulating platelets there is no neutral SMase activity, but they do have S-SMase enzymatic activity. It has been shown that in response to thrombin induced platelet activation, S-SMase is released extracellulary and a parallel decrease in intracellular L-SMase is observed.

Role in disease

Niemann-Pick Type A and Type B

The lysosomal storage disorders Niemann-Pick disease, SMPD1-associated (Type A and B) are characterized by a deficiencies in Acid Sphingomyelinase. Diagnosis is confirmed by an aSMase activity less than 10% in the peripheral blood lymphocytes. Caused by a mutation in the SMPD1 gene, it is found in 1:250,000 in the population. Mutations to this gene are more commonly found in those of

Ashkenazi Jewish Ashkenazi Jews ( ; he, יְהוּדֵי אַשְׁכְּנַז, translit=Yehudei Ashkenaz, ; yi, אַשכּנזישע ייִדן, Ashkenazishe Yidn), also known as Ashkenazic Jews or ''Ashkenazim'',, Ashkenazi Hebrew pronunciation: , singu ...

descent (1:80-1:100) or of North African descent.

Niemann-Pick Type C

Niemann-Pick Type C (NPC) is also a lysosomal storage disorder, but instead is caused by a mutation in either

NPC1 Niemann-Pick disease, type C1 (NPC1) is a disease of a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the ''NPC1'' gene (chromosome location 18q11). Function NPC1 was identi ...

NPC2 The epididymal secretory protein E1, also known as NPC2( Niemann-Pick intracellular cholesterol transporter 2), is one of two main lysosomal transport proteins that assist in the regulation of cellular cholesterol by exportation of LDL-derived chol ...

gene. Despite having a functional SMPD1 gene, NPC fibroblasts were shown to have inhibited aSMase activity. The functional loss of aSMase activity may also be due to altered trafficking (causing accumulation of cholesterol) or by direct action on the enzyme. Additionally, the disregulation of BMP/LBPA in NPC may contribute to the decreased aSMase activity, as LBPA has been shown to enhance enzymatic activity.

Cardiovascular pathophysiological conditions

Atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...

occurs from the thickening of the artery walls through depositing of cholesterol and triglyceride on the cell walls. Lipid deposits are encouraged by high levels of circulating

LDL Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...

, often caused by inadequate removal by HDL particles. Acid SMase has been shown to accelerate atherosclerotic lesion progression through promoting aggregation of lipoproteins to arterial walls. Inhibition of aSMases is a current therapeutic target for the treatment of

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...

Diabetes

Secreted aSMase may also play a role in

Diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

. Inflammation induced S-SMase activation may contribute to insulin resistance through the increased generation of ceramide.

References

{{Portal bar, Biology, border=no EC 3.1.4 Lysosomal storage diseases