Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of

sphingolipid Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because ...

found in animal

cell membranes The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

, especially in the membranous

myelin sheath Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

that surrounds some

nerve cell A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...

axons An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, th ...

. It usually consists of

phosphocholine Phosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP and choline into phosphocholine and ADP. Phosphocholine is a molecule ...

and

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 ...

, or a

phosphoethanolamine Phosphorylethanolamine or phosphoethanolamine is an ethanolamine derivative that is used to construct two different categories of phospholipids. One category termed a glycerophospholipid and the other a sphingomyelin, or more specifically within th ...

head group; therefore, sphingomyelins can also be classified as sphingophospholipids. In humans, SPH represents ~85% of all sphingolipids, and typically make up 10–20 mol % of

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

lipids. Sphingomyelin was first isolated by

German German(s) may refer to: * Germany (of or related to) **Germania (historical use) * Germans, citizens of Germany, people of German ancestry, or native speakers of the German language ** For citizens of Germany, see also German nationality law **Ger ...

chemist A chemist (from Greek ''chēm(ía)'' alchemy; replacing ''chymist'' from Medieval Latin ''alchemist'') is a scientist trained in the study of chemistry. Chemists study the composition of matter and its properties. Chemists carefully describe th ...

Johann L.W. Thudicum in the 1880s. The structure of sphingomyelin was first reported in 1927 as N-acyl-sphingosine-1-phosphorylcholine. Sphingomyelin content in mammals ranges from 2 to 15% in most tissues, with higher concentrations found in nerve tissues, red blood cells, and the ocular lenses. Sphingomyelin has significant structural and functional roles in the cell. It is a plasma membrane component and participates in many signaling pathways. The metabolism of sphingomyelin creates many products that play significant roles in the cell.

Physical characteristics

Composition

Sphingomyelin consists of a

head group, a

sphingosine Sphingosine (2-amino-4-trans-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholip ...

, and a

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

. It is one of the few membrane phospholipids not synthesized from glycerol. The sphingosine and fatty acid can collectively be categorized as a ceramide. This composition allows sphingomyelin to play significant roles in signaling pathways: the degradation and synthesis of sphingomyelin produce important second messengers for signal transduction. Sphingomyelin obtained from natural sources, such as eggs or bovine brain, contains fatty acids of various chain length. Sphingomyelin with set chain length, such as palmitoylsphingomyelin with a saturated 16 acyl chain, is available commercially.

Properties

Ideally, sphingomyelin molecules are shaped like a cylinder, however many molecules of sphingomyelin have a significant chain mismatch (the lengths of the two hydrophobic chains are significantly different). The hydrophobic chains of sphingomyelin tend to be much more saturated than other phospholipids. The main transition phase temperature of sphingomyelins is also higher compared to the phase transition temperature of similar phospholipids, near 37 C. This can introduce lateral heterogeneity in the membrane, generating domains in the membrane bilayer. Sphingomyelin undergoes significant interactions with cholesterol. Cholesterol has the ability to eliminate the liquid to solid phase transition in phospholipids. Due to sphingomyelin transition temperature being within physiological temperature ranges,

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

can play a significant role in the phase of sphingomyelin. Sphingomyelin are also more prone to intermolecular hydrogen bonding than other phospholipids.

Location

Sphingomyelin is synthesized at the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER), where it can be found in low amounts, and at the ''trans'' Golgi. It is enriched at the

with a greater concentration on the outer than the inner leaflet. The Golgi complex represents an intermediate between the ER and plasma membrane, with slightly higher concentrations towards the trans side.

Metabolism

Synthesis

The synthesis of sphingomyelin involves the enzymatic transfer of a phosphocholine from

phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soyb ...

to a ceramide. The first committed step of sphingomyelin synthesis involves the condensation of

L-serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

and

palmitoyl-CoA Palmitoyl-CoA is an acyl-CoA thioester. It is an "activated" form of palmitic acid and can be transported into the mitochondrial matrix by the carnitine shuttle system (which transports fatty acyl-CoA molecules into the mitochondria), and once insi ...

. This reaction is catalyzed by

serine palmitoyltransferase In enzymology, a serine C-palmitoyltransferase () is an enzyme that catalyzes the chemical reaction: :palmitoyl-CoA + L-serine \rightleftharpoons CoA + 3-dehydro-D-sphinganine + CO2 Thus, the two substrates of this enzyme are palmitoyl-CoA ...

. The product of this reaction is reduced, yielding dihydrosphingosine. The dihydrosphingosine undergoes N-acylation followed by desaturation to yield a ceramide. Each one of these reactions occurs at the cytosolic surface of the

. The ceramide is transported to the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...

where it can be converted to sphingomyelin. Sphingomyelin synthase is responsible for the production of sphingomyelin from ceramide. Diacylglycerol is produced as a byproduct when the phosphocholine is transferred.

Degradation

Sphingomyelin breakdown is responsible for initiating many universal signaling pathways. It is hydrolyzed by sphingomyelinases (sphingomyelin specific type-C phospholipases). The phosphocholine head group is released into the aqueous environment while the ceramide diffuses through the membrane.

Function

Membranes

The membranous

that surrounds and electrically insulates many nerve cell

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...

s is particularly rich in sphingomyelin, suggesting its role as an insulator of nerve fibers. The

of other cells is also abundant in sphingomyelin, though it is largely to be found in the exoplasmic leaflet of the cell membrane. There is, however, some evidence that there may also be a sphingomyelin pool in the inner leaflet of the membrane. Moreover, neutral sphingomyelinase-2 – an enzyme that breaks down sphingomyelin into

- has been found to localise exclusively to the inner leaflet, further suggesting that there may be sphingomyelin present there.

Signal transduction

The function of sphingomyelin remained unclear until it was found to have a role in

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

. It has been discovered that sphingomyelin plays a significant role in cell signaling pathways. The synthesis of sphingomyelin at the plasma membrane by sphingomyelin synthase 2 produces diacylglycerol, which is a lipid-soluble second messenger that can pass along a signal cascade. In addition, the degradation of sphingomyelin can produce ceramide which is involved in the apoptotic signaling pathway.

Apoptosis

Sphingomyelin has been found to have a role in cell

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

by hydrolyzing into

. Studies in the late 1990s had found that ceramide was produced in a variety of conditions leading to apoptosis. It was then hypothesized that sphingomyelin hydrolysis and ceramide signaling were essential in the decision of whether a cell dies. In the early 2000s new studies emerged that defined a new role for sphingomyelin hydrolysis in apoptosis, determining not only when a cell dies but how. After more experimentation it has been shown that if sphingomyelin hydrolysis happens at a sufficiently early point in the pathway the production of ceramide may influence either the rate and form of cell death or work to release blocks on downstream events.

Lipid rafts

Sphingomyelin, as well as other sphingolipids, are associated with

lipid microdomain Lipid microdomains are formed when lipids undergo lateral phase separations yielding stable coexisting lamellar domains. These phase separations can be induced by changes in temperature, pressure, ionic strength or by the addition of divalent cat ...

s in the plasma membrane known as

lipid raft The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial. ...

s. Lipid rafts are characterized by the lipid molecules being in the lipid ordered phase, offering more structure and rigidity compared to the rest of the plasma membrane. In the rafts, the acyl chains have low chain motion but the molecules have high lateral mobility. This order is in part due to the higher transition temperature of sphingolipids as well as the interactions of these lipids with cholesterol. Cholesterol is a relatively small, nonpolar molecule that can fill the space between the sphingolipids that is a result of the large acyl chains. Lipid rafts are thought to be involved in many cell processes, such as membrane sorting and trafficking, signal transduction, and cell polarization. Excessive sphingomyelin in lipid rafts may lead to

insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...

. Due to the specific types of lipids in these microdomains, lipid rafts can accumulate certain types of proteins associated with them, thereby increasing the special functions they possess. Lipid rafts have been speculated to be involved in the cascade of cell apoptosis.

Abnormalities and associated diseases

Sphingomyelin can accumulate in a rare

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...

disease called

Niemann–Pick disease Niemann–Pick disease is a group of severe inherited metabolic disorders, in which sphingomyelin accumulates in lysosomes in cells (the lysosomes normally degrade material that comes from out of cells). These disorders involve the dysfunctional ...

, types A and B. It is a

genetically-inherited Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cell (biology), cells or orga ...

disease caused by a deficiency 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 ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

acid sphingomyelinase Acid sphingomyelinase is one of the enzymes that make up the sphingomyelinase (SMase) family, responsible for catalyzing the breakdown of sphingomyelin to ceramide and phosphorylcholine. They are organized into alkaline, neutral, and acidic SMase de ...

, which causes the accumulation of sphingomyelin in

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

lungs The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of th ...

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

, and

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

, causing irreversible neurological damage. Of the two types involving

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. ...

, type A occurs in infants. It is characterized by

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

, an enlarged

, and profound

damage. Children with this type rarely live beyond 18 months. Type B involves an enlarged liver and spleen, which usually occurs in the pre-teen years. The brain is not affected. Most patients present with <1% normal levels of the enzyme in comparison to normal levels. A hemolytic protein, lysenin, may be a valuable probe for sphingomyelin detection in cells of Niemann-Pick A patients. As a result of the autoimmune disease

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

(MS), the

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

sheath of neuronal cells in the brain and spinal cord is degraded, resulting in loss of signal transduction capability. MS patients exhibit upregulation of certain

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

in the cerebrospinal fluid, particularly

tumor necrosis factor alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

. This activates sphingomyelinase, an enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide; sphingomyelinase activity has been observed in conjunction with cellular apoptosis. An excess of sphingomyelin in the red blood cell membrane (as in

abetalipoproteinemia Abetalipoproteinemia (also known as: Bassen-Kornzweig syndrome, microsomal triglyceride transfer protein deficiency disease, MTP deficiency, and betalipoprotein deficiency syndrome) is a disorder that interferes with the normal absorption of fat ...

) causes excess lipid accumulation in the outer leaflet of the

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

. This results in abnormally shaped red cells called

acanthocytes Acanthocyte (from the Greek word ἄκανθα ''acantha'', meaning 'thorn'), in biology and medicine, refers to an abnormal form of red blood cell that has a spiked cell membrane, due to thorny projections. A similar term is spur cells. Often ...

Additional images

Image:Sphingomyelin-horizontal-3D-balls.png,

Ball-and-stick model In chemistry, the ball-and-stick model is a molecular model of a chemical substance which displays both the three-dimensional position of the atoms and the bonds between them. The atoms are typically represented by spheres, connected by rods w ...

of sphingomyelin Image:Sphingomyelin-horizontal-2D-skeletal.png,

Skeletal formula The skeletal formula, or line-angle formula or shorthand formula, of an organic compound is a type of molecular structural formula that serves as a shorthand representation of a molecule's bonding and some details of its molecular geometry. A ...

of sphingomyelin Image:Ceramid.svg ,

Image:Sphingosine structure.svg ,

Sphingosine Sphingosine (2-amino-4-trans-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholip ...

References

External links

* {{Phospholipids Phospholipids Membrane biology