MODULE 4.1.4 COMPOUND LIPIDS

PHOSPHOLIPIDS-LECITHIN, PHOSPHATIDYL INOSITOL, CEPHALINS, PLASMOLOGENS, GLYCOLIPIDS, SPHINGOLIPIDS

1.LECITHIN

An example of a phosphatidylcholine, a type of phospholipid in lecithin. Red - choline and phosphate group; Black - glycerol; Green - unsaturated fatty acid; Blue - saturated fatty acid

Lecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues composed of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol).

Lecithin was first isolated in 1846 by the French chemist and pharmacist Theodore Gobley.[1] In 1850, he named the phosphatidylcholine léchithine.[2] Gobley originally isolated lecithin from egg yolk—λέκιθος lekithos is "egg yolk" in Ancient Greek—and established the complete chemical formula of phosphatidylcholine in 1874;[3] in between, he had demonstrated the presence of lecithin in a variety of biological matters, including venous blood, bile, human brain tissue, fish eggs, fish roe, and chicken and sheep brain.

Lecithin can easily be extracted chemically (using hexane, ethanol, acetone, petroleum ether, benzene, etc.) or mechanically. It is usually available from sources such as soybeans, eggs, milk, marine sources, rapeseed, cottonseed, and sunflower. It has low solubility in water, but is an excellent emulsifier. In aqueous solution, its phospholipids can form either liposomes, bilayer sheets, micelles, or lamellar structures, depending on hydration and temperature. This results in a type of surfactant that usually is classified as amphipathic. Lecithin is sold as a food supplement and for medical uses. In cooking, it is sometimes used as an emulsifier and to prevent sticking, for example in nonstick cooking spray.

Biology

Lecithin, as a food additive, is also dietary source of several active compounds: Choline and its metabolites are needed for several physiological purposes, including cell membrane signaling

1

and cholinergic neurotransmission, and is a major source for methyl groups via its metabolite, trimethylglycine (betaine). Phosphatidylcholine occurs in all cellular organisms, being one of the major components of the phospholipid portion of the cell membrane.

While lecitihin is also a rich source of a variety of types of dietary fats, the small amounts of lecithin typically used for food additive purposes mean it is not a significant source of fats.

Production

Commercial lecithin, as used by food manufacturers, is a mixture of phospholipids in oil. The lecithin can be obtained by water degumming the extracted oil of seeds. It is a mixture of various phospholipids, and the composition depends on the origin of the lecithin. A major source of lecithin is soybean oil. Because of the EU requirement to declare additions of allergens in foods, in addition to regulations regarding genetically modified crops, a gradual shift to other sources of lecithin (e.g., sunflower oil) is taking place. The main phospholipids in lecithin from soya and sunflower are phosphatidyl choline, phosphatidyl inositol, phosphatidyl ethanolamine, and phosphatidic acid. They often are abbreviated to PC, PI, PE, and PA, respectively. Purified phospholipids are produced by companies commercially.

Hydrolysed lecithin

To modify the performance of lecithin to make it suitable for the product to which it is added, it may be hydrolysed enzymatically. In hydrolysed lecithins, a portion of the phospholipids have one fatty acid removed by phospholipase. Such phospholipids are called lysophospholipids. The most commonly used phospholipase is phospholipase A2, which removes the fatty acid at the C2 position of glycerol. Lecithins may also be modified by a process called fractionation. During this process, lecithin is mixed with an alcohol, usually ethanol. Some phospholipids, such as phosphatidylcholine, have good solubility in ethanol, whereas most other phospholipids do not dissolve well in ethanol. The ethanol is separated from the lecithin sludge, after which the ethanol is removed by evaporation to obtain a phosphatidylcholine-enriched lecithin fraction.

Genetically modified crops as a source of lecithin

As described above, lecithin is highly processed. Therefore, genetically modified (GM) protein or DNA from the original GM crop from which it is derived often is undetectable – in other words, it is not substantially different from lecithin derived from non-GM crops.[4] Nonetheless, consumer concerns about genetically modified food have extended to highly purified derivatives from GM food, such as lecithin.[5] This concern led to policy and regulatory changes in the European Union in 2000, when Commission Regulation (EC) 50/2000 was passed[6] which required labelling of food containing additives derived from GMOs, including lecithin. Because it is nearly impossible to detect the origin of derivatives such as lecithin, the European regulations require those who wish to sell lecithin in Europe to use a meticulous system of identity preservation (IP).[4][7]

2

Properties and applications

Lecithin has emulsification and lubricant properties, and is a surfactant. It can be totally metabolized (see Inositol) by humans, so is well tolerated by humans and nontoxic when ingested; some other emulsifiers can only be excreted via the kidneys.

The major components of commercial soybean-derived lecithin are:[8]

33–35% Soybean oil 20–21% Inositol phosphatides 19–21% Phosphatidylcholine 8–20% Phosphatidylethanolamine 5–11% Other phosphatides 5% Free carbohydrates 2–5% Sterols 1% Moisture

Lecithin is used for applications in human food, animal feed, pharmaceuticals, paints, and other industrial applications.

Applications include:

In the pharmaceutical industry, it acts as a wetting, stabilizing agent and a choline enrichment carrier, helps in emulsifications and encapsulation, and is a good dispersing agent. It can be used in manufacture of intravenous fat infusions and for therapeutic use.

In animal feed, it enriches fat and protein and improves pelletization. In the paint industry, it forms protective coatings for surfaces with painting and printing

ink, has antioxidant properties, helps as a rust inhibitor, is a colour-intensifying agent, catalyst, conditioning aid modifier, and dispersing aid; it is a good stabilizing and suspending agent, emulsifier, and wetting agent, helps in maintaining uniform mixture of several pigments, helps in grinding of metal oxide pigments, is a spreading and mixing aid, prevents hard settling of pigments, eliminates foam in water-based paints, and helps in fast dispersion of latex-based paints.

Lecithin also may be used as a release agent for plastics, an antisludge additive in motor lubricants, an antigumming agent in gasoline, and an emulsifier, spreading agent, and antioxidant in textile, rubber, and other industries.

Food additive

The nontoxicity of lecithin leads to its use with food, as an additive or in food preparation. It is used commercially in foods requiring a natural emulsifier or lubricant.

In confectionery, it reduces viscosity, replaces more expensive ingredients, controls sugar crystallization and the flow properties of chocolate, helps in the homogeneous mixing of

3

ingredients, improves shelf life for some products, and can be used as a coating. In emulsions and fat spreads, it stabilizes emulsions, reduces spattering during frying, improves texture of spreads and flavour release. In doughs and bakery, it reduces fat and egg requirements, helps even distribution of ingredients in dough, stabilizes fermentation, increases volume, protects yeast cells in dough when frozen, and acts as a releasing agent to prevent sticking and simplify cleaning. It improves wetting properties of hydrophilic powders (e.g., low-fat proteins) and lipophilic powders (e.g., cocoa powder), controls dust, and helps complete dispersion in water.[9]

Lecithin keeps cocoa and cocoa butter in a candy bar from separating. It can be used as a component of cooking sprays to prevent sticking and as a releasing agent. In margarines, especially those containing high levels of fat (>75%), lecithin is added as an 'antispattering' agent for shallow frying.

Lecithin is approved by the United States Food and Drug Administration for human consumption with the status "generally recognized as safe". Lecithin is admitted by the EU as a food additive, designated as E322. Research studies show soy-derived lecithin has significant effects on lowering serum cholesterol and triglycerides, while increasing HDL ("good cholesterol") levels in the blood of rats.[10][11][12]

Dietary supplement

Because it contains phosphatidylcholines, lecithin is a source of choline, an essential nutrient.[13]

[14] Clinical studies have shown benefit in acne, in improving liver function, and in lowering cholesterol, but clinical studies in dementia and dyskinesias have found no benefit.[14][15][16] An earlier study using a small sample (20 men divided in 3 groups) did not detect statistically significant short term (2-4 weeks) effects on cholesterol in hyperlipidaemic men.[17]

La Leche League recommends its use to prevent blocked or plugged milk ducts which can lead to mastitis in breastfeeding women.[18]

Compatibility with special diets

Egg-derived lecithin is not usually a concern for those allergic to eggs since commercially available egg lecithin is highly purified and devoid of allergy-causing egg proteins.[19] Egg lecithin is not a concern for those on low-cholesterol diets, because the lecithin found in eggs markedly inhibits the absorption of the cholesterol contained in eggs.[20]

Possible link to heart disease

A growing body of evidence indicates lecithin is converted by gut bacteria into trimethylamine-N-oxide(TMAO), which is released into circulation, and may with time contribute to atherosclerosis and heart attacks.[21][22][23]

Religious restrictions

Soy-derived lecithin is considered by some to be kitniyot and prohibited on Passover for Ashkenazi Jews when many grain-based foods are forbidden, but not at other times. This does

4

not necessarily affect Sephardi Jews, who do not have the same restrictions on rice and kitniyot during Pesach/Passover.[24]

Muslims are not forbidden to eat lecithin per se; however, since it may be derived from animal as well as plant sources, care must be taken to ensure this source is halal. Lecithin derived from plants and egg yolks is permissible, as is that derived from animals slaughtered according to the rules of dhabihah.[25]

2. Phosphatidylinositol

Phosphatidylinositol consists of a family of lipids as illustrated on the right, a class of the phosphatidylglycerides. In such molecules the isomer of the inositol group is assumed to be the myo- conformer unless otherwise stated. Typically phosphatidylinositols form a minor component on the cytosolic side of eukaryotic cell membranes. The phosphate group gives the molecules a negative charge at physiological pH.

The form of phosphatidylinositol comprising the isomer muco -inositol acts as a sensory receptor in the taste function of the sensory system. In this context it is often referred to as PtdIns, but that does not imply any molecular difference from phosphatidylinositols comprising the myo- conformers of inositol.

5

The phosphatidylinositol can be phosphorylated to form phosphatidylinositol phosphate (PI-4-P, referred to as PIP in close context or informally), phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositol trisphosphate (PIP3). All lipids based on phosphatidylinositol are known as inositides, or sometimes phosphoinositides.

Biosynthesis

The neurologically important PtdIns is synthesized as a liquid crystalline region of the outer lemma of the cilia of the sodium path (Na path) sensory receptors exposed to the mucosa in mammals and some other vertebrates (Family Chordata). This specific form of phosphatidylinositol formed with muco -Inositol (CAS 488-55-1) is NOT shown at right. This compound forms the sensory receptor of the sodium path under the molecular biochemical model of the gustatory modality.

Biosynthesis of phosphatidylinositol catalyzed by phosphatidylinositol synthase. Figure adapted from Christopher, K.; van Holde, K.E.; Ahern, Kevin G. Biochemistry Third Edition. Pearson Education, Inc: Singapore, 2005; p 678.[1]

The synthesis of phosphatidylinositol in the laboratory is catalyzed by phosphatidylinositol synthase and involves CDP-diacylglycerol and L-myo-inositol.[

6

Chemistry

PI has a polar and non-polar region, making the lipid an amphiphile. Phosphatidylinositol is classified as a glycerophospholipid that contains a glycerol backbone, two non-polar fatty acid tails, a phosphate group substituted with an inositol polar head group.

The most common fatty acids of phosphoinositides are stearic acid in the SN1 position and arachidonic acid, in the SN2 position. Hydrolysis of phosphoinositides yield one mole of glycerol, two moles of fatty acids, one mole of inositol and one, two, or three moles of phosphoric acids, depending on the number of phosphates on the inositol rings. Phosphoinositides are regarded as the most acidic phospholipids.

The specific fatty acids of PdtIns, and their conformation, employed in the sensory neurons has not been elucidated.

Phosphoinositides

Phosphorylated forms of phosphatidylinositol (PI) are called phosphoinositides and play important roles in lipid signaling, cell signaling and membrane trafficking. The inositol ring can be phosphorylated by a variety of kinases on the three, four and five hydroxyl groups in seven different combinations. However, the two and six hydroxyl group is typically not phosphorylated due to steric hindrance.

All seven variations of the following phosphoinositides have been found in animals:

Phosphatidylinositol monophosphates:

Phosphatidylinositol 3-phosphate , also known as PtdIns3P or PI(3)P Phosphatidylinositol 4-phosphate , also known as PtdIns4P or PI(4)P Phosphatidylinositol 5-phosphate , also known as PtdIns5P or PI(5)P

Phosphatidylinositol bisphophosphates:

Phosphatidylinositol 3,4-bisphosphate , also known as PtdIns(3,4)P or PI(3,4)P2

Phosphatidylinositol 3,5-bisphosphate , also known as PtdIns(3,5)P or PI(3,5)P2

Phosphatidylinositol 4,5-bisphosphate , also known as PtdIns(4,5)P, PI(4,5)P2 or often simply referred to as PIP2

Phosphatidylinositol trisphophosphate:

Phosphatidylinositol 3,4,5-trisphosphate , also known as PtdIns(3,4,5)P or PI(3,4,5)P3

These phosphoinositides are also found in plant cells, with the exception of PIP3.

3. CEPHALINS:

7

natural compounds of the complex lipid group. They are widely distributed in plant and animal organisms as components of biological membranes. Nerve tissue is particularly abundant in cephalins (cephalins were first isolated from the cerebrum).

Cephalin molecules are formed from glycerol, fatty acids, phosphoric acid, and aminoethyl alcohol (ethanolamine phosphatides) or serine (serine phosphatides) radicals. The presence of ionized (neutral pH value) phosphoric acid and amine radicals gives cephalins a polar character and to a great extent determines their chemical and functional properties. Individual cephalins differ from one another by the nature of their fatty-acid content (as a rule, one fatty acid is unsaturated). The term “cephalins” is primarily used to designate unrefined fractions of corresponding phospholipids and not individual chemical substances.

4. PLASMOLOGENS

Plasmalogen

From Wikipedia, the free encyclopedia

Example of a phosphatidylethanolamine plasmalogen with the characteristic vinyl ether linkage at the sn-1 position and an ester linkage at the sn-2 position

Plasmalogens are a type of ether phospholipid characterized by the presence of a vinyl ether linkage at the sn-1 position and an ester linkage at the sn-2 position.[1][2][3] In mammals, the sn-1 position is typically derived from C16:0, C18:0, or C18:1 fatty alcohols while the sn-2 position is most commonly occupied by polyunsaturated fatty acids (PUFAs). The most common head

8

groups present in mammalian plasmalogens are ethanolamine (designated plasmenylethalomines) or choline (designated plasmenylcholines).

Functions

Plasmalogens are found in numerous human tissues, with particular enrichment in the nervous, immune, and cardiovascular system.[1][2][3] In human heart tissue, nearly 30–40% of choline glycerophospholipids are plasmalogens. Even more striking is the fact that almost 30% of the glycerophospholipids in the adult human brain and up to 70% of myelin sheath ethanolamine glycerophospholipids are plasmalogens.[4]

Although the functions of plasmalogens have not yet been fully elucidated, it has been demonstrated that they can protect mammalian cells against the damaging effects of Reactive oxygen species.[1][2][3] In addition, they have been implicated as being signaling molecules and modulators of membrane dynamics.

History

Plasmalogens were first described by Feulgen and Voit in 1924 based on studies of tissue sections.[1] They treated these tissue sections with acid or mercuric chloride as part of a method to stain the nucleus. This resulted in the breakage of the plasmalogen vinyl-ether bond to yield aldehydes. In turn, the latter reacted with a fuchsine-sulfurous acid stain used in this nuclear staining method and gave rise to colored compounds inside the cytoplasm of the cells. Plasmalogens were named based on the fact that these colored compounds were present in the "plasmal" or inside of the cell.[1]

9

Biosynthesis

Plasmalogen-Biosynthesis

Biosynthesis of plasmalogens (PLs) begins with association of peroxisomal matrix enzymes GNPAT (glycerone phosphate acyl transferase) and AGPS (alkyl-glycerone phosphate synthase) on the luminal side of the peroxisomal membrane.[5] These two enzymes can physically interact with each other to increase efficiency. Therefore fibroblasts without AGPS activity have a reduced GNPAT level and activity.[6][7]

The first step of the biosynthesis is catalyzed by GNPAT. This enzyme acylates dihydroxyacetone phosphate (DHAP) at the sn-1 position. This is followed by the exchange of the acyl group for an alkyl group by AGPS.[8] The 1-alkyl-DHAP is then reduced to 1-O-alkyl-2-hydroxy-sn-glycerophosphate (GPA) by an acyl/alkyl-DHAP reductase located in both peroxisomal and endoplasmatic reticulum (ER) membranes.[9] All other modifications occur in the ER. There an acyl group is placed at the sn-2 position by an alkyl/acyl GPA acyltransferase and the phosphate group is removed by a phosphatidic acid phosphatase to form 1-O-alkyl-2-acyl-sn-glycerol.

Using CDP-ethanolamine a phosphotransferase forms 1-O-alkyl-2-acyl-sn-GPEtn. After dehydrogenation at the 1- and 2-positions of the alkyl group by an electron transport system and plasmenylethanolamine desaturase the vinyl ether bond of plasmalogens is finally formed. Plasmenylcholine is formed from 1-O-alkyl-2-acyl-sn-glycerol by choline phosphotransferase. As there is no plasmenylcholine desaturase choline plasmalogens can be formed only after

10

hydrolysis of ethanolamine PLs to 1-O-(1Z-alkenyl)-2-acyl-sn-glycerol that can be modified by choline phosphotransferase and CDP choline.

Pathology

Peroxisome biogenesis disorders are autosomal recessive disorders often characterized by impaired plasmalogen biosynthesis. In these cases, the peroxisomal enzyme GNPAT, necessary for the initial steps of plasmologen biosynthesis, is mislocalized to the cytoplasm where it is inactive. In addition, genetic mutations in the GNPAT or AGPS genes can result in plasmalogen deficiencies, which lead to the development of rhizomelic chondrodysplasia punctata (RCDP) type 2 or 3, respectively. In such cases, both copies of the GNPAT or AGPS gene must be mutated in order for disease to manifest. Unlike the peroxisome biogenesis disorders, other aspects of peroxisome assembly in RCDP2 and RCDP3 patients are normal as is their ability to metabolize very long chain fatty acids. Individuals with severe plasmalogen deficiencies frequently show abnormal neurological development, skeletal malformation, impaired respiration, and cataracts. Plasmalogen-knockout mice show similar alterations like arrest of spermatogenesis, development of cataract and defects in central nervous system myelination.

Possible disease links

Reduced levels of brain tissue plasmalogens have been associated with Alzheimer's Disease,[16][17]

[18][19] X-linked adrenoleukodystrophy, and Down syndrome.

Plasmalogens and evolution

In addition to mammals, plasmalogens are also found in invertebrates and single cell organisms protozoans. Among bacteria they have been found in many anaerobic species including Clostridia, Megasphaera, and Veillonella. Plasmalogens have been shown to have a complex evolutionary history based on the fact that their biosynthetic pathways differ in aerobic and anaerobic organisms.[23]

Recently, it has been demonstrated that the red blood cells of humans and great apes (chimpanzees, bonobos, gorillas, and orangutans) have differences in their plasmalogen composition.[3] Total RBC plasmalogen levels were found to be lower in humans than bonobos, chimpanzees, and gorillas, but higher than orangutans. Gene expression data from all these species caused the authors to speculate that other human and great ape cells and tissues differ in plasmalogen levels. Although the consequences of these potential differences are unknown, cross-species differences in tissue plasmalogens could influence organ functions and multiple biological processes.

5. GLYCOLIPIDS

Glycolipids are lipids with a carbohydrate attached. Their role is to provide energy and also serve as markers for cellular recognition. The carbohydrates are found on the outer surface of

11

all eukaryotic cell membranes. They extend from the phospholipid bilayer into the aqueous environment outside the cell where it acts as a recognition site for specific chemicals as well as helping to maintain the stability of the membrane and attaching cells to one another to form tissues.

Metabolism

The carbohydrate structure of the glycolipid is controlled by the glycosyltransferases that add the lipids and glycosylhydrolases that modify the glycan after addition.

Sphingolipidoses can be associated with defects in metabolism.

Types of glycolipids

The following is an incomplete listing of glycolipid types.

This list is incomplete; you can help by expanding it.

Glyceroglycolipids o Galactolipids o Sulfolipids (SQDG)

Glycosphingolipids o Cerebrosides

Galactocerebrosides o Greatocerbicides

Glucocerebrosides Sulfatides

o Gangliosides (the most complex animal glycolipids; contain negatively charged oligosacchrides with one or more sialic acid residues; more than 200 [1] different gangliosides have been identified; they are most abundant in nerve cells)

o Globosides

12

o Glycophosphosphingolipids (complex glycophospholipids from fungi, including yeasts, and in plants, where they were originally called "phytoglycolipids" by Herbert Carter, et al., may comprise as complicated a set of compounds as the negatively charged gangliosides in animals. The head group of a glycolipid is composed of sugars.

Glycosylphosphatidylinositols

6. SPHINGOLIPIDS

Sphingolipids general structures

Sphingolipids, or glycosylceramides, 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 for the mythological Sphinx because of their enigmatic nature.[1] These compounds play important roles in signal transmission and cell recognition. Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact on neural tissue. A sphingolipid with an R group consisting of a hydrogen atom only is a ceramide. Other common R groups include phosphocholine, yielding a sphingomyelin, and various sugar monomers or dimers, yielding cerebrosides and globosides, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.

Structure

The long-chain bases, sometimes simply known as sphingoid bases, are the first non-transient products of de novo sphingolipid synthesis in both yeast and mammals. These compounds, specifically known as phytosphingosine and dihydrosphingosine (also known as sphinganine,[2]

13

although this term is less common), are mainly C18 compounds, with somewhat lower levels of C20 bases.[3] Ceramides and glycosphingolipids are N-acyl derivatives of these compounds.[4]

The sphingosine backbone is O-linked to a (usually) charged head group such as ethanolamine, serine, or choline.

The backbone is also amide-linked to an acyl group, such as a fatty acid.

Types

Simple sphingolipids, which include the sphingoid bases and ceramides, make up the early products of the sphingolipid synthetic pathways.

Sphingoid bases are the fundamental building blocks of all sphingolipids. The main mammalian sphingoid bases are dihydrosphingosine and sphingosine, while dihydrosphingosine and phytosphingosine are the principle sphingoid bases in yeast.[5][6]

Sphingosine, dihydrosphingosine, and phytosphingosine may be phosphorylated. Ceramides , as a general class, are N-acylated sphingoid bases lacking additional head

groups. o Dihydroceramide is produced by N-acylation of dihydrosphingosine.

Dihydroceramide is found in both yeast and mammalian systems.o Ceramide is produced in mammalian systems by desaturation of

dihydroceramide by dihydroceramide desaturase 1 (DES1). This highly bioactive molecule may also be phosphorylated to form ceramide-1-phosphate.

o Phytoceramide is produced in yeast by hydroxylation of dihydroceramide at C-4.

Complex sphingolipids may be formed by addition of head groups to ceramide or phytoceramide:

Sphingomyelins have a phosphocholine or phosphoethanolamine molecule with an ester linkage to the 1-hydroxy group of a ceramide.

Glycosphingolipids are ceramides with one or more sugar residues joined in a β-glycosidic linkage at the 1-hydroxyl position (see image).

o Cerebrosides have a single glucose or galactose at the 1-hydroxy position. Sulfatides are sulfated cerebrosides.

o Gangliosides have at least three sugars, one of which must be sialic acid. Inositol -containing ceramides, which are derived from phytoceramide, are produced in

yeast. These include inositol phosphorylceramide, mannose inositol phosphorylceramide, and mannose diinositol phosphorylceramide.

Mammalian sphingolipid metabolism

De novo sphingolipid synthesis begins with formation of 3-keto-dihydrosphingosine by serine palmitoyltransferase.[7] The preferred substrates for this reaction are palmitoyl-CoA and serine. However, studies have demonstrated that serine palmitoyltransferase has some activity toward

14

other species of fatty acyl-CoA[8] and alternative amino acids,[9] and the diversity of sphingoid bases has recently been reviewed.[10] Next, 3-keto-dihydrosphingosine is reduced to form dihydrosphingosine. Dihydrosphingosine is acylated by a (dihydro)-ceramide synthase, such as Lass1p or Lass2p (also termed as CerS), to form dihydroceramide.[11] This is desaturated to form ceramide.[12]

Metabolic pathways of various forms of sphingolipids. Sphingolipidoses are labeled at corresponding stages that are deficient.

Ceramide may subsequently have several fates. It may be phosphorylated by ceramide kinase to form ceramide-1-phosphate. Alternatively, it may be glycosylated by glucosylceramide synthase or galactosylceramide synthase. Additionally, it can be converted to sphingomyelin by the addition of a phosphorylcholine headgroup by sphingomyelin synthase. Diacylglycerol is generated by this process. Finally, ceramide may be broken down by a ceramidase to form sphingosine. Sphingosine may be phosphorylated to form sphingosine-1-phosphate. This may be dephosphorylated to reform sphingosine.[13]

Breakdown pathways allow the reversion of these metabolites to ceramide. The complex glycosphingolipids are hydrolyzed to glucosylceramide and galactosylceramide. These lipids are then hydrolyzed by beta-glucosidases and beta-galactosidases to regenerate ceramide. Similarly, sphingomyelin may be broken down by sphingomyelinase to form ceramide.

The only route by which sphingolipids are converted to non-sphingolipids is through sphingosine-1-phosphate lyase. This forms ethanolamine phosphate and hexadecenal.[14]

15

Functions of mammalian sphingolipids

Sphingolipids are commonly believed to protect the cell surface against harmful environmental factors by forming a mechanically stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer. Certain complex glycosphingolipids were found to be involved in specific functions, such as cell recognition and signaling. Cell recognition depends mainly on the physical properties of the sphingolipids, whereas signaling involves specific interactions of the glycan structures of glycosphingolipids with similar lipids present on neighboring cells or with proteins.

Recently, simple sphingolipid metabolites, such as ceramide and sphingosine-1-phosphate, have been shown to be important mediators in the signaling cascades involved in apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, senescence, and differentiation.[15][16][17][18][19][20] Ceramide-based lipids self-aggregate in cell membranes and form separate phases less fluid than the bulk phospholipids. These sphingolipid-based microdomains, or "lipid rafts" were originally proposed to sort membrane proteins along the cellular pathways of membrane transport. At present, most research focuses on the organizing function during signal transduction.[21]

Sphingolipids are synthesized in a pathway that begins in the ER and is completed in the Golgi apparatus, but these lipids are enriched in the plasma membrane and in endosomes, where they perform many of their functions.[22] Transport occurs via vesicles and monomeric transport in the cytosol. Sphingolipids are virtually absent from mitochondria and the ER, but constitute a 20-35 molar fraction of plasma membrane lipids.[23]

In experimental animals, feeding sphingolipids inhibits colon carcinogenesis, reduces (bad) LDL cholesterol and elevates (good) HDL cholesterol.[24]

Yeast sphingolipids

Because of the incredible complexity of mammalian systems, yeast are often used as a model organism for working out new pathways. These single-celled organisms are often more genetically tractable than mammalian cells, and strain libraries are available to supply strains harboring almost any non-lethal open reading frame single deletion. The two most commonly used yeasts are Saccharomyces cerevisiae and Schizosaccharomyces pombe, although research is also done in the pathological yeast Candida albicans.

In addition to the important structural functions of complex sphingolipids (inositol phosphorylceramide and its mannosylated derivatives), the sphingoid bases phytosphingosine and dihydrosphingosine (sphinganine) play vital signaling roles in S. cerevisiae. These effects include regulation of endocytosis, ubiquitin-dependent proteolysis (and, thus, regulation of nutrient uptake [25]), cytoskeletal dynamics, the cell cycle, translation, posttranslational protein modification, and the heat stress response.[26] Additionally, modulation of sphingolipid metabolism by phosphatidylinositol (4,5)-bisphosphate signaling via Slm1p and Slm2p and calcineurin has recently been described.[27] Additionally, a substrate-level interaction has been

16

shown between complex sphingolipid synthesis and cycling of phosphatidylinositol 4-phosphate by the phosphatidylinositol kinase Stt4p and the lipid phosphatase Sac1p.[28]

Plant sphingolipids

Higher plants contain a wider variety of sphingolipids than animals and fungi.

Disorders

There are several disorders of sphingolipid metabolism, known as sphingolipidoses. The main members of this group are Niemann-Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay-Sachs disease and Metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but notably Fabry disease is X-linked. Taken together, sphingolipidoses have an incidence of approximately 1 in 10.000, but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.

17