Summary

Glycerolipids are based on the trihydric alcohol glycerol. Phosphoglycerides are synthesized in one of three basic pathways. Either a CDP-base derivative reacts with diacylglycerol to produce the phospholipid or CDP-diacylglycerol can be used as an intermediate. The third type of pathway involves the conversion of one phospholipid into another. As a generalization, phosphatidylcholine and phosphatidylethanolamine are made by the CDP-base pathway in eukaryotes while the CDP-diacylglycerol pathway is used for acidic phos-pholipids such as phosphatidylglycerol and phos-phatidylinositol. In both these pathways the hydrophobic part of the phospholipid ultimately derives from the acylation of glycerol 3-phosphate by the Kennedy pathway. The resultant phospha-tidic acid can then be dephosphorylated to yield diacylglycerol or transferred to a cytidine nucleo-tide to produce CDP-diacylglycerol.

Different organisms make their phosphoglycer-ides in different ways. For example, E. coli makes all its phosphoglycerides from CDP-diacylglycerol. Moreover, whereas animals make phosphati-dylserine by an exchange reaction, using another phosphoglyceride, micro-organisms form it from CDP-diacylglycerol and then use phosphatidylser-ine as a key intermediate to synthesize other phosphoglycerides.

The plasmalogen derivatives of phospholipids are made by the same basic pathway as the more usual diacyl analogues except that a l-ether,2-acyl-glycerol substrate is used instead of diacylglycerol. The first documented example of a biologically active phosphoglyceride is platelet activating factor (PAF). Like plasmalogens, PAF contains an ether link at position l, but with an acetyl moiety at position 2. PAF is bound to platelets via specific receptors. It has general effects on intracellular regulation, alters inflammatory responses and interacts with other biologically active lipids.

Phospholipases, responsible for the degradation of phospholipids, often have unique characteristics as enzymes. They usually operate best at the surface of immiscible solvents such as with lipid micelles. The micellar nature of their substrates makes the application of classical enzyme kinetics difficult. Many phospholipases (and lipases) are extremely stable proteins, which exhibit activity in organic solvents and at remarkably high temperatures.

Dependent on the position of attack, phospholi-pases are classified as A, B, C or D. Phospholipases A remove a fatty acid from phospholipids and are subdivided as Al or A2 according to which acyl group is hydrolysed. They are important not only in lipid degradation but also in the turnover of acyl groups and in the release of fatty acids for particular purposes such as eicosanoid production. Phospholipase B removes the remaining fatty acid from a monoacyl (lyso) phospholipid while phos-pholipase C action gives rise to diacylglycerol and a phosphate-base moiety. A phosphatidylinositol-4,5-bisphosphate-specific phospholipase C is responsible for the generation of second messengers from this lipid. Phospholipase D removes the base moiety from a phospholipid to yield phos-phatidate. Phospholipase D enzymes are very active in many plant tissues and can give rise to analytical artefacts if their activity is not carefully controlled. In addition, phospholipase D is recognized as being very important for lipid-signalling reactions in both plants and animals.

In photosynthetic membranes, the major lipid constituents are glycosylglycerides. Mono-galactosyldiacylglycerol is formed by the transfer of galactose from UDP-galactose to diacylglycerol. Digalactosyldiacylglycerol can then be synthesized either by transfer of a second galactose from UDP-galactose to monogalactosyldiacylglycerol or by inter-lipid transfer between two molecules of monogalactosyldiacylglycerol. The formation of the third major glycosylglyceride, the plant sulpholipid (sulphoquinovosyldiacylglycerol) remains undefined although UDP-glucose appears to be a precursor of UDP-sulphoquinovose, which is then used for transfer of sulphoquinovose to diacylglycerol.

Sphingolipids are based on sphingosine bases. Condensation of palmitoyl-CoA with serine yields 3-ketosphinganine, which can then be modified to produce other bases, after acylation of the amino group to yield a ceramide. Once ceramides have been synthesized, their alcohol moiety can be gly-cosylated to various degrees to form cerebrosides, neutral ceramides or gangliosides. Substrate-specific enzymes are used for the transfer of individual sugars during these syntheses. Usually UDP-sugars are the source of the sugar moiety although N-acetyl neuraminic acid is transferred from its CMP derivative. By contrast, sphingomyelin is produced by reaction of a ceramide with phosphatidylcho-line.

Sphingolipids are broken down by substrate-specific enzymes. Sialic acid residues are removed by neuraminidases, galactose by galactosidases and glucose by glucosidases, etc. Almost all of these enzymes are found in lysosomes and their absence gives rise to the accumulation of the respective substrate sphingolipid in tissues. This causes various disease states known as lipidoses.

Cholesterol (and other sterols) is derived from acetyl-CoA. By a series of reactions the 5C-isoprene unit is formed and this can then self-condense to give a series of IOC, 15C, 30C, etc. isoprenoid molecules. Reduction of hydroxymethylglutaryl-CoA (HMG-CoA) is a key regulatory step in the overall process. The enzyme HMG-CoA reductase is regulated at the transcriptional level and by post-transcriptional methods. To form sterols from the open-chain isoprenes requires cyclization and various other modifications are also needed to form the final cholesterol molecule.

A new mevalonate-independent pathway for isopentenyl diphosphate formation has been found in algae and plants. This uses 1-deoxy-D-xylulose-5-phosphate rather than mevalonate as precursor of the isoprene unit.

Cholesterol itself is an important metabolic intermediate - being converted to cholesterol esters, to bile acids, to cholecalciferol (and vitamin D) or to various steroid hormones by different tissues. The synthesis of cholesterol and the regulation of its plasma circulating levels or conversion to other compounds is normally carefully controlled. Several enzymes of the cholesterol bio-synthetic pathway are controlled through a specific transcription factor, the sterol regulatory element binding protein. Furthermore, the ratio of cholesterol to cholesterol ester is carefully regulated in different tissues by the activity of various acyl-transferases.

Many membrane lipids can have specific roles in tissues in addition to their function in membrane structure. Many of these functions relate to their actions as lipid-signalling molecules where they can control diverse aspects of cellular activity such as hormone action, cell differentiation and apoptosis.

One specialized function is found in pulmonary surfactant where dipalmitoylphosphatidylcholine is crucial for the properties of the monolayer at the alveolar air-liquid interface. This monolayer lowers surface tension and prevents lung collapse when breathing out. There are also significant amounts of phosphatidylglycerol (which is unusual for animals) and this phosphoglyceride is believed to aid in the formation and maintenance of the surface layer. Deficiencies in pulmonary surfactant production can lead to respiratory distress. In premature babies this condition can be treated with exogenous surfactants, either artificial or extracted from animal lungs.

Several inborn errors of metabolism exist that involve deficiencies of specific enzymes of lipid metabolism. Prominent amongst these are a series of lipidoses in which sphingolipids build up in various tissues owing to reduced activity of a specific breakdown enzyme. The diseases are autosomal recessive and are particularly serious if the brain is involved. Carriers, who are heterozygous, can be diagnosed because they have 50% of the normal enzyme levels in their tissues. It has proved possible to treat some of the lipidoses by enzyme replacement therapy where the missing enzyme is supplied in liposomes and injected into patients.

Several phospholipids, apart from PAF, are important in cell signalling. The role of inositol phosphoglycerides was the first to be recognized here. In particular, the catabolism of phosphatidyl-

inositol-4,5-b¿sphosphate was found to be stimulated by a whole series of important agonists. The latter cause activation of a selective phospholipase C which catalyses the formation of diacylglycerol and inositol-l,4,5-ír¿sphosphate - both of which have second messenger functions. Diacylglycerol is involved in the activation of protein kinases C. In addition, it can be hydrolysed to yield significant quantities of arachidonate, which is a precursor of eicosanoids. On the other hand, the water-soluble inositol-l,4,5-ír¿sphosphate causes Ca2+ release from intercellular stores and activation of Ca/cal-modulin protein kinases. The activity of the various protein kinases then regulates a host of cellular functions from metabolic regulation to differentiation. In addition to their role in the plasma membrane, inositol phosphoglycerides are also important in the cell nucleus where they are involved in the control of transcription, DNA replication and chromatin structure.

Phosphatidylinositol-3-kinase can generate other important signalling molecules. For example, some forms of protein kinase C are specifically stimulated by phosphatidylinositol-3,4,5-ír¿sphosphate and this lipid can also activate some other types of serine/threonine kinases, of the Akt family. Phos-phatidylinositol-3-kinase itself can act as a protein kinase and, hence, directly activate other cellular signalling pathways. It is also present in the nucleus.

In both plants and animals, phospholipase D activity has been shown to be involved in a wide variety of cellular and physiological processes including phytohormone action (in plants), vesicular trafficking, secretion, cytoskeletal arrangements, myosis, tumour promotion, pathogenesis and senescence. Some phospholipase Ds have binding sites for phosphatidylinositol-4,5-b¿sphos-phate and this provides a connection (cross-talk) between two lipid-signalling pathways. The product of phospholipase D action (phosphatidic acid) is usually rapidly converted to diacylglycerol and both phosphatidic acid and diacylglycerol have independent signalling activities.

Not only do phosphoglycerides have signalling functions, but so do a number of sphingolipids or sphingolipid-derived compounds. Sphingolipids themselves play roles in cellular responses to the environment, modulating receptor responses, membrane trafficking and in controlling morphological changes during growth and differentiation. Catabolic products of sphingolipids such as the sphingolipid bases and ceramide or ceramide 1-phosphate are signalling molecules. For example, ceramide is important in growth arrest, apoptosis and inflammatory responses. It can also inhibit phospholipase D to provide another example of cross-talk between lipid-signalling pathways. Likewise sphingosine bases will interact with lipid metabolism by altering phospholipase C and D activity and eicosanoid production. They also have multiple effects on protein kinases. Although only recently discovered, sphingolipid-derived compounds have a huge array of effects on cells because of their activities in regulating protein kinases, calcium homeostasis and through interactions with other lipid-signalling pathways.

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Responses

  • kari penttinen
    Why udp or cdp derivatives of sugars are used for their transfer to other molecuels?
    8 years ago

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