Membranes phosphoglycerides

Of the two major phosphohpid classes present in membranes, phosphoglycerides are the more common and consist of a glycerol backbone to which are attached two fatty acids in ester linkage and a phosphorylated alcohol (Figure 41-2). The fatty acid constiments are usually even-numbered carbon molecules, most commonly containing 16 or 18 carbons. They are unbranched and can be saturated or unsamrated. The simplest phosphoglyceride is phosphatidic acid, which is... 

Two questions can be raised regarding the use of these phosphothioates in studies with phospholipase A2. The first is the low total reactivity of phospholipase A2 toward DPPSC as compared to DPPC (without the thio substituent), which is only 4% relative to the natural isomer. The second question relates to the possible chirality of the phosphorus in a membrane phosphoglyceride. To date, the first question appears not to be of immediate importance since the course of the reaction is similar in the thio and nonthio derivatives. As regards the second question, it has not been possible to establish with confidence the configuration of the phosphorus in membrane-bound phosphoglycerides. 

Structure of a lipid bilayer membrane. Phosphoglycerides can aggregate into a bilayer membrane with their polar heads exposed to the aqueous solution and the hydrocarbon tails protected within. This lipid bilayer is an important part of the cell membrane. 

Phosphoglycerides are complex lipids that serve as the major components of cell membranes. Phosphoglycerides and related compounds are also referred to as phospholipids. In these compounds, one of the —OH groups of glycerol is joined by an ester linkage to phosphoric acid, which in turn is linked to another alcohol (usually an aminoalcohol). 

Anandamide amidase recognizes and hydrolyzes 2-AG (Goparaju, 1999 Di Marzo, 1999 Lang, 1999) however, there is evidence for the existence of another specific hydrolase [monoacylglycerol (MAG) lipase] that hydrolyzes 2-AG (D. Piomelli and A. Makriyannis, 2000, personal communication). In addition to this pathway, 2-AG diffuses rapidly into the cell membrane where it could be either hydrolyzed to arachidonic acid and glycerol or esterified back to phosphoglycerides (Di Marzo, 1999b). 

Lipids are transported between membranes. As indicated above, lipids are often biosynthesized in one intracellular membrane and must be transported to other intracellular compartments for membrane biogenesis. Because lipids are insoluble in water, special mechanisms must exist for the inter- and intracellular transport of membrane lipids. Vesicular trafficking, cytoplasmic transfer-exchange proteins and direct transfer across membrane contacts can transport lipids from one membrane to another. The best understood of such mechanisms is vesicular transport, wherein the lipid molecules are sorted into membrane vesicles that bud out from the donor membrane and travel to and then fuse with the recipient membrane. The well characterized transport of plasma cholesterol into cells via receptor-mediated endocytosis is a useful model of this type of lipid transport. [9, 20]. A brain specific transporter for cholesterol has been identified (see Chapter 5). It is believed that transport of cholesterol from the endoplasmic reticulum to other membranes and of glycolipids from the Golgi bodies to the plasma membrane is mediated by similar mechanisms. The transport of phosphoglycerides is less clearly understood. Recent evidence suggests that net phospholipid movement between subcellular membranes may occur via specialized zones of apposition, as characterized for transfer of PtdSer between mitochondria and the endoplasmic reticulum [21]. 

The anaemia in B deficiency is caused by an inability to produce sufficient of the methylating agent S-adenosyhnethionine. This is required by proliferating cells for methyl group transfer, needed for synthesis of the deoxythymidine nucleotide for DNA synthesis (see below and Chapter 20). This leads to failure of the development of the nucleus in the precursor cells for erythrocytes. The neuropathy, which affects peripheral nerves as well as those in the brain, is probably due to lack of methionine for methyl transfer to form choline from ethanolamine, which is required for synthesis of phosphoglycerides and sphingomyelin which are required for formation of myelin and cell membranes. Hence, the neuropathy results from a... 

Cholesterol The pathway for synthesis of cholesterol is described in Appendix 11.9. Cholesterol is important in the structure of membranes since it can occupy the space that is available between the polyunsaturated fatty acids in the phospholipid (Chapter 4). In this position, cholesterol restricts movement of the fatty acids that are components of the phosphoglycerides and hence reduces membrane fluidity. Cholesterol can be synthesised de novo in proliferating cells but it can also be derived from uptake of LDL by the cells, which will depend on the presence of receptors for the relevant apoUpoproteins on the membranes of these cells (Appendix 11.3). 

A. The three major types of amphipathic lipids found in membranes are the gly-cerophospholipids (also called phosphoglycerides), the sphingolipids, and cholesterol. 

Inclusion of other molecules of irregular shape within membranes also lowers Tm. However, a molecule of cholesterol can pack into a bilayer with a cross-sectional area of 0.39 nm2, just equal to that of two hydrocarbon chains.49 It tends to harden membranes above Tm but increases mobility of hydrocarbon chains below Tm.97 -100 A complex of cholesterol and phosphatidylcholine may form a separate phase within the membrane.101102 The ether-linked plasmalogens may account for over 30% of the phosphoglycerides of the white matter of the brain and of heart and ether linked phospholipids are the major lipids of many anaerobic bacteria.103 Their Tm values are a few degrees higher than those of the corresponding acyl phospholipids.104... 

There are several methods to selectively open up closed polymeric membrane compartments in order to release entrapped substances (Fig. 37). For uncorking a polymerized vesicle, its membrane has to contain destabilizable areas which could possibly be opened up by variation of pH 70), temperature increase71), photochemical destabilization 72), or enzymatic processes. Such an enzymatic process is the hydrolysis of a natural phospholipid by phospholipase A2 (Fig. 38). This enzyme cleaves the ester bond in position two of a natural phosphoglyceride producing a lysophospholipid and a fatty acid which are both water soluble. This leads to complete destruction of the membrane. 

Two main types of lipids occur in biological membranes phospholipids and sterols. The predominant phospholipids in most membranes are phosphoglycerides, which are phosphate esters of the three-carbon alcohol, glycerol. A typical structure is that of phosphatidylcholine (lecithin) ... 

In addition to phosphoglycerides, membranes from animal cells usually contain a second group of phospholipids, the sphingolipids. Sphingomyelin, which is representative of this group, has the structure... 

Numerous studies have pointed to an important role for cholesterol during proliferation and progression of cancer (e.g., ref. 612-615). Rapidly dividing cancer cells have two major routes to fulfill their need for cholesterol to form new cell membrane endogenous synthesis of cholesterol and/or receptor-mediated uptake of exogenous LDL particle-associated cholesterol and cholesterol esters (ref. 612,613,615). Each LDL particle contains a cholesterol ester core surrounded by a polar shell of phospholipids (primarily phosphoglycerides), free cholesterol, and apolipoprotein B (ref. 616-618). Once bound to its cell surface receptor, LDL is internalized by receptor-mediated endocytosis and degraded in lysosomes, and the subsequently released cholesterol may be used for membrane synthesis by the tumor (ref. 619). 

This phospholipid is a most prominent member of the phosphoglyceride class of compounds, which frequently account for 50-60% of the total lipid in a cell (or a membrane). 

The main point in this section is to illustrate that the configuration of the polar head group can infuence the reactivity of phospholipase A2. Conceivably this same effect could translate to membrane biochemical pathways involving phosphoglycerides. If further details on the phosphothioates are desired, the review article by Bruzik and Tsai (1991) is recommended. 

When attention is directed toward the phospholipase.C found in mammalian tissue, a rather unique and different substrate profile is evident. It appears that the most favored substrate status must be assigned to the inositol- containing phosphoglycerides, namely, phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP2). There is some evidence that the plasma membrane of certain mammalian cells contains a phospholipase C with high specificity for the bisphosphate, PIP2. The latter enzymatic interaction would be closely associated with the signal transduction pathway in mammalian cells. 

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