Phosphatidylserine serine

CDP-ethanolamine -4- a,/S-diglyceride — CMP phosphatidylethanolamine CDP-choline - - a,0-diglyceride CMP + lecithin CDP-choline - - iV-acylsphingosine — sphingomyelin CMP CDP-a,0-diglyceride -1- serine — phosphatidylserine - - CMP Teichoic Acid Synthesis... 

Exchange of Ethanolamine for Serine Converts Phosphatidylethanolamine to Phosphatidylserine... 

Mammals synthesize phosphatidylserine (PS) in a calcium ion-dependent reaction involving aminoalcohol exchange (Figure 25.21). The enzyme catalyzing this reaction is associated with the endoplasmic reticulum and will accept phosphatidylethanolamine (PE) and other phospholipid substrates. A mitochondrial PS decarboxylase can subsequently convert PS to PE. No other pathway converting serine to ethanolamine has been found. 

Two routes to phospholipid biosynthesis are known in either, the participation of CTP is necessary. The first route involves phosphatidic acid in phosphoglyceride biosynthesis. Phosphatidic acid reacts with CTP to yield CDP-diglyceride which, as a coenzyme, can participate in the transfer of diglyceride onto serine (or inositol) to produce phosphatidylserine (or phosphatidylinositol). Serine phosphatides are liable to decarboxylation (pyridoxal phosphate acting... 

FIGURE 1 2-2 Schematic diagram of the phosphorylation sites on each of the four 60kDa subunits of tyrosine hydroxylase (TOHase). Serine residues at the N-terminus of each of the four subunits of TOHase can be phosphorylated by at least five protein kinases. (J), Calcium/calmodulin-dependent protein kinase II (CaM KII) phosphorylates serine residue 19 and to a lesser extent serine 40. (2), cAMP-dependent protein kinase (PKA) phosphorylates serine residue 40. (3), Calcium/phosphatidylserine-activated protein kinase (PKC) phosphorylates serine 40. (4), Extracellular receptor-activated protein kinase (ERK) phosphorylates serine 31. (5), A cdc-like protein kinase phosphorylates serine 8. Phosphorylation on either serine 19 or 40 increases the activity of TOHase. Serine 19 phosphorylation requires the presence of an activator protein , also known as 14-3-3 protein, for the expression of increased activity. Phosphorylation of serines 8 and 31 has little effect on catalytic activity. The model shown includes the activation of ERK by an ERK kinase. The ERK kinase is activated by phosphorylation by PKC. (With permission from reference [72].)... 

Phosphatidylserine (PS) in mammalian cells is synthesized through an exchange of free L-serine with the base moiety of pre-existing... 

Figure 1. Synthetic pathway for PS and PE in mammalian cells. The major steps occuring in the synthesis and interconversion of PS and PE are shown. The PS synthases condense serine with a phosphatidyl moiety derived from PC and PE. The nascent PS can be converted to PE by decarboxylation. PE can also be formed by transfer of a phosphoethanolamine moiety from CDP-ethanolamine to diacylglycerol via the Kennedy pathway. The abbreviations used are PC, phosphatidylcholine PS, phosphatidylserine PE, phosphatidylethanolamine DG, diacylglycerol PSD, phosphatidylserine decarboxylase PSS, PS synthase.

Buratta, S., Migliorati, G., Marchetti, C., Mambrini, R., Riccardi, C., and Mozzi, R., 2000, Dexamethasone increases the incorporation of [3H]serine into phosphatidylserine and the activity of serine base exchange enzyme in mouse thymocytes a possible relation between serine base exchange enzyme and apoptosis. MoZ. Cell. Biochem. 211 61-67. 

Phosphatidylcholine (lecithin) is the most abundant phospholipid in membranes. Phosphatidylethanolamine (cephalin) has an ethanolamine residue instead of choline, and phosphatidylserine has a serine residue. In phosphatidylinositol, phosphatidate is esterified with the sugarlike cyclic polyalcohol myo-inositol. A doubly phosphorylated derivative of this phospholipid, phosphatidylinositol 4,5-bisphosphate, is a special component of membranes, which, by enzymatic cleavage, can give rise to two second messengers, diacylglycerol (DAG) and inositol l,4,5trisphosphate (InsPsi see p.386). 

Phosphatidylcholine (l Ethanolamine CDP-ethanolamine Phosphatidylethanolamine (l Palmitoyl CoA Phosphatidylserine Sphingosine Serine... 

This enzyme catalyzes the reaction of a phospholipid (for example, phosphatidylserine) with ethanolamine to produce phosphatidylethanolamine and the free base (/.c., the amine-containing metabolite serine), thereby preserving the phosphodiester linkage. Ethanolamine can be replaced with serine, choline, monomethyletha-nolamine, and dimethylethanolamine. 

Phosphatidylserine and phosphatidylglycerol can serve as precursors of other membrane lipids in bacteria (Fig. 21-25). Decarboxylation of the serine moiety in phosphatidylserine, catalyzed by phosphatidylserine decarboxylase, yields phosphatidylethanolamine. In E. coli, condensation of two molecules of phosphatidylglycerol, with elimination of one glycerol, yields... 

Yeast, like bacteria, can produce phosphatidylserine by condensation of CDP-diacylglycerol and serine, and can synthesize phosphatidylethanolamine from phosphatidylserine in the reaction catalyzed by phosphatidylserine decarboxylase (Fig. 21-27). In mammalian ceils, an alternative route to phosphatidylserine is a head-group... 

In bacteria, phosphatidylserine is formed by the condensation of serine with CDP-diacylglycerol decarboxylation of phosphatidylserine produces phosphatidylethanolamine. Phosphatidylglycerol is formed by condensation of CDP-diacylglycerol with glycerol 3-phosphate, followed by removal of the phosphate in monoester linkage. 

The diacylglycerols released by phospholipase C diffuse laterally through the bilayer and, together with the incoming Ca2+, activate protein kinases C. These kinases also require phosphatidylserine for their activity and phosphorylate serine and threonine side chains in a variety of proteins.329 330b They are stimulated by the released unsaturated diacylglycerols. In addition protein kinases C can be activated by phorbol esters, which are the best known tumor promoters (Box 11-D). The diacylglycerol requirement favors a function for these protein kinases in membranes. They also appear to cooperate with calmodulin to activate the Ca2+-dependent contraction of smooth muscle.330... 

The formation of phosphatidylserine and possibly other phospholipids in animal tissues may also be accomplished by exchange reactions (Eq. 21-10, step a). 82 83 At the same time, decarboxylation of phosphatidylserine back to phosphatidylethanolamine (Eq. 21-10, step b) also takes place, the net effect being a catalytic cycle for decarboxylation of serine to ethano-lamine. The latter can react with CTP to initiate synthesis of new phospholipid molecules or can be converted to phosphatidylcholine (step c). However, unless there is an excess of methionine and folate in the diet, choline is an essential human nutrient.184... 

Apparently the synthesis via serine and phosphatidylserine cannot provide an adequate amount of choline, which is present in the body not only in phosphatidylcholine but in plasmalogens, sphingomyelins, and the neurotransmitter acetylcholine.185... 

In prokaryotes, phosphatidylserine is made from CDP-diacylglycerol (see fig. 19.3). The enzyme for this reaction is absent in animal cells, which rely on a base exchange reaction in which serine and ethanolamine are interchanged (fig. 19.8). Although the reaction is reversible, it usually proceeds in the direction of phosphatidylserine synthesis. Phosphatidylserine can be converted back to phos-phatidylethanolamine by a decarboxylation reaction in the mitochondria. This may be the preferred route for phosphatidylethanolamine biosynthesis in some animal cells. Furthermore these two reactions (see fig. 19.8) establish a cycle that has the net effect of converting serine into ethanolamine. This is the main route for ethanolamine synthesis... 

Phosphatidylserine biosynthesis in animals is catalyzed by a base exchange enzyme on the endoplasmic reticulum. Decarboxylation of phosphatidylserine occurs in mitochondria. The cyclic process of phosphatidylserine formation from phosphatidylethanolamine and the reformation of phosphatidylethanolamine by decarboxylation has the net effect of converting serine to ethanolamine. This is a major mechanism for the synthesis of ethanolamine in many eukaryotes. 

PKC is a serine/threonine protein kinase comprised of at least 11 isozymic forms (Nishizuka 1995 Liu and Heckman 1998). These isozymic forms have been classified as atypical, classical, and novel. Classical PKCs (a, pi, pH, and y) are activated by Ca2+, DAG, phosphatidylserine (PS), and the tumor promoter phorbol 12-myristate 13-acetate (PMA). Novel PKCs (6, e, r, i, and 0) are activated by DAG, PS, and unsaturated fatty acids, while atypical PKCs (C, A, and 0 are insensitive to DAG but are activated by PS and phosphatidylinositides (reviewed in Liu and Heckman 1998 Newton and Johnson 1998 Nakanishi et al. 1993). PKCs have been implicated in a wide variety of cellular responses, including growth, differentiation, gene expression, angiogenesis, contractility, and vesicle trafficking (Nishizuka 1995). 

Above, /V-(carboxymethyl)phosphatidylcthanolamine was reported to be present in red blood cell membranes to the extent of 0.14 mmol mol-1 ethanolamine,142 yet /V-fcarboxymcthyl)phosphatidylserinc has been obtained in 0.44 mmol mol-1 serine,140 even though the ratio of phosphatidylethanolamine to phosphatidylserine is about 2 1. Such preferential modification of phosphatidylserine was unexpected. 

Notwithstanding its limited status in the biochemical behavior of a cell, phosphatidylserine is nevertheless an interesting compound. It is the only amino acid-containing phosphoglyceride found in mammalian cells. Furthermore, it exists only in the diacyl form, with no evidence to date for an alkylacyl or alkenylacyl form. Thus, it can be described as a 1,2-diacyl-, m-glycero-3-phospho-L-serine. 

Phospholipase A2 Action. Incubation of phosphatidylserine with phospholipase A2 obtained from Crotalus adamanteus or Naja Naja snake venom will show that the serine-containing phosphoglyceride was smoothly and completely converted to a lysophosphatidylserine with liberation of 1 mol of fatty acid per mole of lipid P. The experimental procedure was the same as the one described before in this and in the previous chapter. The products of the reaction can be recovered by thin-layer chromatography on Whatman K6 plates in a solvent system of chloroform-acetone-methanol-acetic acid-water (4.5 2 1 1.3 0.5, v/v). 

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