Lippincott's Biochemistry Chapter 17 - Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism PDF

Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism MEMBRANE EXTRACELWLAR SPACE I. PHOSPHOLIPID OVERVIEW Phospholipids are polar, ionic compounds composed of an alcohol 1hat is attached by a phosphodiest...

Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism MEMBRANE EXTRACELWLAR SPACE I. PHOSPHOLIPID OVERVIEW Phospholipids are polar, ionic compounds composed of an alcohol 1hat is attached by a phosphodiester bond to either diacylglycerol (DAG) ~rophoblc tall "-....l',.--'--'"" 0 t Glycerol backbone Polar head II or sphingosine. Like fatty acids (FA), phospholipids are amphipathic in C-O-CH1 nature. That is, each has a hydrophilic head, which is the phosphate group 9 I c·O-fi* + r;aHa plus whatever alcohol is attached to it (for example, serine, ethanolamine, and choline; highlighted in blue in Fig. 17.1A), and a long, hydropho- CH1 ®- CH~H I bic tail containing FA or FA-derived hydrocarbons (shown in orange in coo- Fig. 17.1A). Phospholipids are the predominant lipids of cell membranes. Phoaphatldyl rlne In membranes, 1he hydrophobic portion of a phospholipid molecule is associated with the nonpolar portions of other membrane constituents, such as glycolipids, proteins, and cholesterol. The hydrophilic (polar} head of the phospholipid extends outward, interacting with the intracellular or extracellular aqueous environment (see Fig. 17.1A). Membrane phos- pholipids also function as a reservoir for intracellular messengers, and, for some proteins, phospholipids serve as anchors to cell membranes. PhOlphatldylethanolamlne Nonmembrane phospholipids serve additional functions in the body, for example, as components of lung surfactant and essential components of bile, where their detergent properties aid cholesterol solubilization. 0 " C-O-CH1 II. PHOSPHOLIPID STRUCTURE I I?C-0-~ CH3 I CH1-@CHP"L,ltt /I There are two classes of phospholipids: those that have glycerol (from CHaCHa Phoephldldylchollne glucose) as a backbone and those 1hat have sphingosine (from serine and palmitate). Both classes are found as structural components of mem- 0 branes, and bo1h play a role in 1he generation of lipid signaling molecules. " C-O-CH1 I 9C-0-CH A. Glycerophospholipids Phospholipids that contain glycerol are called glycerophospholipids °"··® Phosphatidic acid (or phosphoglycerides}. Glycerophospholipids constitute 1he major class of phospholipids and are the predominant lipids in membranes. Figure 17.1 All contain (or are derivatives of) phosphatidic acid (PA), which is DAG A. Structures of some glycerophos· with a phosphate group on carbon 3 (Fig. 17.1 B). PA is the simplest pholipids. B. Phosphatidic acid. phosphoglyceride and is 1he precursor of the other members of 1his ® =phosphate (an anion). group. 201 202 17. Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism 1. From phosphatidic acid and an alcohol: The phosphate group / T"\---g"O on PA can be esterified to a compound containing an alcohol group (see Fig. 17.1). For example: Serine + PA -+ phosphatidylserine (PS) I Ethanolamine + PA -+ phosphatidylethanolamine (PE) 9 9 yli:! Choline + PA -+ phosphatidylcholine (PC) (lecithin) ~ 9H~- - C- 0 - C - H - COCH HI I Inositol + PA -+ phosphatidylinositol (Pl) I CH2-®-C!-ti!- y - C~-®-Ci-ti! Glycerol + PA -+ phosphatidylglycerol (PG) Polar ~ OH head 2. Cardiolipin: Two molecules of PA esterified through their phos- C&rdlollpln phate groups to an additional molecule of glycerol form cardio- lipin, or diphosphatidylglycerol (Fig. 17.2). Cardiolipin is found in membranes in bacteria and eukaryotes. In eukaryotes, cardiolipin Figure 17.2 is virtually exclusive to the inner mitochondrial membrane, where it maintains the structure and function of certain respiratory com- Structure of cardiolipin (diphosphati· dylglycerol}. ® = phosphate. plexes of the electron transport chain. [Note: Cardiolipin is antigenic and is recognized by antibodies {Ab) raised against Treponema pallidum, the bacterium that causes syphilis. The Wasserman test for syphilis detects these Ab.] 3. Plaamalogens: When the FA at carbon 1 of a glycerophospho- lipid is replaced by an unsaturated alkyl group attached by an ether (rather than by an ester) linkage to the core glycerol molecule, an ether phosphoglyceride known as a plasmalogen is produced. For example, phosphatidalethanolamine, which is abundant in nerve Unuturated tissue (Fig. 17.3A), is the plasmalogen that is similar in structure 9 ~· / '?H20- CH = CH to phosphatidylethanolamine. Phosphatidalcholine (abundant in heart muscle) is the other quantitatively significant ether lipid in - C- 0 - CH 0 mammals. [Note: Plasmalogens have "al" rather than "yl in their I 11 + names.] 'A;;( CH2-0 - ~- OCH2PH2NH:i.,oup t 0- 4. Platelet-activating factor: A second example of an ether glyc- erophospholipid is platelet-activating factor (PAF), which has a Glycerol backbone saturated alkyl group in an ether link to carbon 1 and an acetyl Phoephelldalelhanolemlne residue (rather than a FA) at carbon 2 of the glycerol backbone (Fig. 17.3B). PAF is synthesized and released by a variety of cell types. It binds to surface receptors, triggering potent thrombotic and acute inflammatory events. For example, PAF activates inflam- matory cells and mediates hypersensitivity, acute inflammatory, and anaphylactic reactions. It causes platelets to aggregate and activate and neutrophils and alveolar macrophages to generate superoxide radicals to kill bacteria (see p. 150). It also lowers blood pressure. [Note: PAF is one of the most potent bioaclive molecules known, causing effects at concentrations as low as 10-11 mol/I.] Platele1'4.Ctlvatlng factor B. Sphlngophosphollplds: Sphlngomyelln The backbone of sphingomyelin is the amino alcohol sphingosine, Figure 17.3 rather than glycerol (Fig. 17.4). A long-chain-length FA (LCFA) is The ether glycerophospholipids. attached to the amino group of sphingosine through an amide link- A. The plasmalogen phosphati- age, producing a ceramide, which can also serve as a precursor dalethanolamine. B. Platelet- of glycolipids (see p. 209). The alcohol group at carbon 1 of sphin- activating factor. ( is a long, gosine is esterified to phosphorylcholine, producing sphingomyelin, hydrophobic hydrocarbon chain.) the only significant sphingophospholipid in humans. Sphingomyelin Ill. Phospholipid Synthesis 203 is an important constituent of the myelin sheath of nerve fibers. [Note: The myelin sheath is a layered, membranous structure that Ceramide CHa insulates and protects neuronal axons of the central nervous sys-.__........... I tem {CNS).] CH2-~-ctitCH2't° 9 J 1 ~bH3 C- NH- 1H L... Chollna L Ill. PHOSPHOLIPID SYNTHESIS CH- OH : Glycerophospholipid synthesis involves either the donation of PA from cytidine diphosphate (CDP)·DAG to an alcohol or the donation of the -- /--~'~---] Fatty acid phosphomonoester of the alcohol from CDP-alcohol to DAG (Fig.17.5). In both cases, the CDP-bound structure is considered an activated intermediate, and cytidine monophosphate (CMP) is released as a side Figure 17.4 product. Therefore, a key concept in glycerophospholipid synthesis is Structure of sphlngomyelln, showing activation, of either DAG or the alcohol to be added, by linkage with CDP. sphlngoslne (In green box) and [Note: This is similar in principle to the activation of sugars by their attach- ceramide components (in dashed ment to uridine diphosphate (UDP) (seep. 126).) The FA esterified to the box). ® = phosphate. glycerol alcohol groups can vary widely, contributing to the heterogeneity of this group of compounds, with saturated FA typically found at carbon Phomphldldlc add 1 and unsaturated ones at carbon 2. Most phospholipids are synthesized in the smooth endoplasmic reticulum (SER). From there, they are trans- ported to the Golgi and then to membranes of organelles or the plasma membrane or are secreted from the cell by exocytosis. [Note: Ether lipid synthesis from dihydroxyacetone phosphate begins in peroxisomes.] t: " H:zY-O-C 0 A. Phosphatidic acid -c-o- II cI -H 0 H~-O- CDP PA is the precursor of other glycerophospholipids. The steps in its synthesis from glycerol 3-phosphate and two fatty acyl coenzyme A CDP-dlacylglycerol ALCOHOL t=~ (CoA} molecules were illustrated in Figure 16.14, p. 189, in which PA is shown as a precursor of triacylglycerol (TAG). 0 II Essentially all cells except mature erythrocytes can synthe- H~ -0- C size phospholipids, whereas TAG synthesis occurs essentially C- O- C - H only in the liver, adipose tissue, lactating mammary glands, II I and intestinal mucosal cells. 0 H~ -® -Ak:ohol B. Phosphatldylchollna and phosphatlctylethanolamlne The neutral phospholipids PC and PE are the most abundant phos- pholipids in most eukaryotic cells. The primary route of their synthesis 0II uses choline and ethanolamine obtained either from the diet or from 9 H~- o- c the turnover of the body's phospholipids. [Note: In the liver, PC also - C-O-C- H can be synthesized from PS and PE (see 2. below).] H~- OH Pi 1. Synthesis from preexisting choline and ethanolamlne: These Dlacylglyoerol ~ Phoaphalklo acid synthetic pathways involve the phosphorylation of choline or etha- nolamine by kinases, followed by conversion to the activated form, Figure 17.5 CDP-choline or CDP-ethanolamina. Finally, choline phosphate or Glycerophospholipid synthesis ethanolamine phosphate is transferred from the nucleotide (leav- requires activation of either ing CMP) to a molecule of DAG (see Fig. 17.5). diacylglycerol or an alcohol by linkage to cytidine diphosphate (CDP). CMP and CTP = cytidine mono· and triphosphates; P1 =inorganic phosphate; PPi =pyrophosphate. ( is a fatty acid hydrocarbon chain.) 204 17. Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism a. Significance of chollna raudllzatlon: The reutilization of choline is important because, although humans can synthesize choline ~ novo. the amount made is insufficient for our needs. Thus, cho- line is an essential dietary nutrient with an adequate intake (see p. 358) of 550 mg for men and 425 mg for women. [Note: Choline is also used forthe synthesis of acetylcholine, a neurotransmitter.] Phoaphalldyleerlne Ethanolamlne b. Phosphatldylchollne In lung surfactant: The pathway described above is 'the principal pathway for the synthesis of dipalmitoylphos- I Phosphatkiyl- ~ 1 Pho6phatklyf- phatidylcholine (DPPC or, dipalmitoyl lecithin). In DPPC, positions 1 and 2 on the glycerol are occupied by palmitate, a saturated S6ffne ethanoltJmJr1tr LCFA. DPPC, made and secreted by type II pneumocytes, is a decarboxylase ssrine major lipid component of lung surfactant, which is 'the extracellu- (besu.:=ge lar fluid layer lining the alveoli. Surfactant serves to decrease the reaction) surface tension of this fluid layer, reducing the pressure needed to 0 ~/ \ reinflate alveoli, thereby preventing alveolar collapse (atelectasis). [Note: Surfactant is a complex mixture of lipids (90%) and proteins + II C·O- CH2 i:™a (10%}, with DPPC being the major component for reducing sur- 9 I HO·CHz«;:H face tension.] C·O-