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Biochemistry_Lippincott_683	Biochemistry_Lippinco	chain-length specificity. Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency causes a decrease in fatty acid oxidation (process stops once a medium-chain fatty acid is produced), resulting in hypoketonemia and severe hypoglycemia. Oxidation of fatty acids with an odd number of carbons proceeds two carbons at a time (producing acetyl CoA) until three-carbon propionyl CoA remains. This compound is carboxylated to methylmalonyl CoA (by biotin-and ATP-requiring propionyl CoA carboxylase), which is then converted to succinyl CoA (a gluconeogenic precursor) by vitamin B12-requiring methylmalonyl CoA mutase. A genetic error in the mutase or vitamin B12 deficiency causes methylmalonic acidemia and aciduria. β-Oxidation of unsaturated fatty acids requires additional enzymes. β-Oxidation of verylong-chain fatty acids and α-oxidation of branched-chain fatty acids occur in the peroxisome. Deficiencies result in X-linked adrenoleukodystrophy and Refsum disease, respectively. ω-Oxidation,	Biochemistry_Lippinco. chain-length specificity. Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency causes a decrease in fatty acid oxidation (process stops once a medium-chain fatty acid is produced), resulting in hypoketonemia and severe hypoglycemia. Oxidation of fatty acids with an odd number of carbons proceeds two carbons at a time (producing acetyl CoA) until three-carbon propionyl CoA remains. This compound is carboxylated to methylmalonyl CoA (by biotin-and ATP-requiring propionyl CoA carboxylase), which is then converted to succinyl CoA (a gluconeogenic precursor) by vitamin B12-requiring methylmalonyl CoA mutase. A genetic error in the mutase or vitamin B12 deficiency causes methylmalonic acidemia and aciduria. β-Oxidation of unsaturated fatty acids requires additional enzymes. β-Oxidation of verylong-chain fatty acids and α-oxidation of branched-chain fatty acids occur in the peroxisome. Deficiencies result in X-linked adrenoleukodystrophy and Refsum disease, respectively. ω-Oxidation,
Biochemistry_Lippincott_684	Biochemistry_Lippinco	verylong-chain fatty acids and α-oxidation of branched-chain fatty acids occur in the peroxisome. Deficiencies result in X-linked adrenoleukodystrophy and Refsum disease, respectively. ω-Oxidation, normally a minor pathway, occurs in the SER. Liver mitochondria can convert acetyl CoA derived from fatty acid oxidation into acetoacetate and 3-hydroxybutyrate (ketone bodies). Peripheral tissues possessing mitochondria can oxidize 3hydroxybutyrate to acetoacetate, which can be cleaved to two acetyl CoA, thereby producing energy for the cell. Unlike fatty acids, ketone bodies are utilized by the brain and, therefore, are important fuels during a fast. Because the liver lacks thiophorase required to degrade ketone bodies, it synthesizes them specifically for the peripheral tissues. Ketoacidosis occurs when the rate of ketone body formation is greater than the rate of use, as is seen in cases of uncontrolled type 1 diabetes mellitus.	Biochemistry_Lippinco. verylong-chain fatty acids and α-oxidation of branched-chain fatty acids occur in the peroxisome. Deficiencies result in X-linked adrenoleukodystrophy and Refsum disease, respectively. ω-Oxidation, normally a minor pathway, occurs in the SER. Liver mitochondria can convert acetyl CoA derived from fatty acid oxidation into acetoacetate and 3-hydroxybutyrate (ketone bodies). Peripheral tissues possessing mitochondria can oxidize 3hydroxybutyrate to acetoacetate, which can be cleaved to two acetyl CoA, thereby producing energy for the cell. Unlike fatty acids, ketone bodies are utilized by the brain and, therefore, are important fuels during a fast. Because the liver lacks thiophorase required to degrade ketone bodies, it synthesizes them specifically for the peripheral tissues. Ketoacidosis occurs when the rate of ketone body formation is greater than the rate of use, as is seen in cases of uncontrolled type 1 diabetes mellitus.
Biochemistry_Lippincott_685	Biochemistry_Lippinco	tricarboxylic acid; VLDL = very-low-density lipoprotein. Choose the ONE best answer. 6.1. When oleic acid, 18:1(9), is desaturated at carbon 6 and then elongated, what is the correct representation of the product? A. 19:2(7,9) B. 20:2 (ω-6) C. 20:2(6,9) D. 20:2(8,11) Correct answer = D. Fatty acids are elongated in the smooth endoplasmic reticulum by adding two carbons at a time to the carboxylate end (carbon 1) of the molecule. This pushes the double bonds at carbon 6 and carbon 9 farther away from carbon 1. The 20:2(8,11) product is an ω-9 (n-9) fatty acid. 6.2. A 4-month-old child is being evaluated for fasting hypoglycemia. Laboratory tests at admission reveal low levels of ketone bodies (hypoketonemia), free carnitine, and long-chain acylcarnitines in the blood. Free fatty acid levels in the blood were elevated. Deficiency of which of the following would best explain these findings? A. Adipose triglyceride lipase B. Carnitine transporter	Biochemistry_Lippinco. tricarboxylic acid; VLDL = very-low-density lipoprotein. Choose the ONE best answer. 6.1. When oleic acid, 18:1(9), is desaturated at carbon 6 and then elongated, what is the correct representation of the product? A. 19:2(7,9) B. 20:2 (ω-6) C. 20:2(6,9) D. 20:2(8,11) Correct answer = D. Fatty acids are elongated in the smooth endoplasmic reticulum by adding two carbons at a time to the carboxylate end (carbon 1) of the molecule. This pushes the double bonds at carbon 6 and carbon 9 farther away from carbon 1. The 20:2(8,11) product is an ω-9 (n-9) fatty acid. 6.2. A 4-month-old child is being evaluated for fasting hypoglycemia. Laboratory tests at admission reveal low levels of ketone bodies (hypoketonemia), free carnitine, and long-chain acylcarnitines in the blood. Free fatty acid levels in the blood were elevated. Deficiency of which of the following would best explain these findings? A. Adipose triglyceride lipase B. Carnitine transporter
Biochemistry_Lippincott_686	Biochemistry_Lippinco	A. Adipose triglyceride lipase B. Carnitine transporter C. Carnitine palmitoyltransferase-I D. Long-chain fatty acid dehydrogenase Correct answer = B. A defect in the carnitine transporter (primary carnitine deficiency) would result in low levels of carnitine in the blood (as a result of increased urinary loss) and low levels in the tissues. In the liver, this decreases fatty acid oxidation and ketogenesis. Consequently, blood levels of free fatty acids rise. Deficiencies of adipose triglyceride lipase would decrease fatty acid availability. Deficiency of carnitine palmitoyltransferase I would result in elevated blood carnitine. Defects in any of the enzymes of β-oxidation would result in secondary carnitine deficiency, with a rise in acylcarnitines.	Biochemistry_Lippinco. A. Adipose triglyceride lipase B. Carnitine transporter C. Carnitine palmitoyltransferase-I D. Long-chain fatty acid dehydrogenase Correct answer = B. A defect in the carnitine transporter (primary carnitine deficiency) would result in low levels of carnitine in the blood (as a result of increased urinary loss) and low levels in the tissues. In the liver, this decreases fatty acid oxidation and ketogenesis. Consequently, blood levels of free fatty acids rise. Deficiencies of adipose triglyceride lipase would decrease fatty acid availability. Deficiency of carnitine palmitoyltransferase I would result in elevated blood carnitine. Defects in any of the enzymes of β-oxidation would result in secondary carnitine deficiency, with a rise in acylcarnitines.
Biochemistry_Lippincott_687	Biochemistry_Lippinco	6.3. A teenager, concerned about his weight, attempts to maintain a fat-free diet for a period of several weeks. If his ability to synthesize various lipids were examined, he would be found to be most deficient in his ability to synthesize: A. cholesterol. B. glycolipids. C. phospholipids. D. prostaglandins. E. triacylglycerol. Correct answer = D. Prostaglandins are synthesized from arachidonic acid. Arachidonic acid is synthesized from linoleic acid, an essential fatty acid obtained by humans from dietary lipids. The teenager would be able to synthesize all other compounds but, presumably, in somewhat decreased amounts.	Biochemistry_Lippinco. 6.3. A teenager, concerned about his weight, attempts to maintain a fat-free diet for a period of several weeks. If his ability to synthesize various lipids were examined, he would be found to be most deficient in his ability to synthesize: A. cholesterol. B. glycolipids. C. phospholipids. D. prostaglandins. E. triacylglycerol. Correct answer = D. Prostaglandins are synthesized from arachidonic acid. Arachidonic acid is synthesized from linoleic acid, an essential fatty acid obtained by humans from dietary lipids. The teenager would be able to synthesize all other compounds but, presumably, in somewhat decreased amounts.
Biochemistry_Lippincott_688	Biochemistry_Lippinco	6.4. A 6-month-old boy was hospitalized following a seizure. History revealed that for several days prior, his appetite was decreased owing to a stomach virus. At admission, his blood glucose was 24 mg/dl (age-referenced normal is 60–100). His urine was negative for ketone bodies and positive for a variety of dicarboxylic acids. Blood carnitine levels (free and acyl bound) were normal. A tentative diagnosis of medium-chain fatty acyl coenzyme A dehydrogenase (MCAD) deficiency is made. In patients with MCAD deficiency, the fasting hypoglycemia is a consequence of: A. decreased acetyl coenzyme A production. B. decreased ability to convert acetyl coenzyme A to glucose. C. increased conversion of acetyl coenzyme A to acetoacetate. D. increased production of ATP and nicotinamide adenine dinucleotide.	Biochemistry_Lippinco. 6.4. A 6-month-old boy was hospitalized following a seizure. History revealed that for several days prior, his appetite was decreased owing to a stomach virus. At admission, his blood glucose was 24 mg/dl (age-referenced normal is 60–100). His urine was negative for ketone bodies and positive for a variety of dicarboxylic acids. Blood carnitine levels (free and acyl bound) were normal. A tentative diagnosis of medium-chain fatty acyl coenzyme A dehydrogenase (MCAD) deficiency is made. In patients with MCAD deficiency, the fasting hypoglycemia is a consequence of: A. decreased acetyl coenzyme A production. B. decreased ability to convert acetyl coenzyme A to glucose. C. increased conversion of acetyl coenzyme A to acetoacetate. D. increased production of ATP and nicotinamide adenine dinucleotide.
Biochemistry_Lippincott_689	Biochemistry_Lippinco	B. decreased ability to convert acetyl coenzyme A to glucose. C. increased conversion of acetyl coenzyme A to acetoacetate. D. increased production of ATP and nicotinamide adenine dinucleotide. Correct answer = A. Impaired oxidation of fatty acids <12 carbons in length results in decreased production of acetyl-coenzyme A (CoA), the allosteric activator of pyruvate carboxylase, a gluconeogenic enzyme, and, thus, glucose levels fall. Acetyl CoA can never be used for the net synthesis of glucose. Acetoacetate is a ketone body, and with medium-chain fatty acyl CoA dehydrogenase deficiency, ketogenesis is decreased as a result of decreased production of the substrate, acetyl CoA. Impaired fatty acid oxidation means that less ATP and nicotinamide adenine dinucleotide are made, and both are needed for gluconeogenesis.	Biochemistry_Lippinco. B. decreased ability to convert acetyl coenzyme A to glucose. C. increased conversion of acetyl coenzyme A to acetoacetate. D. increased production of ATP and nicotinamide adenine dinucleotide. Correct answer = A. Impaired oxidation of fatty acids <12 carbons in length results in decreased production of acetyl-coenzyme A (CoA), the allosteric activator of pyruvate carboxylase, a gluconeogenic enzyme, and, thus, glucose levels fall. Acetyl CoA can never be used for the net synthesis of glucose. Acetoacetate is a ketone body, and with medium-chain fatty acyl CoA dehydrogenase deficiency, ketogenesis is decreased as a result of decreased production of the substrate, acetyl CoA. Impaired fatty acid oxidation means that less ATP and nicotinamide adenine dinucleotide are made, and both are needed for gluconeogenesis.
Biochemistry_Lippincott_690	Biochemistry_Lippinco	6.5. Explain why with Zellweger syndrome both very-long-chain fatty acids (VLCFA) and long-chain phytanic acid accumulate, whereas with X-linked adrenoleukodystrophy, only VLCFA accumulate. Zellweger syndrome is caused by an inability to target matrix proteins to the peroxisome. Therefore, all peroxisomal activities are affected because functional peroxisomes are unable to be formed. In X-linked adrenoleukodystrophy, the defect is an inability to transport VLCFA into the peroxisome, but other peroxisomal functions, such as α-oxidation, are normal. Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism 17 For additional ancillary materials related to this chapter, please visit thePoint. I. PHOSPHOLIPID OVERVIEW	Biochemistry_Lippinco. 6.5. Explain why with Zellweger syndrome both very-long-chain fatty acids (VLCFA) and long-chain phytanic acid accumulate, whereas with X-linked adrenoleukodystrophy, only VLCFA accumulate. Zellweger syndrome is caused by an inability to target matrix proteins to the peroxisome. Therefore, all peroxisomal activities are affected because functional peroxisomes are unable to be formed. In X-linked adrenoleukodystrophy, the defect is an inability to transport VLCFA into the peroxisome, but other peroxisomal functions, such as α-oxidation, are normal. Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism 17 For additional ancillary materials related to this chapter, please visit thePoint. I. PHOSPHOLIPID OVERVIEW
Biochemistry_Lippincott_691	Biochemistry_Lippinco	Phospholipids are polar, ionic compounds composed of an alcohol that is attached by a phosphodiester bond to either diacylglycerol (DAG) or sphingosine. Like fatty acids (FA), phospholipids are amphipathic in nature. That is, each has a hydrophilic head, which is the phosphate group plus whatever alcohol is attached to it (for example, serine, ethanolamine, and choline; highlighted in blue in Fig. 17.1A), and a long, hydrophobic tail containing FA or FA-derived hydrocarbons (shown in orange in Fig. 17.1A). Phospholipids are the predominant lipids of cell membranes. In membranes, the 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 phospholipids also function as a reservoir for intracellular messengers,	Biochemistry_Lippinco. Phospholipids are polar, ionic compounds composed of an alcohol that is attached by a phosphodiester bond to either diacylglycerol (DAG) or sphingosine. Like fatty acids (FA), phospholipids are amphipathic in nature. That is, each has a hydrophilic head, which is the phosphate group plus whatever alcohol is attached to it (for example, serine, ethanolamine, and choline; highlighted in blue in Fig. 17.1A), and a long, hydrophobic tail containing FA or FA-derived hydrocarbons (shown in orange in Fig. 17.1A). Phospholipids are the predominant lipids of cell membranes. In membranes, the 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 phospholipids also function as a reservoir for intracellular messengers,
Biochemistry_Lippincott_692	Biochemistry_Lippinco	extends outward, interacting with the intracellular or extracellular aqueous environment (see Fig. 17.1A). Membrane phospholipids also function as a reservoir for intracellular messengers, and, for some proteins, phospholipids serve as anchors to cell membranes. 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.	Biochemistry_Lippinco. extends outward, interacting with the intracellular or extracellular aqueous environment (see Fig. 17.1A). Membrane phospholipids also function as a reservoir for intracellular messengers, and, for some proteins, phospholipids serve as anchors to cell membranes. 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.
Biochemistry_Lippincott_693	Biochemistry_Lippinco	II. PHOSPHOLIPID STRUCTURE There are two classes of phospholipids: those that have glycerol (from glucose) as a backbone and those that have sphingosine (from serine and palmitate). Both classes are found as structural components of membranes, and both play a role in the generation of lipid signaling molecules. A. Glycerophospholipids Phospholipids that contain glycerol are called glycerophospholipids (or phosphoglycerides). Glycerophospholipids constitute the major class of phospholipids and are the predominant lipids in membranes. All contain (or are derivatives of) phosphatidic acid (PA), which is DAG with a phosphate group on carbon 3 (Fig. 17.1B). PA is the simplest phosphoglyceride and is the precursor of the other members of this group. 1. From phosphatidic acid and an alcohol: The phosphate group on PA can be esterified to a compound containing an alcohol group (see Fig. 17.1). For example: 2.	Biochemistry_Lippinco. II. PHOSPHOLIPID STRUCTURE There are two classes of phospholipids: those that have glycerol (from glucose) as a backbone and those that have sphingosine (from serine and palmitate). Both classes are found as structural components of membranes, and both play a role in the generation of lipid signaling molecules. A. Glycerophospholipids Phospholipids that contain glycerol are called glycerophospholipids (or phosphoglycerides). Glycerophospholipids constitute the major class of phospholipids and are the predominant lipids in membranes. All contain (or are derivatives of) phosphatidic acid (PA), which is DAG with a phosphate group on carbon 3 (Fig. 17.1B). PA is the simplest phosphoglyceride and is the precursor of the other members of this group. 1. From phosphatidic acid and an alcohol: The phosphate group on PA can be esterified to a compound containing an alcohol group (see Fig. 17.1). For example: 2.
Biochemistry_Lippincott_694	Biochemistry_Lippinco	1. From phosphatidic acid and an alcohol: The phosphate group on PA can be esterified to a compound containing an alcohol group (see Fig. 17.1). For example: 2. Cardiolipin: Two molecules of PA esterified through their phosphate groups to an additional molecule of glycerol form cardiolipin, or diphosphatidylglycerol (Fig. 17.2). Cardiolipin is found in membranes in bacteria and eukaryotes. In eukaryotes, cardiolipin is virtually exclusive to the inner mitochondrial membrane, where it maintains the structure and function of certain respiratory complexes of the electron transport chain. [Note: Cardiolipin is antigenic and is recognized by antibodies 3.	Biochemistry_Lippinco. 1. From phosphatidic acid and an alcohol: The phosphate group on PA can be esterified to a compound containing an alcohol group (see Fig. 17.1). For example: 2. Cardiolipin: Two molecules of PA esterified through their phosphate groups to an additional molecule of glycerol form cardiolipin, or diphosphatidylglycerol (Fig. 17.2). Cardiolipin is found in membranes in bacteria and eukaryotes. In eukaryotes, cardiolipin is virtually exclusive to the inner mitochondrial membrane, where it maintains the structure and function of certain respiratory complexes of the electron transport chain. [Note: Cardiolipin is antigenic and is recognized by antibodies 3.
Biochemistry_Lippincott_695	Biochemistry_Lippinco	Plasmalogens: When the FA at carbon 1 of a glycerophospholipid 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 tissue (Fig. 17.3A), is the plasmalogen that is similar in structure to (Ab) raised against Treponema pallidum, the bacterium that causes syphilis. The Wasserman test for syphilis detects these Ab.] phosphatidylethanolamine. Phosphatidalcholine (abundant in heart muscle) is the other quantitatively significant ether lipid in mammals. [Note: Plasmalogens have “al” rather than “yl” in their names.] plasmalogen phosphatidalethanolamine. B. Platelet-activating factor. ( is a long, hydrophobic hydrocarbon chain.) 4. Platelet-activating factor: A second example of an ether glycerophospholipid is platelet-activating factor (PAF), which has a saturated alkyl group in an ether	Biochemistry_Lippinco. Plasmalogens: When the FA at carbon 1 of a glycerophospholipid 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 tissue (Fig. 17.3A), is the plasmalogen that is similar in structure to (Ab) raised against Treponema pallidum, the bacterium that causes syphilis. The Wasserman test for syphilis detects these Ab.] phosphatidylethanolamine. Phosphatidalcholine (abundant in heart muscle) is the other quantitatively significant ether lipid in mammals. [Note: Plasmalogens have “al” rather than “yl” in their names.] plasmalogen phosphatidalethanolamine. B. Platelet-activating factor. ( is a long, hydrophobic hydrocarbon chain.) 4. Platelet-activating factor: A second example of an ether glycerophospholipid is platelet-activating factor (PAF), which has a saturated alkyl group in an ether
Biochemistry_Lippincott_696	Biochemistry_Lippinco	hydrophobic hydrocarbon chain.) 4. Platelet-activating factor: A second example of an ether glycerophospholipid is platelet-activating factor (PAF), which has a saturated alkyl group in an ether link to carbon 1 and an acetyl 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 inflammatory 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 bioactive molecules known, causing effects at concentrations as low as 10−11 mol/l.]	Biochemistry_Lippinco. hydrophobic hydrocarbon chain.) 4. Platelet-activating factor: A second example of an ether glycerophospholipid is platelet-activating factor (PAF), which has a saturated alkyl group in an ether link to carbon 1 and an acetyl 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 inflammatory 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 bioactive molecules known, causing effects at concentrations as low as 10−11 mol/l.]
Biochemistry_Lippincott_697	Biochemistry_Lippinco	B. Sphingophospholipids: Sphingomyelin The backbone of sphingomyelin is the amino alcohol sphingosine, rather than glycerol (Fig. 17.4). A long-chain-length FA (LCFA) is attached to the amino group of sphingosine through an amide linkage, producing a ceramide, which can also serve as a precursor of glycolipids (see p. 209). The alcohol group at carbon 1 of sphingosine is esterified to phosphorylcholine, producing sphingomyelin, the only significant sphingophospholipid in humans. Sphingomyelin is an important constituent of the myelin sheath of nerve fibers. [Note: The myelin sheath is a layered, membranous structure that insulates and protects neuronal axons of the central nervous system (CNS).] III. PHOSPHOLIPID SYNTHESIS	Biochemistry_Lippinco. B. Sphingophospholipids: Sphingomyelin The backbone of sphingomyelin is the amino alcohol sphingosine, rather than glycerol (Fig. 17.4). A long-chain-length FA (LCFA) is attached to the amino group of sphingosine through an amide linkage, producing a ceramide, which can also serve as a precursor of glycolipids (see p. 209). The alcohol group at carbon 1 of sphingosine is esterified to phosphorylcholine, producing sphingomyelin, the only significant sphingophospholipid in humans. Sphingomyelin is an important constituent of the myelin sheath of nerve fibers. [Note: The myelin sheath is a layered, membranous structure that insulates and protects neuronal axons of the central nervous system (CNS).] III. PHOSPHOLIPID SYNTHESIS
Biochemistry_Lippincott_698	Biochemistry_Lippinco	Glycerophospholipid synthesis involves either the donation of PA from cytidine diphosphate (CDP)-DAG to an alcohol or the donation of the 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 product. Therefore, a key concept in glycerophospholipid synthesis is activation, of either DAG or the alcohol to be added, by linkage with CDP. [Note: This is similar in principle to the activation of sugars by their attachment to uridine diphosphate (UDP) (see p. 126).] The FA esterified to the glycerol alcohol groups can vary widely, contributing to the heterogeneity of this group of compounds, with saturated FA typically found at carbon 1 and unsaturated ones at carbon 2. Most phospholipids are synthesized in the smooth endoplasmic reticulum (SER). From there, they are transported to the Golgi and then to membranes of organelles or the plasma	Biochemistry_Lippinco. Glycerophospholipid synthesis involves either the donation of PA from cytidine diphosphate (CDP)-DAG to an alcohol or the donation of the 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 product. Therefore, a key concept in glycerophospholipid synthesis is activation, of either DAG or the alcohol to be added, by linkage with CDP. [Note: This is similar in principle to the activation of sugars by their attachment to uridine diphosphate (UDP) (see p. 126).] The FA esterified to the glycerol alcohol groups can vary widely, contributing to the heterogeneity of this group of compounds, with saturated FA typically found at carbon 1 and unsaturated ones at carbon 2. Most phospholipids are synthesized in the smooth endoplasmic reticulum (SER). From there, they are transported to the Golgi and then to membranes of organelles or the plasma
Biochemistry_Lippincott_699	Biochemistry_Lippinco	ones at carbon 2. Most phospholipids are synthesized in the smooth endoplasmic reticulum (SER). From there, they are transported 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.] pyrophosphate. ( is a fatty acid hydrocarbon chain.)	Biochemistry_Lippinco. ones at carbon 2. Most phospholipids are synthesized in the smooth endoplasmic reticulum (SER). From there, they are transported 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.] pyrophosphate. ( is a fatty acid hydrocarbon chain.)
Biochemistry_Lippincott_700	Biochemistry_Lippinco	A. Phosphatidic acid PA is the precursor of other glycerophospholipids. The steps in its synthesis from glycerol 3-phosphate and two fatty acyl coenzyme A (CoA) molecules were illustrated in Figure 16.14, p. 189, in which PA is shown as a precursor of triacylglycerol (TAG). Essentially all cells except mature erythrocytes can synthesize phospholipids, whereas TAG synthesis occurs essentially only in the liver, adipose tissue, lactating mammary glands, and intestinal mucosal cells. B. Phosphatidylcholine and phosphatidylethanolamine	Biochemistry_Lippinco. A. Phosphatidic acid PA is the precursor of other glycerophospholipids. The steps in its synthesis from glycerol 3-phosphate and two fatty acyl coenzyme A (CoA) molecules were illustrated in Figure 16.14, p. 189, in which PA is shown as a precursor of triacylglycerol (TAG). Essentially all cells except mature erythrocytes can synthesize phospholipids, whereas TAG synthesis occurs essentially only in the liver, adipose tissue, lactating mammary glands, and intestinal mucosal cells. B. Phosphatidylcholine and phosphatidylethanolamine
Biochemistry_Lippincott_701	Biochemistry_Lippinco	B. Phosphatidylcholine and phosphatidylethanolamine The neutral phospholipids PC and PE are the most abundant phospholipids in most eukaryotic cells. The primary route of their synthesis uses choline and ethanolamine obtained either from the diet or from the turnover of the body’s phospholipids. [Note: In the liver, PC also can be synthesized from PS and PE (see 2. below).] 1. Synthesis from preexisting choline and ethanolamine: These synthetic pathways involve the phosphorylation of choline or ethanolamine by kinases, followed by conversion to the activated form, CDP-choline or CDP-ethanolamine. Finally, choline phosphate or ethanolamine phosphate is transferred from the nucleotide (leaving CMP) to a molecule of DAG (see Fig. 17.5). a.	Biochemistry_Lippinco. B. Phosphatidylcholine and phosphatidylethanolamine The neutral phospholipids PC and PE are the most abundant phospholipids in most eukaryotic cells. The primary route of their synthesis uses choline and ethanolamine obtained either from the diet or from the turnover of the body’s phospholipids. [Note: In the liver, PC also can be synthesized from PS and PE (see 2. below).] 1. Synthesis from preexisting choline and ethanolamine: These synthetic pathways involve the phosphorylation of choline or ethanolamine by kinases, followed by conversion to the activated form, CDP-choline or CDP-ethanolamine. Finally, choline phosphate or ethanolamine phosphate is transferred from the nucleotide (leaving CMP) to a molecule of DAG (see Fig. 17.5). a.
Biochemistry_Lippincott_702	Biochemistry_Lippinco	a. Significance of choline reutilization: The reutilization of choline is important because, although humans can synthesize choline de novo, the amount made is insufficient for our needs. Thus, choline 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 for the synthesis of acetylcholine, a neurotransmitter.] b.	Biochemistry_Lippinco. a. Significance of choline reutilization: The reutilization of choline is important because, although humans can synthesize choline de novo, the amount made is insufficient for our needs. Thus, choline 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 for the synthesis of acetylcholine, a neurotransmitter.] b.
Biochemistry_Lippincott_703	Biochemistry_Lippinco	Phosphatidylcholine in lung surfactant: The pathway described above is the principal pathway for the synthesis of dipalmitoylphosphatidylcholine (DPPC or, dipalmitoyl lecithin). In DPPC, positions 1 and 2 on the glycerol are occupied by palmitate, a saturated LCFA. DPPC, made and secreted by type II pneumocytes, is a major lipid component of lung surfactant, which is the extracellular fluid layer lining the alveoli. Surfactant serves to decrease the surface tension of this fluid layer, reducing the pressure needed to reinflate alveoli, thereby preventing alveolar collapse (atelectasis). [Note: Surfactant is a complex mixture of lipids (90%) and proteins (10%), with DPPC being the major component for reducing surface tension.]	Biochemistry_Lippinco. Phosphatidylcholine in lung surfactant: The pathway described above is the principal pathway for the synthesis of dipalmitoylphosphatidylcholine (DPPC or, dipalmitoyl lecithin). In DPPC, positions 1 and 2 on the glycerol are occupied by palmitate, a saturated LCFA. DPPC, made and secreted by type II pneumocytes, is a major lipid component of lung surfactant, which is the extracellular fluid layer lining the alveoli. Surfactant serves to decrease the surface tension of this fluid layer, reducing the pressure needed to reinflate alveoli, thereby preventing alveolar collapse (atelectasis). [Note: Surfactant is a complex mixture of lipids (90%) and proteins (10%), with DPPC being the major component for reducing surface tension.]
Biochemistry_Lippincott_704	Biochemistry_Lippinco	Fetal lung maturity can be gauged by determining the DPPC/sphingomyelin ratio, usually written as L (for lecithin)/S, in amniotic fluid. A value ≥2 is evidence of maturity, because it reflects the shift from sphingomyelin to DPPC synthesis that occurs in pneumocytes at ~32 weeks’ gestation.	Biochemistry_Lippinco. Fetal lung maturity can be gauged by determining the DPPC/sphingomyelin ratio, usually written as L (for lecithin)/S, in amniotic fluid. A value ≥2 is evidence of maturity, because it reflects the shift from sphingomyelin to DPPC synthesis that occurs in pneumocytes at ~32 weeks’ gestation.
Biochemistry_Lippincott_705	Biochemistry_Lippinco	c. Lung maturity: Respiratory distress syndrome (RDS) in preterm infants is associated with insufficient surfactant production and/or secretion and is a significant cause of all neonatal deaths in Western countries. Lung maturation can be accelerated by giving the mother glucocorticoids shortly before delivery to induce expression of specific genes. Postnatal administration of natural or synthetic surfactant (by intratracheal instillation) is also used. [Note: Acute RDS, seen in all age groups, is the result of alveolar damage (due to infection, injury, or aspiration) that causes fluid to accumulate in the alveoli, impeding the exchange of oxygen (O2) and carbon dioxide (CO2).] 2. Phosphatidylcholine synthesis from phosphatidylserine: The liver requires a mechanism for producing PC, even when free choline levels are low, because it exports significant amounts of PC in the bile and as a component of plasma lipoproteins. To provide the needed PC, PS is decarboxylated to PE by PS	Biochemistry_Lippinco. c. Lung maturity: Respiratory distress syndrome (RDS) in preterm infants is associated with insufficient surfactant production and/or secretion and is a significant cause of all neonatal deaths in Western countries. Lung maturation can be accelerated by giving the mother glucocorticoids shortly before delivery to induce expression of specific genes. Postnatal administration of natural or synthetic surfactant (by intratracheal instillation) is also used. [Note: Acute RDS, seen in all age groups, is the result of alveolar damage (due to infection, injury, or aspiration) that causes fluid to accumulate in the alveoli, impeding the exchange of oxygen (O2) and carbon dioxide (CO2).] 2. Phosphatidylcholine synthesis from phosphatidylserine: The liver requires a mechanism for producing PC, even when free choline levels are low, because it exports significant amounts of PC in the bile and as a component of plasma lipoproteins. To provide the needed PC, PS is decarboxylated to PE by PS
Biochemistry_Lippincott_706	Biochemistry_Lippinco	even when free choline levels are low, because it exports significant amounts of PC in the bile and as a component of plasma lipoproteins. To provide the needed PC, PS is decarboxylated to PE by PS decarboxylase. PE then undergoes three methylation steps to produce PC, as illustrated in Figure 17.6. Sadenosylmethionine is the methyl group donor (see p. 264).	Biochemistry_Lippinco. even when free choline levels are low, because it exports significant amounts of PC in the bile and as a component of plasma lipoproteins. To provide the needed PC, PS is decarboxylated to PE by PS decarboxylase. PE then undergoes three methylation steps to produce PC, as illustrated in Figure 17.6. Sadenosylmethionine is the methyl group donor (see p. 264).
Biochemistry_Lippincott_707	Biochemistry_Lippinco	C. Phosphatidylserine PS synthesis in mammalian tissues is provided by the base exchange reaction, in which the ethanolamine of PE is exchanged for free serine (see Fig. 17.6). This reaction, although reversible, is used primarily to produce the PS required for membrane synthesis. PS has a net negative charge. (See online Chapter 35 for the role of PS in clotting.) D. Phosphatidylinositol	Biochemistry_Lippinco. C. Phosphatidylserine PS synthesis in mammalian tissues is provided by the base exchange reaction, in which the ethanolamine of PE is exchanged for free serine (see Fig. 17.6). This reaction, although reversible, is used primarily to produce the PS required for membrane synthesis. PS has a net negative charge. (See online Chapter 35 for the role of PS in clotting.) D. Phosphatidylinositol
Biochemistry_Lippincott_708	Biochemistry_Lippinco	PI is synthesized from free inositol and CDP-DAG, as shown in Figure 17.5. PI is an unusual phospholipid in that it most frequently contains stearic acid on carbon 1 and arachidonic acid on carbon 2 of the glycerol. Therefore, PI serves as a reservoir of arachidonic acid in membranes and, thus, provides the substrate for prostaglandin (see p. 213) synthesis when required. Like PS, PI has a net negative charge. [Note: There is asymmetry in the phospholipid composition of the cell membrane. PS and PI, for example, are found primarily on the inner leaflet. Asymmetry is achieved by ATP-dependent enzymes known as “flippases” and “floppases.”] 1. Role in signal transduction across membranes: The phosphorylation of membrane-bound PI produces polyphosphoinositides such as phosphatidylinositol 4,5-bisphosphate ([PIP2]; Fig. 17.7). The cleavage of PIP2 by phospholipase C occurs in response to the binding of various neurotransmitters, hormones, and growth factors to G protein–coupled receptors	Biochemistry_Lippinco. PI is synthesized from free inositol and CDP-DAG, as shown in Figure 17.5. PI is an unusual phospholipid in that it most frequently contains stearic acid on carbon 1 and arachidonic acid on carbon 2 of the glycerol. Therefore, PI serves as a reservoir of arachidonic acid in membranes and, thus, provides the substrate for prostaglandin (see p. 213) synthesis when required. Like PS, PI has a net negative charge. [Note: There is asymmetry in the phospholipid composition of the cell membrane. PS and PI, for example, are found primarily on the inner leaflet. Asymmetry is achieved by ATP-dependent enzymes known as “flippases” and “floppases.”] 1. Role in signal transduction across membranes: The phosphorylation of membrane-bound PI produces polyphosphoinositides such as phosphatidylinositol 4,5-bisphosphate ([PIP2]; Fig. 17.7). The cleavage of PIP2 by phospholipase C occurs in response to the binding of various neurotransmitters, hormones, and growth factors to G protein–coupled receptors
Biochemistry_Lippincott_709	Biochemistry_Lippinco	([PIP2]; Fig. 17.7). The cleavage of PIP2 by phospholipase C occurs in response to the binding of various neurotransmitters, hormones, and growth factors to G protein–coupled receptors (GPCR), such as the α1 adrenergic receptor, on the cell membrane and activation of the Gq α-subunit (Fig. 17.8). The products of this cleavage, inositol 1,4,5-trisphosphate (IP3) and DAG, mediate the mobilization of intracellular calcium and the activation of protein kinase	Biochemistry_Lippinco. ([PIP2]; Fig. 17.7). The cleavage of PIP2 by phospholipase C occurs in response to the binding of various neurotransmitters, hormones, and growth factors to G protein–coupled receptors (GPCR), such as the α1 adrenergic receptor, on the cell membrane and activation of the Gq α-subunit (Fig. 17.8). The products of this cleavage, inositol 1,4,5-trisphosphate (IP3) and DAG, mediate the mobilization of intracellular calcium and the activation of protein kinase
Biochemistry_Lippincott_710	Biochemistry_Lippinco	C, which act synergistically to evoke specific cellular responses. Signal transduction across the membrane is, thus, accomplished.	Biochemistry_Lippinco. C, which act synergistically to evoke specific cellular responses. Signal transduction across the membrane is, thus, accomplished.
Biochemistry_Lippincott_711	Biochemistry_Lippinco	2. Role in membrane protein anchoring: Specific proteins can be covalently attached through a carbohydrate bridge to membrane-bound PI (Fig. 17.9). For example, lipoprotein lipase, an enzyme that degrades triacylglycerol in lipoprotein particles (see p. 228), is attached to capillary endothelial cells by a glycosyl phosphatidylinositol (GPI) anchor. [Note: GPI-linked proteins are also found in a variety of parasitic protozoans, such as trypanosomes and leishmania.] Being attached to a membrane lipid (rather than being an integral part of the membrane) allows GPI-anchored proteins increased lateral mobility on the extracellular surface of the plasma membrane. The protein can be cleaved from its anchor by the action of phospholipase C (see Fig. 17.9). [Note: A deficiency in the synthesis of GPI in hematopoietic cells results in the hemolytic disease paroxysmal nocturnal hemoglobinuria, because GPI-anchored proteins protect blood cells from complement-mediated lysis.]	Biochemistry_Lippinco. 2. Role in membrane protein anchoring: Specific proteins can be covalently attached through a carbohydrate bridge to membrane-bound PI (Fig. 17.9). For example, lipoprotein lipase, an enzyme that degrades triacylglycerol in lipoprotein particles (see p. 228), is attached to capillary endothelial cells by a glycosyl phosphatidylinositol (GPI) anchor. [Note: GPI-linked proteins are also found in a variety of parasitic protozoans, such as trypanosomes and leishmania.] Being attached to a membrane lipid (rather than being an integral part of the membrane) allows GPI-anchored proteins increased lateral mobility on the extracellular surface of the plasma membrane. The protein can be cleaved from its anchor by the action of phospholipase C (see Fig. 17.9). [Note: A deficiency in the synthesis of GPI in hematopoietic cells results in the hemolytic disease paroxysmal nocturnal hemoglobinuria, because GPI-anchored proteins protect blood cells from complement-mediated lysis.]
Biochemistry_Lippincott_712	Biochemistry_Lippinco	E. Phosphatidylglycerol and cardiolipin Phosphatidylglycerol occurs in relatively large amounts in mitochondrial membranes and is a precursor of cardiolipin (diphosphatidyglycerol). It is synthesized from CDP-DAG and glycerol 3-phosphate. Cardiolipin (see Fig. 17.2) is synthesized by the transfer of DAG 3-phosphate from CDPDAG to a pre-existing molecule of phosphatidylglycerol. F. Sphingomyelin	Biochemistry_Lippinco. E. Phosphatidylglycerol and cardiolipin Phosphatidylglycerol occurs in relatively large amounts in mitochondrial membranes and is a precursor of cardiolipin (diphosphatidyglycerol). It is synthesized from CDP-DAG and glycerol 3-phosphate. Cardiolipin (see Fig. 17.2) is synthesized by the transfer of DAG 3-phosphate from CDPDAG to a pre-existing molecule of phosphatidylglycerol. F. Sphingomyelin
Biochemistry_Lippincott_713	Biochemistry_Lippinco	F. Sphingomyelin Sphingomyelin, a sphingosine-based phospholipid, is found in cell membranes and in the myelin sheath. The synthesis of sphingomyelin is shown in Figure 17.10. Briefly, palmitoyl CoA condenses with serine, as CoA and the carboxyl group (as CO2) of serine are lost. [Note: This reaction, like the decarboxylation reactions involved in the synthesis of PE from PS and of regulators from amino acids (for example, the catecholamines from tyrosine; see p. 286), requires pyridoxal phosphate (a derivative of vitamin B6) as a coenzyme.] The product is reduced in a nicotinamide adenine dinucleotide phosphate (NADPH)-requiring reaction to sphinganine (dihydrosphingosine). The sphinganine is acylated at the amino group with one of a variety of LCFA and then desaturated to produce a ceramide, the immediate precursor of sphingomyelin (and other sphingolipids, as described on p. 208).	Biochemistry_Lippinco. F. Sphingomyelin Sphingomyelin, a sphingosine-based phospholipid, is found in cell membranes and in the myelin sheath. The synthesis of sphingomyelin is shown in Figure 17.10. Briefly, palmitoyl CoA condenses with serine, as CoA and the carboxyl group (as CO2) of serine are lost. [Note: This reaction, like the decarboxylation reactions involved in the synthesis of PE from PS and of regulators from amino acids (for example, the catecholamines from tyrosine; see p. 286), requires pyridoxal phosphate (a derivative of vitamin B6) as a coenzyme.] The product is reduced in a nicotinamide adenine dinucleotide phosphate (NADPH)-requiring reaction to sphinganine (dihydrosphingosine). The sphinganine is acylated at the amino group with one of a variety of LCFA and then desaturated to produce a ceramide, the immediate precursor of sphingomyelin (and other sphingolipids, as described on p. 208).
Biochemistry_Lippincott_714	Biochemistry_Lippinco	Ceramides play a key role in maintaining the skin’s water-permeability barrier. Decreased ceramide levels are associated with a number of skin diseases. Phosphorylcholine from PC is transferred to the ceramide, producing sphingomyelin and DAG. [Note: Sphingomyelin of the myelin sheath contains predominantly longer-chain FA such as lignoceric acid and nervonic acid, whereas gray matter of the brain has sphingomyelin that contains primarily stearic acid.] IV. PHOSPHOLIPID DEGRADATION The degradation of phosphoglycerides is performed by phospholipases found in all tissues and pancreatic juice. [Note: For a discussion of phospholipid digestion, see p. 175.] A number of toxins and venoms have phospholipase activity, and several pathogenic bacteria produce phospholipases that dissolve cell membranes and allow the spread of infection. Sphingomyelin is degraded by the lysosomal phospholipase, sphingomyelinase (see B. below). A. Phosphoglycerides	Biochemistry_Lippinco. Ceramides play a key role in maintaining the skin’s water-permeability barrier. Decreased ceramide levels are associated with a number of skin diseases. Phosphorylcholine from PC is transferred to the ceramide, producing sphingomyelin and DAG. [Note: Sphingomyelin of the myelin sheath contains predominantly longer-chain FA such as lignoceric acid and nervonic acid, whereas gray matter of the brain has sphingomyelin that contains primarily stearic acid.] IV. PHOSPHOLIPID DEGRADATION The degradation of phosphoglycerides is performed by phospholipases found in all tissues and pancreatic juice. [Note: For a discussion of phospholipid digestion, see p. 175.] A number of toxins and venoms have phospholipase activity, and several pathogenic bacteria produce phospholipases that dissolve cell membranes and allow the spread of infection. Sphingomyelin is degraded by the lysosomal phospholipase, sphingomyelinase (see B. below). A. Phosphoglycerides
Biochemistry_Lippincott_715	Biochemistry_Lippinco	Phospholipases hydrolyze the phosphodiester bonds of phosphoglycerides, with each enzyme cleaving the phospholipid at a specific site. The major phospholipases are shown in Figure 17.11. [Note: Removal of the FA from carbon 1 or 2 of a phosphoglyceride produces a lysophosphoglyceride, which is the substrate for lysophospholipases.] Phospholipases release molecules that can serve as second messengers (for example, DAG and IP3) or that are the substrates for synthesis of messengers (for example, arachidonic acid). Phospholipases are responsible not only for degrading phospholipids but also for remodeling them. For example, phospholipases A1 and A2 remove specific FA from membrane-bound phospholipids, which can be replaced with different FA using fatty acyl CoA transferase. This mechanism is used as one way to create the unique lung surfactant DPCC (see p. 204) and to insure that carbon 2 of PI (and sometimes of PC) is bound to arachidonic acid. [Note: Barth syndrome, a rare X-linked	Biochemistry_Lippinco. Phospholipases hydrolyze the phosphodiester bonds of phosphoglycerides, with each enzyme cleaving the phospholipid at a specific site. The major phospholipases are shown in Figure 17.11. [Note: Removal of the FA from carbon 1 or 2 of a phosphoglyceride produces a lysophosphoglyceride, which is the substrate for lysophospholipases.] Phospholipases release molecules that can serve as second messengers (for example, DAG and IP3) or that are the substrates for synthesis of messengers (for example, arachidonic acid). Phospholipases are responsible not only for degrading phospholipids but also for remodeling them. For example, phospholipases A1 and A2 remove specific FA from membrane-bound phospholipids, which can be replaced with different FA using fatty acyl CoA transferase. This mechanism is used as one way to create the unique lung surfactant DPCC (see p. 204) and to insure that carbon 2 of PI (and sometimes of PC) is bound to arachidonic acid. [Note: Barth syndrome, a rare X-linked
Biochemistry_Lippincott_716	Biochemistry_Lippinco	is used as one way to create the unique lung surfactant DPCC (see p. 204) and to insure that carbon 2 of PI (and sometimes of PC) is bound to arachidonic acid. [Note: Barth syndrome, a rare X-linked disorder characterized by cardiomyopathy, muscle weakness, and neutropenia, is the result of defects in cardiolipin remodeling.] phosphatidylinositol 4,5-bisphosphate; R1 and R2 = fatty acids; X = an alcohol.	Biochemistry_Lippinco. is used as one way to create the unique lung surfactant DPCC (see p. 204) and to insure that carbon 2 of PI (and sometimes of PC) is bound to arachidonic acid. [Note: Barth syndrome, a rare X-linked disorder characterized by cardiomyopathy, muscle weakness, and neutropenia, is the result of defects in cardiolipin remodeling.] phosphatidylinositol 4,5-bisphosphate; R1 and R2 = fatty acids; X = an alcohol.
Biochemistry_Lippincott_717	Biochemistry_Lippinco	B. Sphingomyelin	Biochemistry_Lippinco. B. Sphingomyelin
Biochemistry_Lippincott_718	Biochemistry_Lippinco	Sphingomyelin is degraded by sphingomyelinase, a lysosomal enzyme that removes phosphorylcholine, leaving a ceramide. The ceramide is, in turn, cleaved by ceramidase into sphingosine and a free FA (Fig. 17.12). [Note: The released ceramide and sphingosine regulate signal transduction pathways, in part by influencing the activity of protein kinase C and, thus, the phosphorylation of its protein substrates. They also promote apoptosis.] Niemann-Pick disease (types A and B) is an autosomal-recessive disorder caused by the inability to degrade sphingomyelin due to a deficiency of sphingomyelinase, a type of phospholipase C. In the severe infantile form (type A, which shows <1% of normal enzymic activity), the liver and spleen are the primary sites of lipid deposits and are, therefore, greatly enlarged. The lipid consists primarily of the sphingomyelin that cannot be degraded (Fig. 17.13). Infants with this lysosomal storage disease experience rapid and progressive neurodegeneration as a	Biochemistry_Lippinco. Sphingomyelin is degraded by sphingomyelinase, a lysosomal enzyme that removes phosphorylcholine, leaving a ceramide. The ceramide is, in turn, cleaved by ceramidase into sphingosine and a free FA (Fig. 17.12). [Note: The released ceramide and sphingosine regulate signal transduction pathways, in part by influencing the activity of protein kinase C and, thus, the phosphorylation of its protein substrates. They also promote apoptosis.] Niemann-Pick disease (types A and B) is an autosomal-recessive disorder caused by the inability to degrade sphingomyelin due to a deficiency of sphingomyelinase, a type of phospholipase C. In the severe infantile form (type A, which shows <1% of normal enzymic activity), the liver and spleen are the primary sites of lipid deposits and are, therefore, greatly enlarged. The lipid consists primarily of the sphingomyelin that cannot be degraded (Fig. 17.13). Infants with this lysosomal storage disease experience rapid and progressive neurodegeneration as a
Biochemistry_Lippincott_719	Biochemistry_Lippinco	enlarged. The lipid consists primarily of the sphingomyelin that cannot be degraded (Fig. 17.13). Infants with this lysosomal storage disease experience rapid and progressive neurodegeneration as a result of deposition of sphingomyelin in the CNS, and they die in early childhood. A less severe variant (type B, which shows up to 10% of normal activity) with a later age of onset and a longer survival time causes little to no damage to neural tissue, but lungs, spleen, liver, and bone marrow are affected, resulting in a chronic form of the disease. Although Niemann-Pick disease occurs in all ethnic groups, type A occurs with greater frequency in the Ashkenazi Jewish population.	Biochemistry_Lippinco. enlarged. The lipid consists primarily of the sphingomyelin that cannot be degraded (Fig. 17.13). Infants with this lysosomal storage disease experience rapid and progressive neurodegeneration as a result of deposition of sphingomyelin in the CNS, and they die in early childhood. A less severe variant (type B, which shows up to 10% of normal activity) with a later age of onset and a longer survival time causes little to no damage to neural tissue, but lungs, spleen, liver, and bone marrow are affected, resulting in a chronic form of the disease. Although Niemann-Pick disease occurs in all ethnic groups, type A occurs with greater frequency in the Ashkenazi Jewish population.
Biochemistry_Lippincott_720	Biochemistry_Lippinco	type A.] V. GLYCOLIPID OVERVIEW Glycolipids are molecules that contain both carbohydrate and lipid components. Like the phospholipid sphingomyelin, glycolipids are derivatives of ceramides in which a LCFA is attached to the amino alcohol sphingosine. Therefore, they are more precisely called glycosphingolipids. [Note: Thus, ceramides are the precursors of both phosphorylated and glycosylated sphingolipids.] Like the phospholipids, glycosphingolipids are essential components of all membranes in the body, but they are found in greatest amounts in nerve tissue. They are located in the outer leaflet of the plasma membrane, where they interact with the extracellular environment. As such, they play a role in the regulation of cellular interactions (for example, adhesion and recognition), growth, and development.	Biochemistry_Lippinco. type A.] V. GLYCOLIPID OVERVIEW Glycolipids are molecules that contain both carbohydrate and lipid components. Like the phospholipid sphingomyelin, glycolipids are derivatives of ceramides in which a LCFA is attached to the amino alcohol sphingosine. Therefore, they are more precisely called glycosphingolipids. [Note: Thus, ceramides are the precursors of both phosphorylated and glycosylated sphingolipids.] Like the phospholipids, glycosphingolipids are essential components of all membranes in the body, but they are found in greatest amounts in nerve tissue. They are located in the outer leaflet of the plasma membrane, where they interact with the extracellular environment. As such, they play a role in the regulation of cellular interactions (for example, adhesion and recognition), growth, and development.
Biochemistry_Lippincott_721	Biochemistry_Lippinco	Membrane glycosphingolipids associate with cholesterol and GPI-anchored proteins to form lipid rafts, laterally mobile microdomains of the plasma membrane that function to organize and regulate membrane signaling and trafficking functions. Glycosphingolipids are antigenic and are the source of ABO blood group antigens (see p. 165), various embryonic antigens specific for particular stages of fetal development, and some tumor antigens. [Note: The carbohydrate portion of a glycolipid is the antigenic determinant.] They have been coopted for use as cell surface receptors for cholera and tetanus toxins as well as for certain viruses and microbes. Genetic disorders associated with an inability to properly degrade the glycosphingolipids result in lysosomal accumulation of these compounds. [Note: Changes in the carbohydrate portion of glycosphingolipids (and glycoproteins) are characteristic of transformed cells (cells with dysregulated growth).] VI. GLYCOSPHINGOLIPID STRUCTURE	Biochemistry_Lippinco. Membrane glycosphingolipids associate with cholesterol and GPI-anchored proteins to form lipid rafts, laterally mobile microdomains of the plasma membrane that function to organize and regulate membrane signaling and trafficking functions. Glycosphingolipids are antigenic and are the source of ABO blood group antigens (see p. 165), various embryonic antigens specific for particular stages of fetal development, and some tumor antigens. [Note: The carbohydrate portion of a glycolipid is the antigenic determinant.] They have been coopted for use as cell surface receptors for cholera and tetanus toxins as well as for certain viruses and microbes. Genetic disorders associated with an inability to properly degrade the glycosphingolipids result in lysosomal accumulation of these compounds. [Note: Changes in the carbohydrate portion of glycosphingolipids (and glycoproteins) are characteristic of transformed cells (cells with dysregulated growth).] VI. GLYCOSPHINGOLIPID STRUCTURE
Biochemistry_Lippincott_722	Biochemistry_Lippinco	VI. GLYCOSPHINGOLIPID STRUCTURE The glycosphingolipids differ from sphingomyelin in that they do not contain phosphate, and the polar head function is provided by a monosaccharide or oligosaccharide attached directly to the ceramide by an O-glycosidic bond (Fig. 17.14). The number and type of carbohydrate moieties present determine the type of glycosphingolipid. A. Neutral glycosphingolipids	Biochemistry_Lippinco. VI. GLYCOSPHINGOLIPID STRUCTURE The glycosphingolipids differ from sphingomyelin in that they do not contain phosphate, and the polar head function is provided by a monosaccharide or oligosaccharide attached directly to the ceramide by an O-glycosidic bond (Fig. 17.14). The number and type of carbohydrate moieties present determine the type of glycosphingolipid. A. Neutral glycosphingolipids