Lipid Metabolism (Lipid final.PDF)

 Lipid metabolism lipid metabolism and its link to carbohydrate metabolism Beta oxidation and lipogenesis (biosynthesis of fatty acids) Triglyceride biosynthesis Phospholipids synthesis Ketone bodies an...

 Lipid metabolism lipid metabolism and its link to carbohydrate metabolism Beta oxidation and lipogenesis (biosynthesis of fatty acids) Triglyceride biosynthesis Phospholipids synthesis Ketone bodies and propionate metabolism Lipid storage diseases Cholesterol biosynthesis. 14-Sep-24 2  Functions of lipid Storage of energy for long-term use (e.g. triglycerides) Hormonal roles (e.g. steroids such as oestrogen and testosterone) Insulation – both thermal (triglycerides) and electrical (sphingolipids) Protection of internal organs (e.g. triglycerides and waxes) Structural components of cells (e.g. phospholipids and cholesterol) 14-Sep-24 3  Types of lipids Triglycerides: Function as a long-term energy source in animals (fats) and plants (oils) Phospholipids: Structural component of cell membranes Steroids: Act as hormones in plants and animals, and is a structural component of animal cell membranes (cholesterol) Waxes: Act as a protective layer against water loss in plant leaves and animal skin Carotenoids: Light-absorbing accessory pigment in plants (involved in photosynthesis) Glycolipids: Complexes of carbohydrate and lipid that function as cell receptor and cell recognition molecules 14-Sep-24 4  lipoproteins Lipids are insoluble in water and need to form complexes with proteins (lipoproteins) in order to be transported in the blood Different classes of lipoprotein carry variable amounts of the different types of fats (phospholipid, triglycerides, cholesterol) a) Chylomicrons are produced in the intestine and conduct fats to the liver, skeletal muscles and adipose tissue via the lacteals b) Low density lipoproteins (LDLs) carry fat around the entire body within the bloodstream c) High density lipoproteins (HDLs) collect fat from cells and tissues and return it to the liver d) Very low density lipoproteins (VLDLs) and intermediate density lipoproteins (IDLs) exist as transitional forms between chylomicrons and LDLs 14-Sep-24 5 14-Sep-24 6  Lipid absorption Lipids within the digestive system will tend to hydrophobically aggregate to form large fat globules Bile salts, secreted from the gall bladder, emulsify these fat globules and break them up into smaller droplets Hydrolytic enzymes called lipases then digest the fats into their component parts When the fatty acids are absorbed into the epithelial cells of the intestinal lining, they are combined to form triglycerides 14-Sep-24 7  Cont’ The triglycerides are combined with proteins inside the Golgi apparatus to form chylomicrons Chylomicrons are released from the epithelial cells and are transported via the lacteals to the liver While in the liver, chylomicrons may be modified to form a variety of lipoproteins a) Low density lipoproteins will transport lipids via the bloodstream to cells b) High density lipoproteins will scavenge excess lipids from the bloodstream and tissues and return them to the liver 14-Sep-24 8  1. Triglycerides Fats (Triglycerides) are ingested as food or synthesized by adipocytes or hepatocytes from carbohydrate precursors Lipid metabolism entails  the oxidation of fatty acids to either generate energy or synthesize new lipids from smaller constituent molecules.  Lipid metabolism is associated with carbohydrate metabolism, as products of glucose (such as acetyl CoA) can be converted into lipids. Triglycerides are a highly concentrated store 9 of energy 14-Sep-24   Lipid metabolism begins in the intestine where ingested triglycerides (Fats) are Broken down into smaller chain fatty acids and subsequently monoglycerides by pancreatic lipases.  When the food reaches the small intestine in form of chyme, a digestive hormone cholecystokinin (CCK) is released by the intestinal mucosa.  CCK stimulates the release of pancreatic lipase from the pancreas and stimulates contraction of the gall bladder to release stored bile salts into the intestine.  CCK can also travel to the brain where it can act as hunger suppressant. 14-Sep-24 10   Together, the pancreatic lipases and bile salts break down triglycerides into free fatty acids  The fatty acids can be transported across the intestinal membrane.  However once they cross the membrane, the fatty acids can recombine again to form triglyceride molecules.  Within the intestinal cells, these triglycerides are packaged along with cholesterol molecules into phospholipid vesicles called Chylomicrons 14-Sep-24 11   The chylomicrons enable fats and cholesterol to move within the aqueous environment of the lymphatic and circulatory systems.  Chylomicrons leave the intestinal cells (enterocytes) by exocytosis and enter the lymphatic system via the lacteals in the villi of the intestines.  From the lymphatic system, the chylomicrons are transported to the circulatory system.  Once in circulation, they can either go to the liver or be stored in fat cells (adipocytes) that comprise adipose (fat) tissues found throughout the body 14-Sep-24 12  Overview of fatty Introduction acid synthesis 13 14-Sep-24  Utilization of Fats as a source of Fuel  To obtain energy from fats, triglycerides must be first broken down by hydrolysis into two principle components, fatty acid and glycerol.  This processes is known as lipolysis and it takes place in the cytoplasm.  The resulting fatty acid is then oxidized by β-oxidation into acetyl CoA, which is used by the Krebs cycle. The glycerol enters glycolysis pathway via Dihydroxyacetone phosphate(DHAP).  One triglyceride molecule yields three fatty acid molecules with as much as 16 or more carbon in each, fat molecules yields more energy than carbohydrates and therefore an important source of energy for human body.  Therefore when glucose levels are low, fats can be converted to acetyl CoA molecules and used to generate ATP through aerobic respiration 14-Sep-24 14 2.1 Breakdown of Triacylglycerols In the adipose tissue, lipases are activated by hormone signaled phosphorylation 15 14-Sep-24 2.1 Breakdown of Triacylglycerols The glycerol is absorbed by the liver and converted to glycolytic intermediates. 16 14-Sep-24 2.1 Breakdown of Triacylglycerols The lipases break the triacylglycerols down to fatty acids and glycerol The fatty acids are transported in the blood by serum albumin 17 14-Sep-24  β-oxidation of Fatty acids  The breakdown of fatty acids, called fatty acid oxidation or beta- oxidation begins in the cytoplasm where fatty acids are converted into fatty acyl CoA molecules.  The Fatty acyl CoA combines with carnitine to create fatty acyl carnitine molecule which helps to transport fatty acid across the mitochondrial membrane.  Once inside the mitochondrial matrix, the fatty acyl carnitine molecule is converted back to fatty acyl CoA and then to Acetyl CoA.  The newly formed acetyl CoA enters the Krebs cycle and is used to produce ATP in the same way as acetyl CoA derived from pyruvate 14-Sep-24 18  19 14-Sep-24 2.4 Fatty acid oxidation Each round in fatty acid degradation involves four reactions 1. oxidation to trans-Δ2-Enoly- CoA 20 14-Sep-24 2.4 Fatty acid oxidation Each round in fatty acid degradation involves four reactions 2. Hydration to L–3– Hydroxylacyl CoA 21 14-Sep-24 2.4 Fatty acid oxidation Each round in fatty acid degradation involves four reactions 3. Oxidation to 3–Ketoacyl CoA 22 14-Sep-24 2.4 Fatty acid oxidation Each round in fatty acid degradation involves four reactions 4. Thiolysis to produce Acetyl–CoA 23 14-Sep-24 2.4 Fatty acid oxidation Each round in fatty acid degradation involves four reactions The process repeats itself 24 14-Sep-24 2.4 Fatty acid oxidation Each round in fatty acid degradation involves four reactions 25 14-Sep-24  Ketogenesis When acetyl CoA created from beta oxidation of fatty acids and kreb’s cycle is overloaded, the acetyl CoA is diverted to create Ketone bodies. These ketone bodies can serve as a source of fuel if glucose levels are too low in the body. Ketone bodies serve as fuel in times of prolonged starvation or when patients suffer from uncontrolled diabetes and cannot utilize most of the circulating glucose In ketone synthesis reaction, excess acetyl CoA is converted into hydroxymethylglutaryl CoA (HMG CoA). HMG CoA is a precursor of cholesterol and is an intermediate that is subsequently converted to β- hydroxybutyrate, the primary ketone body in the blood. 14-Sep-24 26 14-Sep-24 27  Ketone Body Oxidation  Organs such as the brain that are thought to depend solely on glucose can also use ketone bodies as an alternative source of energy.  This keeps the brain functioning when blood glucose is low.  When ketone bodies are produced faster than they are used, they can be broken down into CO2 and acetone.  The acetone is removed by exhalation. One symptom of ketogenesis is that the patients breath smells sweet like alcohol. This provides one way of telling if a diabetic is properly controlling the disease.  The carbon dioxide produced can acidify the blood, leading to diabetic ketoacidosis, a dangerous condition in diabetics. 14-Sep-24 28  Ketone Body Oxidation 14-Sep-24 29  Beta hydroxybutarate is oxidized to acetoactetate and NADH is released. An HS-CoA molecule is added to acetoacetate, forming acetoacetyl CoA. The carbon atom within acetoacetyl CoA then detaches splitting the molecule into two. This carbon then attaches another free HS-CoA resulting in two acetyl CoA molecules. These two acetyl CoA molecules are then processed through the Kreb’S cycle to generate energy 14-Sep-24 30  Lipid synthesis  When glucose levels are plentiful, the excess acetyl CoA generated by glycolysis can be converted to fatty acid, triglycerides, cholesterol, steroids and bile salts.  Lipogenesis is the process in which fats are created from the excess acetyl CoA. It take place in the cytoplasm of the adipocytes (fat cells) and hepatocytes (liver cells).  When one ingests more carbohydrates than the body needs, the system uses acetyl CoA to turn the excess into fat.  Lipogenesis begins with acetyl CoA and advances by subsequent addition of two carbon atoms from another acetyl CoA; the process is repeated until fatty acids are of the appropriate lengths.  Because this is a bond creating process, ATP is consumed.  The triglycerides and lipids produced are stored in the adipose tissues until when they are needed. 14-Sep-24 31 14-Sep-24 32   Although lipogenesis occurs in the cytoplasm, the necessary to note that acetyl CoA is created in the mitochondria and cannot be transported across the mitochondrial membrane.  To solve this, pyruvate is converted into both oxaloacetate (pyruvate carboxylase) and acetyl CoA (pyruvate dehydrogenase).  Oxaloacetate and acetyl CoA combine to form citrate which can cross the mitochondrial membrane and enters the cytoplasm.  In the cytoplasm, the citrate is converted back to oxaloacetate and acetyl CoA. Oxaloacetate is converted into malate then to pyruvate. Pyruvate crosses back across the mitochondrial membrane to wait for the next cycle of lipogenesis.  The acetyl CoA is converted to malonyl CoA that is used to synthesize fatty acids 14-Sep-24 33 4.1 Formation of Malonyl Coenzyme A Formation of malonyl–CoA is the committed step in fatty acid synthesis. vk 14-Sep-24 4.2 Acyl Carrier Protein The intermediates in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP) 35 14-Sep-24 4.3 Elongation In bacteria the enzymes that are involved in elongation are separate proteins; in higher organisms the activities all reside on the same polypeptide. To start an elongation cycle, Acetyl–CoA and Malonyl–CoA are each transferred to an acyl carrier protein 36 14-Sep-24 4.3 Elongation Acyl-malonyl ACP condensing enzyme forms Acetoacetyl-ACP. 37 14-Sep-24 4.3 Elongation The next three reactions are similar to the reverse of fatty acid degradation, except The NADPH is used instead of NADH and FADH2 The D–enantiomer of Hydroxybutarate is formed instead of the L–enantiomer 38 14-Sep-24 4.3 Elongation The elongation cycle is repeated six more times, using malonyl– CoA each time, to produce palmityl–ACP. A thioesterase then cleaves the palmityl–CoA from the ACP. 39 14-Sep-24 6.1 Elongation and Unsaturation Elongation and unsaturation convert palmitoyl–CoA to other fatty acids. Reactions occur on the cytosolic face of the endoplasmic reticulum. Malonyl–CoA is the donor in elongation reactions 40 14-Sep-24 Regulation of Fatty acid metabolism Fatty acid synthesis occurs in the cytosol. Fatty acid oxidation occurs in the mitochondria. The separation of these 2 distinct metabolic events is important from a regulatory standpoint (Compartmentalization). Acetyl CoA carboxylase catalyzes the formation of malonyl CoA from acetyl CoA. This is a key regulatory step in fatty acid synthesis. Highly regulated. 14-Sep-24 41 Futile cycles Both fatty acids synthesis and breakdown can not be on at the same time. Malonyl CoA the first product of the committed step in fatty acid synthesis inhibits Carnitine palmitoyl transferase I the enzyme that transfers fatty acyl CoA to carnitine for transport to the mitochondria in Beta oxidation of fatty acids. Fatty acyl- CoA the first product of beta oxidation of fatty acids inhibits Acetyl-CoA carboxylase, the enzyme that catalyses the first committed step in fatty acid synthesis. 14-Sep-24 42 BIOSYNTHESIS OF PHOSPHOLIPIDS ( structural lipids)   Phospholipids are a class of lipids that consist of two fatty acyl molecules joined together via glycerol to form glycerophospholipid  They contain head group linked by a phosphate residue which determines the type of phospholipid  The head group form the hydrophilic region of the phospholipid while the fatty acyl side chain forms the hydrophobic regions.  Phospholipids are the main constituent of biological membranes Functions  Phospholipids are involved in stabilizing proteins within the membrane  Phospholipids are essential for the absorption, transport and storage of lipids  Phospholipids are secreted into the bile to aid in the digestion and absorption of dietary fat  They form the monolayer on the surface of lipoproteins which function to transport neutral lipids throughout the body  phospholipids serve as a reservoir for signaling molecules, such as arachidonic acid, phosphatidate, diacylglycerol and inositol trisphosphate. 14-Sep-24 44 14-Sep-24 45 14-Sep-24 46  Phosphatidic Acid phosphatidic acid forms the backbone on which the synthesis of other phospholipid species and triacylglycerol is based. Phosphatidic acid synthesis begins with the addition of a fatty acyl-CoA, usually saturated, to glycerol 3-phosphate at the position- 1 to produce lysophosphatidic acid. This reaction is catalyzed by glycerol 3-phosphate acyltransferase and is rate limiting for phosphatidic acid synthesis. A second fatty acyl-CoA, often unsaturated, is added to lysophosphatidic acid at the sn-2 position by acylglycerol-3-acyltransferase to form phosphatidic acid. This occurs primarily in the endoplasmic reticulum. 14-Sep-24 47  Phosphatidic acid can be used in the synthesis of several phospholipids by two different mechanisms. The first mechanism involves the hydrolysis of the phosphate group from phosphatidic acid to yield diacylglycerol. This is achieved through the association of the cytosolic phosphatidic acid phosphatase (also known as lipin) with phosphatidic acid in the endoplasmic reticulum membrane. Diacylglycerol is used in the subsequent biosynthetic pathways for phosphatidylcholine and phosphatidylethanolamine. Diacylglycerol is also the precursor to the main storage form of energy, triacylglycerol. 14-Sep-24 48  The second method whereby phosphatidic acid is used to synthesize additional phospholipids utilizes cytidine triphosphate (CTP) as an energy source and creates a CDP- diacylglycerol molecule. Overall, this mechanism allows for the replacement of the phosphate group of phosphatidic acid by other phosphate functional groups to form phosphatidylinositol, phosphatidylglycerol or cardiolipin (also known as diphosphatidylglycerol). 14-Sep-24 49 14-Sep-24 50  Phosphatidylcholine (PC) (Lecithin) it is an important structural component that contributes to the integrity and function of membranes. (Most abundant) PC is essential for the formation and secretion of very-low-density lipoproteins by the liver, which is responsible for the delivery of hydrophobic cargo (cholesterol and energy in the form of fat) to other organs. This phospholipid also plays a role in bile salt-mediated micelle formation in the intestinal lumen, which facilitates the absorption of lipid-soluble nutrients from the diet. 14-Sep-24 51  Biosynthesis All nucleated mammalian cells synthesize PC via the CDP-choline pathway Choline entering the cell is rapidly phosphorylated by choline kinase, converting choline to phosphocholine The second enzyme in this pathway, CTP: phosphocholine cytidylyltransferase (CT), facilitates the conversion of phosphocholine to CDP-choline The addition of the phosphocholine moiety to diacylglycerol completes the synthesis of PC. This reaction is catalyzed by CDP-choline:1,2- diacylgylcerol cholinephosphotransferase, or CPT, and occurs at the surface of the endoplasmic reticulum. 14-Sep-24 52 14-Sep-24 53 14-Sep-24 54  The second pathway for PC synthesis is the phosphatidylethanolamine N-methyltransferase (PEMT) pathway. PC production via the PEMT pathway occurs primarily in the liver, where the demand for PC is high due to the production and secretion of very-low-density lipoproteins and PC secretion in bile, in addition to the normal cellular requirement for the synthesis of membranes. PEMT is active in the endoplasmic reticulum, where it performs three repeated methylation reactions converting phosphatidylethanolamine (PE) to PC. The methyl donor S-adenosylmethionine is required for each step of the reaction, generating three molecules of S- adenosylhomocysteine for each PC molecule produced. This mechanism contributes approximately 30% of PC produced in the liver, when choline supply is adequate to maintain PC synthesis through the CDP-choline pathway. However, when choline is limiting in the diet, the PEMT pathway is critical for maintaining the supply of PC in the liver. 14-Sep-24 55 14-Sep-24 56  Phosphatidylethanolamine (PE) Biological Function It is important in the formation of new membranes and vesicles, as well as membrane fusion and budding processes. is essential for the growth and stability of these energy-producing organelles since it is enriched in the membranes of mitochondria PE is used in the production of glycosylphosphatidylinositol, which facilitates the anchoring of proteins to the membrane. 14-Sep-24 57  Biosynthesis The decarboxylation of phosphatidylserine via the enzyme Phosphatidylserine decarboxylase found in mitochondrial membranes. PE produced in the mitochondria is also efficiently transported to other membranes within the cell. This process involves phosphatidylserine decarboxylation pathway and the CDP- ethanolamine pathway. 14-Sep-24 58 14-Sep-24 59  PE is also made via the CDP-ethanolamine pathway, using ethanolamine as the substrate. Ethanolamine is phosphorylated to form the head group of PE by ethanolamine kinase (EK) in the cytosol. Phosphoethanolamine reacts with CTP to form CDP-phosphoethanolamine through the action of a cytosolic protein, CTP: phosphoethanolamine cytidylyltransferase (ET). In the final step, phosphoethanolamine is attached to the sn-3 position of diacylglycerol. This reaction is catalyzed by CDP-ethanolamine:1,2- diacylglycerol ethanolaminephosphotransfease (EPT) in the endoplasmic reticulum and yields the end product PE. 14-Sep-24 60 14-Sep-24 61  Biosynthesis of triglycerides Formed via three major pathways a) the sn-glycerol-3-phosphate(Kennedy pathway) b) dihydroxyacetone phosphate pathways, which predominates in liver and adipose tissue, c) monoacylglycerol pathway in the intestines 14-Sep-24 62  Kennedys pathway 14-Sep-24 63 14-Sep-24 64  In the enterocytes of intestines after a meal, up to 75% of the triacylglycerols are formed via a monoacylglycerol pathway. 2-Monoacyl-sn-glycerols and free fatty acids released from dietary triacylglycerols by the action of pancreatic lipase within the intestines are taken up by the enterocytes. There, the monoacylglycerols are first acylated by an acyl coenzyme A:monoacylglycerol acyltransferase with formation of sn-1,2- diacylglycerols mainly as the first intermediate in the process, Monoacylglycerols can also be synthesised by the acylation of glycerol and these can also be acylated. Finally, the acyl coenzyme A:diacylglycerol acyltransferase (DGAT1) reacts with the sn-1,2-diacylglycerols only to form triacylglycerols. 14-Sep-24 65  Phosphatidylserine Distributed widely among animals, plants and microorganisms Greatest concentration on the myelin of the brain tissues L- serine is a non-essential amino acid that is synthesized by most micro-organisms In bacteria, phosphatidyl serine is synthesized by a reaction between serine and CDP- diacylglycerol Most of the synthesized phosphatidylserine is decarboxylated to phospatidylethanolamine 14-Sep-24 66  In animal tissues, phosphatidylserine is synthesized by calcium dependent base exchange reaction in which polar head group of an existing phospholipid is exchanged for L- serine It involves two enzymes, PS synthase 1 and II by utilizing different substrates. The reaction involves exchange of L-serine with phosphatidylcholine, catalysed by PS synthase I, or with phosphatidylethanolamine (PE), catalysed by PS synthase II. It is strictly dependent on calcium ions. PS synthase I is directly inhibited by its product phosphatidylserine, thereby maintaining the correct amounts of this lipid. 14-Sep-24 67 14-Sep-24 68  Phosphatidyl glycerol Phosphatidylglycerol synthesis begins with CDP- diacylglycerol. A reaction between glycerol-P and CDP- diacylglycerol, catalyzed by phosphatidylglycerolphosphate synthase, forms phosphatidylglycerol-P. The latter product is dephosphorylated to form phosphatidylglycerol with phosphatidylglycerolphosphate phosphatase. The reaction pathway provides the second common phospholipid of the E. coli membranes and is also the pathway in animal cells (where phosphatidylglycerol is a minor phospholipid). 14-Sep-24 69 14-Sep-24 70  Sphingolipids Sphingolipid, any member of a class of lipids (fat- soluble constituents of living cells) containing the organic aliphatic amino alcohol sphingosine or a substance structurally similar to it. The sphingolipids include the sphingomyelins and glycosphingolipids (the cerebrosides, sulfatides, globosides and gangliosides). Sphingomyelins are the only sphingolipid class that are also phospholipids (contains a phosphorous group). Sphingolipids are components of all membranes but are particularly abundant in the myelin sheath. They also occur in blood. Ceramides, the simplest form of sphingolipid (sphingosine plus a fatty acid), widely distributed in small amounts in plant and animal tissues. The other sphingolipids are derivatives of ceramides. 14-Sep-24 71  Glycolipids, a large group of sphingolipids, are so called because they contain one or more molecules of sugar (glucose or galactose). Glycolipids, important in immunological activity, include the cerebrosides, gangliosides, and ceramide oligosaccharides. cerebrosides are most abundant in the myelin sheath surrounding nerves. Sulfate-containing cerebrosides, known as sulfatides, occur in the white matter of brain. Gangliosides, most abundant in nerve tissue (especially the gray matter of brain) and certain other tissues (e.g., spleen) are similar to cerebrosides except that, in addition to the sugar component, they contain several other molecules of carbohydrate (N-acetylglucosamine or N-acetylgalactosamine and N-acetylneuramine). Ceramide oligosaccharides also contain several molecules of carbohydrate; an example is globoside from red blood cells. 14-Sep-24 72  SPHINGOLIPIDS Glycosphingolipids are a sub-group of sphingolipids that contain sachharide headgroups 14-Sep-24 73  SPHINGOLIPID BIOSYNTHESIS I 1. Synthesis of 18 carbon sphinganine from palmitoyl- CoA and serine. 14-Sep-24 74  SPHINGOLIPID BIOSYNTHESIS I 2. Attachment of a fatty acid in amide linkage to yield N-acylsphinganine. 14-Sep-24 75  SPHINGOLIPID BIOSYNTHESIS II 3. Desaturation of the sphinganine moiety to form N-acylsphingosine. 14-Sep-24 76  SPHINGOLIPID BIOSYNTHESIS II 4. Attachment of a head group to produce a sphingolipid such as a cerebroside or sphingomyelin. 14-Sep-24 77  B) Synthesis of sphingomyelins: Sphingomyeline is formed of sphingosine base, fatty acyl CoA, phosphate and choline. (Remembr structure, first lecture). Steps of synthesis: see figure 1- Palmitic acid is activated by CoA to give palmitoyl CoA. 2- Combination of palmitoyl CoA with serine to form sphingosine base. 3- Then sphingosine reacts with acyl CoA to form ceramide 4- Ceramide then reacts with lecithin (phosphatidyl choline) to form sphingomyelin and diacylglycerol. Degradation of phospholipids: - Lecithin and cephalins are degraded by plasma phospholipases A1, A2 , C and D.(as before). -Sphigomyelin is degraded by sphingomyleinase 14-Sep-24 78  Abnormal sphingolipid metabolism is a characteristic of a variety of diseases known collectively as sphingolipidosis, or sphingolipodystrophy. One of the more common forms of cerebral sphingolipidosis (or cerebral lipidosis), formerly called amaurotic familial idiocy, is Tay-Sachs disease , a rare, inheritable disorder caused by the accumulation of sphingolipids in the brain. Another inheritable lipidosis is Niemann-Pick disease (q. v.), in which lecithin and sphingomyelin accumulate in various body tissues, such as the spleen and the liver. 14-Sep-24 79  Sphingolipid Storage Diseases Disease Symptom Sph. Lip Enzyme Tay-Sachs Blindness, Ganglioside -hexose- muscles weak GM aminidase A 2 Gaucher’s Liver & spleen Gluco- -glucosidase 17.4 Nonglyceride Lipids enlarge, MR cerebroside Krabbe’s demyelation, Galacto- - MR cerebroside galactosidase Nieman- MR Sphingomyeli Sphingomyelina Pick n se 14-Sep-24 80  Niemann-Pick disease: in children It is one of lipid storage disease in which harmful quantities of fatty substances, or lipids, accumulate in the spleen, liver, lungs, bone marrow, and brain Niemann-Pick disease results from genetic absence of sphingomyelinase enzyme leading to accumulation of sphingomyelin in liver and spleen leading to enlargement of these organs and may cause reduced appetite, abdominal distension and pain, and the enlarged spleen may trap platelets and other blood cells, leading to reduced numbers of these cells in the circulation. The disease is fatal in early life. Sphingomyelin accumulation in the brain results in unsteady gait (ataxia), slurring of speech and difficult swallowing (dysphagia). More widespread disease involving the cerebral crortex cause dementia and seizers. 14-Sep-24 81 Eicosanoids Overview  Eicosanoids are a large group of signaling molecules with potent effects on virtually every tissue in the body  these agents are derived from metabolism of 20- carbon, unsaturated fatty acids (eicosanoic acids). 14-Sep-24 83 eicosanoids The eicosanoids include: 1. the prostaglandins 2. thromboxanes 3. leukotrienes 4. hydroperoxyeicosatetraenoic acids (HPETEs) 5. hydroxyeicosatetraenoic acids (HETEs). 14-Sep-24 84 EIC The eicosanoids all have short plasma half-lives (typically 0.5—5 min). Most catabolism occurs in the lung. Metabolites are excreted in the urine. Thromboxane A2 (TXA2) is rapidly hydrated to the less active TXB2. PGI2 is hydrolyzed to 6-keto-PGF1α. 14-Sep-24 85  Various eicosanoids are synthesized throughout the body synthesis can be very tissue specific: PGI2 is synthesized in endothelial and vascular smooth muscle cells. Thromboxane synthesis occurs primarily in platelets. HPETEs, HETEs, and the leukotrienes are synthesized predominantly in mast cells, white blood cells, airway epithelium, and platelets. 14-Sep-24 86 Biosynthesis Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways: 1. Phospholipase A2-mediated production from membrane phospholipids; this pathway is inhibited by glucocorticoids. 2. Phospholipase C. 14-Sep-24 87 14-Sep-24 88 14-Sep-24 89  Eicosanoids are synthesized by two pathways: 1. The prostaglandin H synthase (COX, cyclooxygenase) pathway produces: A. thromboxane B. the primary prostaglandins prostaglandin E, or PGE prostaglandin F, or PGF prostaglandin D, or PGD) C. prostacyclin (PGI2) 14-Sep-24 90 EIC 2. The lipoxygenase pathway produces: HPETEs-(5-hydroperoxyeicosatetraenoic acid HETEs-Hydroxyeicosatetraenoic acid leukotrienes 14-Sep-24 91