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LIPID Fatty Acid Biosyntheses: When fatty acids are used in metabolism, they are first activated by attaching coenzyme A (CoA) to them. Fatty acyl CoA synthetase enzyme catalyzes this activation step. The product is referred to as acyl CoA. Excess dietary glucose can be converted to fatty acids in the liver and subsequently sent to the adipose tissue for storage. Adipose tissue synthesizes smaller quantities of fatty acids. Insulin promotes many steps in the conversion of glucose to acetyl CoA in the liver: The citrate shuttle transports acetyl CoA groups from the mitochondria to the cytoplasm for fatty acid synthesis. Factors that indirectly promote this process include insulin and high-energy status. AcetylCoACarboxylase: Acetyl CoA is activated in the cytoplasm for incorporation into fatty acids by acetyl CoA carboxylase. This enzyme is the rate-limiting enzyme of fatty acid biosynthesis. Acetyl CoA carboxylase requires 1)biotin.., 2)ATP,..and ..3)CO2. The Fatty Acid Synthase Complex In mammals, the fatty acid synthase complex is a dimer comprising two identical monomers, each containing all seven enzyme activities of fatty acid synthase on one polypeptide chain . Initially, a priming molecule of acetyl-CoA combines with a cysteine_SH group catalyzed by acetyl transacylase . Malonyl-CoA combines with the adjacent _SH on the 4′ phosphopantetheine of ACP of the other monomer, catalyzed by malonyl transacylase (reaction 1b), to form acetyl (acyl)-malonyl enzyme. The acetyl group attacks the methylene group of the malonyl residue, catalyzed by 3ketoacyl synthase, and liberates CO2, forming 3-ketoacyl enzyme (acetoacetyl enzyme) (reaction 2), freeing the cysteine _SH group. Decarboxylation allows the reaction to go to completion, pulling the whole sequence of reactions in the forward direction. The 3-ketoacyl group is reduced, dehydrated, and reduced again (reactions 3, 4, 5) to form the corresponding saturated acyl-S enzyme. A new malonyl-CoA molecule combines with the _SH of 4′-phosphopantetheine, displacing the saturated acyl residue onto the free cysteine _SH group.The sequence of reactions is repeated six more times until a saturated 16-carbon acyl radical (palmityl) has been assembled. It is liberated from the enzyme complex by the activity of a seventh enzyme in the complex, thioesterase (deacylase). The free palmitate must be activated to acyl-CoA before it can proceed via any other metabolic pathway. Biosynthesis of long-chain fatty acids Elongation of Fatty Acid Chains Occurs in the Endoplasmic Reticulum This pathway elongates saturated and unsaturated fatty acyl-CoAs (from C10 upward) by two carbons, using malonyl-CoA as acetyl donor and NADPH as reductant, and is catalyzed by the microsomal fatty acid elongase system of enzymes . Elongation of stearyl-CoA in brain increases rapidly during myelination (Myelination is the process by which a fatty layer, called myelin, accumulates around nerve cells (neurons). Myelin particularly forms around the long shaft, or axon, of neurons. Myelination enables nerve cells to transmit information faster and allows for more complex brain processes. Thus, the process is vitally important to healthy central nervous system functioning) in order to provide C22 and C24 fatty acids for sphingolipids. Biosynthesis of complex lipids Phospholipids: Most of the enzymes involved in this pathway are associated with the membranes of the smooth endoplasmic reticulum. The synthesis of fats and phospholipids starts with glycerol 3-phosphate. This compounds can arise via:  reduction from the glycolytic intermediate glycerone 3-phosphate or dihydroxyacetone 3-phosphate; (enzyme: glycerol- 3phosphate dehydrogenase)  phosphorylation of glycerol deriving from fat degradation (enzyme: glycerol kinase) .  Esterification of glycerol 3 phosphate with a long-chain fatty acid produces a strongly amphipathic lysophosphatidate enzyme: glycerol-3-phosphate acyltransferase . In this reaction, an acyl residue is transferred from the activated precursor acyl-CoA to the hydroxy group at C-1.  A second esterification of this type leads to a phosphatidate (enzyme: 1- acylglycerol-3- phosphate acyltransferase) . Unsaturated acyl residues, particularly oleic acid, are usually incorporated at C-2 of the glycerol. Phosphatidates (anions of phosphatidic acids) are the key molecules in the biosynthesis of fats, phospholipids, and glycolipids.  To biosynthesize fats (triacylglycerols), the phosphate residue is again removed by hydrolysis (enzyme: phosphatidate phosphatase This produces diacylglycerols (DAG).  Transfer of an additional acyl residue to DAG forms triacylglycerols (enzyme: diacylglycerol acyltransferase . This completes the biosynthesis of neutral fats. They are packaged into VLDLs by the liver and released into the blood. Finally, they are stored by adipocytes in the form of insoluble fat droplets.  Transfer of a CMP(Cytidine monophosphate ) residue to phosphatidate gives rise first to CDP-diacylglycerol (enzyme: phosphatidatecytidyl transferase ).  Substitution of the CMP residue by inositol then provides phosphatidylinositol (PtdIns; enzyme: CDPdiacylglycerolinositol-3- phosphatidyl transferase) . and  An additional phosphorylation (enzyme: phosphatidylinositol-4- phosphate kinase ) finally provides phosphatidylinositol- 4,5-bisphosphate . PIP2 is the precursor for the second messengers 2,3-diacylglycerol (DAG) and inositol-1,4,5-trisphosphate  Transfer of a phosphocholine residue to the free OH group gives rise to phosphatidylcholine (lecithin; enzyme: 1-alkyl-2-acetylglycerolcholine phosphotransferase ).The phosphocholine residue is derived from the precursor CDP-choline . Phosphatidylethanolamine is similarly formed from CDPethanolamine and DAG. By contrast, phosphatidyl serine is derived from phosphatidylethanolamine by an exchange of the amino alcohol. Further reactions serve to interconvert the phospholipids—e. g., phosphatidylserine can be converted into phosphatidylethanolamine by decarboxylation, and the latter can then be converted into phosphatidylcholine by methylation Sphingolipid : The biosynthesis of sphingolipids takes place in four stages: (1) synthesis of the 18-carbon amine sphinganine from palmitoyl-CoA and serine; (2) attachment of a fatty acid in amide linkage to yield N-acylsphinganine; (3) desaturation of the sphinganine moiety to form N-acylsphingosine (ceramide); and (4) attachment of a head group to produce a sphingolipid such as a cerebroside or sphingomyelin . The pathway shares several features with the pathways leading to glycerophospholipids: NADPH provides reducing power, and fatty acids enter as their activated CoA derivatives. Phosphatidylcholine, rather than CDP-choline, serves as the donor of phosphocholine in the synthesis of sphingomyelin. Sphingolipids are commonly believed to protect the cell surface against harmful environmental factors by forming a mechanically stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer. Simple sphingolipid metabolites, such as ceramide and sphingosine-1-phosphate, have been shown to be important mediators in the signaling cascades involved in apoptosis, proliferation, stress responses, necrosis, inflammation, and differentiation. Sphingolipids are synthesized in a pathway that begins in the ER and is completed in the Golgi apparatus, but these lipids are enriched in the plasma membrane and in endosomes, where they perform many of their functions. Glycolipids: Glycolipids are widely distributed in every tissue of the body, particularly in nervous tissue such as brain. They occur particularly in the outer leaflet of the plasma membrane, where they contribute to cell surface carbohydrates. The major glycolipids found in animal tissues are glycosphingolipids. They contain ceramide and one or more sugars. Galactosylceramide is a major glyco sphingolipid of brain and other nervous tissue, found in relatively low amounts elsewhere. Structure of galactosylceramide(galactocerebroside,if R = H), and sulfogalactosylceramide(a sulfatide, if R = SO4). Galactosylceramide can be converted to Sulfo -galactosylceramide (sulfatide), present in high amounts in myelin. Glucosylceramide is the predominant simple glycosphingolipid of extra neural tissues, also occurring in the brain in small amounts. Sulfogalactosylceramide and other sulfolipids are formed after further reactions Where PAPS = 3'-Phosphoadenosine 5'-phosphosulfate Glycolipids in blood grouping glycolipids are membrane components composed of lipids that are covalently bonded to monosaccharides or polysaccharides. One type of glycolipid found in human red blood cells is involved in the ABO blood type antigens. The table below shows the relationship between the ABO blood type, the RBC glycolipid and antibodies to the glycolipids in the blood plasma. blood type glycolipid antibodies in blood anti A and anti B O Individuals with type O blood have antibodies RBC of O type blood have this glycolipids in their against the type A and RBCs plasma membranes. type B antigens anti B A individuals of type A blood have antibodies Individuals with type A blood have this type of glycolipid in their RBCs plasma membranes. The against the type B A type glycolipid has the same carbohydrate composition as does the type O antigen with the determinant addition of a additional NAcetylgalactosamine which is the A type antigenic determinant. anti A B Individuals with type B blood have the above kind of glycolipid in their RBC plasma membrane. The B type glycolipid has the same carbohydrate composition as does the type O antigen with the addition of an additional galactose which is the B type antigenic determinant. Individuals of type B blood have antibodies against the type A antigenic determinant neither A or B Individuals with they AB blood have antibodies against neither the the A nor B antigens AB Individuals with type AB blood have both of the above glycolipids in their RBC plasma membranes Gangliosides Gangliosides are complex glycosphingolipids derived from glucosylceramide that contain in addition one or more molecules of a sialic acid. Structure of N-acetylneuraminic acid,a sialic acid (NeuAc) . Neuraminic acid (NeuAc); is the principal sialic acid found in human tissues. Gangliosides are present in nervous tissues in high concentration. They appear to have receptor and other functions. The simplest ganglioside found in tissues is GM3, which contains ceramide, one molecule of glucose, one molecule of galactose, and one molecule of NeuAc. Gangliosides are synthesized from ceramide by the stepwise addition of activated sugars (eg, UDPGlc and UDPGal) and a sialic acid, usually N-acetylneuraminic acid . A large number of gangliosides of increasing molecular weight may be formed. Most of the enzymes transferring sugars from nucleotide sugars (glycosyl transferases) are found in the Golgi apparatus. Glycosphingolipids are constituents of the outer leaflet of plasma membranes and are important in cell adhesion and cell recognition. Certain gangliosides function as receptors for bacterial toxins (eg, for cholera toxin ). Cholera toxin a First binds to GM1 gangliosides on the surface of target cells . Once bound, the entire toxin complex is endocytosed by the cell. The endosome is moved to the Golgi apparatus and after many steps it leads to increased adenylate cyclase activity, which increases the intracellular concentration of 3',5'-cyclic AMP (cAMP) to more than 100-fold over normal and over-activates cytosolic protein kinase A (PKA). These active PKA then phosphorylate the regulator of the chloride channel proteins, which leads to ATP-mediated efflux of chloride ions and leads to secretion of H2O, Na+, K+, and HCO3− into the intestinal lumen. In addition, the entry of Na+ and consequently the entry of water into enterocytes are diminished. The combined effects result in rapid fluid loss from the intestine, up to 2 liters per hour, leading to severe dehydration and other factors associated with cholera, including a rice-water stool. Expression of cholera toxin was shown to be prevented by the drug virstatin, which acts to prevent its transcription. It has been identified as a possible treatment for cholera. Metabolism of Unsaturated Fatty Acids &Eicosanoids Unsaturated fatty acids in phospholipids of the cell membrane are important in maintaining membrane fluidity. A high ratio of polyunsaturated fatty acids to saturated fatty acids (P:S ratio) in the diet is a major factor in lowering plasma cholesterol concentrations and is considered to be beneficial in preventing coronary heart disease. Certain long-chain unsaturated fatty acids of metabolic significance in mammals. Linoleic and α-linolenic acids are the only fatty acids known to be essential for the complete nutrition of many species of animals, including humans, and are known as the nutritionally essential fatty acids. EICOSANOIDS THE C20 POLYUNSATURATED FATTY ACIDS Arachidonate and some other C20 polyunsaturated fatty acids give rise to eicosanoids, physiologically and pharmacologically active compounds known as prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), and lipoxins (LX). Physiologically, they are considered to act as local hormones functioning through G-protein-linked receptors to elicit their biochemical effects. There are three groups of eicosanoids that are synthesized from C20 eicosanoic acids derived from the essential fatty acids linoleate and α-linolenate, or directly from dietary arachidonate and eicosapentaenoate as shown below. Prostaglandin E2 (PGE2). Thromboxane A2 (TXA2). Leukotriene A4 (LTA4). Arachidonic acid synthesis: Arachidonate is usually derived from the 2 position of phospholipids in the plasma membrane by the action of phospholipase A2, but also from the diet. Arachidonate is the substrate for the synthesis of the PG2, TX2 series (prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate. Prostaglandins (PG) contain a five-carbon ring originating from the chain of arachidonic acid. Prostaglandins act in many tissues by regulating the synthesis of the intracellular messenger 3_,5_-cyclic AMP (cAMP). Because cAMP mediates the action of diverse hormones, the prostaglandins affect a wide range of cellular and tissue functions. Some prostaglandins stimulate contraction of the smooth muscle of the uterus during menstruation and labor. Others affect blood flow to specific organs, the wake-sleep cycle, and the responsiveness of certain tissues to hormones such as epinephrine and glucagon. Prostaglandins elevate body temperature (producing fever) and cause inflammation and enhance pain perception . The thromboxanes have a six-membered ring containing an ether. They are produced by platelets and act in the formation of blood clots and the reduction of blood flow to the site of a clot. The nonsteroidal antiinflammatory drugs (NSAIDs)aspirin, ibuprofen, and meclofenamate, for example— were shown to inhibit the enzyme prostaglandin H2 synthase (also called cyclooxygenase or COX1), which catalyzes an early step in the pathway from arachidonate to prostaglandins . Leukotrienes : first found in leukocytes, contain three conjugated double bonds. They are powerful biological signals. For example, leukotriene D4 induces contraction of the muscle lining the airways to the lung. Overproduction of leukotrienes causes asthmatic attacks, and leukotriene synthesis is one target of antiasthmatic drugs such as prednisone. The strong contraction of the smooth muscles of the lung that occurs during anaphylactic shock is part of the potentially fatal allergic reaction in individuals hypersensitive to bee stings, penicillin, or others. CHOLESTEROL MLETABOLISM: Cholesterol is required for membrane synthesis, steroid synthesis, and in the liver, bile acid synthesis.Most cells derive their cholesterol from LDL or HDL, but some cholesterol may be synthesized de novo. Most de novo synthesis occurs in the liver, where cholesterol is synthesized from acetyl CoA in the cytoplasm. The citrate shuttle carries mitochondrial acetyl CoA into the cytoplasm, and NADPH is provided by the PPP and malic enzyme. Important points are noted below 3-Hydroxy-3-methylglutaryl -CoA (HMG-CoA) reductase on the smooth endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin activates the enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product, and the statin drugs competitively inhibit the enzyme. Cholesterol represses the expression of the HMG-CoA reductase gene and also increases degradation of the enzyme. Regulation of the Cholesterol Level in Hepatocytes HMG CoA reductase, the rate-limiting enzyme, is the major control point for cholesterol biosynthesis, and is subject to different kinds of metabolic control. 1. Sterol-dependent regulation of gene expression: Expression of the HMG CoA reductase gene is controlled by a transcription factor (sterol regulatory element-binding protein, or SREBP) that binds to DNA at the sterol regulatory element (SRE) located upstream of the reductase gene. The SREBP is initially associated with the ER membrane, but proteolytic cleavage liberates the active form, which travels to the nucleus. When the SREBP binds, expression of the reductase gene increases. When cholesterol levels are low, activation of SREBP occurs, resulting in increased HMG CoA reductase and, therefore, more cholesterol synthesis.Conversely, high levels of cholesterol prevent activation of the transcription factor. 2. Sterol-independent phosphorylation/dephosphorylation: HMG CoA reductase activity is controlled covalently through the actions of a protein kinase and a phosphoprotein phosphatase The phosphorylated form of the enzyme is inactive, whereas the dephosphorylated form is active. [Note: Protein kinase is activated by AMP, so cholesterol synthesis is decreased when ATP availability is decreased.] 3. Hormonal regulation: The amount (and, therefore, the activity) of HMG CoA reductase is controlled hormonally. An increase in insulin favors up regulation of the expression of the HMG CoA reductase gene. Glucagon has the opposite effect. 4. Inhibition by drugs: The statin drugs, including simvastatin, lovastatin, and mevastatin are structural analogs of HMG CoA, and are reversible, competitive inhibitors of HMG CoA reductase .They are used to decrease plasma cholesterol levels in patients with hypercholesterolemia.