BIOCHEM TRANS 2A - FATTY ACIDS.pdf

BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism BRENDO V. JANDOC, M.D. 1A...

BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism BRENDO V. JANDOC, M.D. 1A B. Nature and Nomenclature OUTLINE o 1 carboxyl group at the end of the I. OVERVIEW OF FATTY ACIDS chain II. DE NOVO SYNTHESIS of FATTY ACIDS o saturated or unsaturated III. CLINICAL ASPECT 1. Saturated Fatty Acids: no double bonds in the chain I. OVERVIEW OF FATTY ACIDS A. Fatty Acids 1. Found in the body as a) Free fatty acids a. Nomenclature (Systematic Name) b) Fatty acyl esters in more complex molecules (TAG) o number of carbons 2. Occurs in all tissues at low levels o suffix -anoic 3. Can be found in the plasma in substantial amounts during o ex: palmitic acid (16 carbons) > hexadecanoic acid i. Fasting ii. Starvation a) Plasma Free Fatty Acids o transported by serum albumin o originate from TAG of adipose tissues or circulating lipoproteins o can be oxidized by most tissues to provide energy 4. Precursors of Many Compounds a) Glycolipids b) Phospholipids c) Sphingolipids d) Prostaglandins e) Cholesteryl esters 5. Esterified Fatty Acids o in the form of TAG o energy reserves 6. Also attached to certain intracellular proteins > enhanced ability of the proteins to associate with membranes b. Structure (General Formula) FATTY ACIDS CH3 - (CH2)n - COOH A. Structure n = specifies the number of methylene groups between methyl and 1. Consists of carboxyl carbons 2. Unsaturated Fatty Acids: have 1 or more double bonds 2. Physiologic pH a. Nomenclature >terminal carboxyl group (-COOH) of pKa of 4.8 > ionizes > i. Delta Numbering System -COO- (anionic group) > affinity for water > amphipathic nature o terminal carboxyl carbon is designated as carbon 3. Long Chain Fatty Acids 1 hydrophobic portion is predominant > highly water-insoluble > o double bond is given the number of the carbon transported in the plasma in association with plasma proteins atom on the carboxyl side of the double bond (albumin) o ex: palmitoleic acid 4. >90% of Fatty Acids Found in the Plasma 16 carbons - contained in circulating lipoprotein particles in the form of double bonds between carbons 9 and 10 a) TAG (primarily) b) Cholesteryl esters c) Phospholipids ii. Systematic Name o number of carbon atoms o number of double bonds (unless it has only 1) o suffix -enoic o ex: palmitoleic acid Trans 2 |ABACCO, ASSISTIN, ALDERITE, BALANZA, BAYAS, BIANG 1 of 9  BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism linoleic acid - prostaglandins (PG) - 18 carbons - prostacyclins (PGIs) - 2 double bonds - thromboxanes (TXs) iii. Another Nomenclature o the carbon to which the carboxyl group is attached (carbon 2) is also called α-carbon o carbon 3 is β-carbon o carbon 4 is the ϒ-carbon o terminal methyl group is the ω-carbon regardless of the chain length *carbons in a fatty acid can also be counted beginning at the omega (or methyl terminal) end of the chain o ex: linoleic acid - 18 : 2 (9, 12) - ω-6-fatty acid linolenic acid - 18 : 3 (9, 12, 15) - ω-3-fatty acid arachidonic acid - ω-6-fatty acid Some fatty acids of physiologic importance b. Structure o double bonds in naturally occurring fatty acids are always in cis configuration o double bonds are spaced at 3 carbon intervals c. Subdivisions i. Monounsaturated (Monoethenoid, Monoenoic) contain 1 double bond ii. Polyunsaturated (Polyethenoid, Polyenoic) contain 2 or more double bonds iii. Eicosanoids derived from eicosa- (20 carbons) polyenoic fatty acid iiia. Comprise o leukotrienes (LTs) o lipoxins (LXs) o prostanoids Trans 2 |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 2 of 9  BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism C. Source II. DE NOVO SYNTHESIS of FATTY ACIDS 1. Nonessential Fatty Acids A. General Features can be synthesized from products of glucose oxidation *large portion of fatty acids used by the body is supplied by the diet 2. Essential Fatty Acids 1. Excess Proteins, Carbohydrates and Other Molecules from o must be obtained from the diet especially linoleic and the Diet linolenic families o (dietary glucose via pyruvate) can be converted to o no human enzymes that can introduce doubles bonds fatty acids > stored as TAG beyond carbon 9 of a fatty acid chain and all double 2. Fatty Acids bonds introduced are separated by 3-carbon intervals o preferred fuel for the heart o fatty acid elongation only occurs by 2-carbon addition > o primary form in which excess fuel is stored in adipose impossible to synthesize de novo certain tissues polyunsaturated fatty acids 3. Synthesis a. Occurs Primarily in the D. Physical Properties o liver 1. Amphipathic o lactating mammary gland o detergent-like b. Lesser Extent o nonpolar (-CH3) and polar (-COOH) ends o adipose tissues o polar end associated with water o kidneys o nonpolar end associated with hydrophobic phase c. Polymerization of 2-Carbons Units Derived from 2. Melting Point (Melting Temperature) Acetyl CoA o factors that increase melting temperature (Tm) > form 16-carbon saturated fatty acid (palmitic acid) o increased the chain length d. Use o addition of double bonds (degree of unsaturation) o ATP o longer chain length > higher melting point o NADPH o greater number of double bonds > lower melting point e. Extent Depends on o presence of unsaturated fatty acids in membrane lipids o amount of fat in the diet > fluid nature o need to convert excess glucose to fatty acids 3. Sensitivity to Oxidation for storage a. Saturated Fatty Acids f. Enzymes relatively resistant to oxidation outside the body o located in the cytosol b. Unsaturated Fatty Acids slowly but spontaneously oxidized in the presence of air > B. Sources of Acetyl CoA rancidification 1. Cytosol a. Acetyl CoA E. Branched-Chain Fatty Acids o from glucose oxidation via glycolysis *almost all fatty acids in mammalian tissues are of the straight-chain 2. Mitochondrial (The Acetyl CoA Shuttle System) variety o CoA portion of acetyl CoA cannot pass the 1. Branched-Chain Fatty Acids in Nature mitochondrial membrane > should be a. Phytanic Acid (3, 7, 11, 15-Tetramethyl Palmitic Acid) transported o significant amounts in dairy products Mitochondrial Acetyl CoA is produced by o inability to degrade > accumulation in plasma and a. oxidation of pyruvate or tissues (Refsum’s disease) b. degradation of o fatty acids F. Essential Fatty Acids o ketone bodies 1. Linoleic Acid o amino acids o precursor of arachidonic acid o deficiency > arachidonic acid becomes essential 2. Linolenic Acid o precursor of other ω-3-fatty acids important for growth and development a. Deficiency o decreased vision o altered learning behaviors Trans 2 |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 3 of 9  BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism f. Pyruvate is transported into the mitochondria by an active transport system g. OAA can be regenerated from pyruvate by the actions of pyruvate carboxylase which requires ATP C. Carboxylation of Acetyl CoA to Form Malonyl CoA o regulated step in fatty acid synthesis a. Enzyme o acetyl CoA carboxylase o enzyme is inactive in multiple carboxylase deficiency (inability to utilize biotin) i. Requires o ATP o HCO3- o coenzymes biotin (covalently bound to the lysyl residue of a. Citrate synthase catalyzes the reaction of acetyl CoA with the carboxylase) OAA > form citrate in the mitochondria b. Citrate is transported into the cytosol by a tricarboxylic acid 1. Short-Term Regulation of Acetyl CoA Carboxylase transport system o this carboxylation reaction is both c. Citrate reacts with CoA in the cytosol > acetyl CoA and OAA o rate-limiting o catalyzed by citrate lyase o regulated step in fatty acid synthesis o requires ATP *occurs when mitochondrial citrate concentration is high o observed when isocitrate dehydrogenase is a. Allosteric Regulation inhibited by the presence of large amounts of o inactive form of acetyl CoA ATP > accumulation of citrate and isocitrate (large carboxylase (consists of protomer amounts of ATP + high citrate concentration > made of 4 subunits) > allosteric enhancement of this pathway to occur) activation by citrate > polymerization of protomers o enzyme is inactivated by (long-chain fatty acyl CoA - the end product of the pathway) -malonyl CoA (intermediate in the pathway) -palmitoyl CoA (end-product of the pathway) >depolymerization of the protomer b. Reversible Phosphorylation i. Epinephrine, Glucagon > enzyme phosphorylation > enzyme inactivation ii. Insulin > acetyl CoA carboxylase dephosphorylation > enzyme activation iii. Adenosine Monophosphate (AMP) -Activated Protein Kinase (AMPK) d. OAA is converted to malate by an NAD+-dependent cytosolic > enzyme phosphorylation malate dehydrogenase o allosterically activated by a rise in AMP e. Malate is decarboxylated > pyruvate relative to ATP o catalyzed by malic enzyme o covalently activated by phosphorylation o forms NADPH from NADP+ via AMPK kinase Trans 2 |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 4 of 9  BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism 2. Prokaryotes o the domain is a separate protein, acyl carrier protein (ACP) 3. Reactions a. Transfer of Acetate o from acetyl CoA to the -SH group of ACP o catalyzed by acetyl CoA-ACP acetyltransacylase Acetyl CoA + ACP > Acetyl-S-ACP + CoA 2. Long-Term Regulation of Acetyl CoA Carboxylase b. Transfer of the Two-Carbon Fragment i. High Calorie Diet (High Calorie-High Carbohydrate Diets) o to a cysteine residue on the enzyme (temporary holding > increased enzyme synthesis > increased fatty acid synthesis site) ii. Low Calorie Diet, Fasting Acetyl-S-ACP + Enzyme > Acetyl-S-Enzyme + ACP > decreased enzyme synthesis > decreased fatty acid iii. Transfer of Malonate o vacant ACP accepts a 3 carbon malonate unit from D. Fatty Acid Synthase: a Multienzyme Complex malonyl CoA 1. Eukaryotes o catalyzed by malonyl CoA-ACP transacylase o consist of a dimer (each monomer has 7 different Malonyl CoA + ACP > Malonyl-S-ACP + CoA-SH enzymatic activities + a domain that covalently iv. One-Carbon Loss from Malonyl Group binds a molecule of 4’-phosphopantetheine) o malonyl group loses the HCO3- originally added by a. 4’-Phosphopantetheine acetyl CoA carboxylase > nucleophilic attack on the o derivative of pantothenic acid thioester bond linking the acetyl group to the cysteine o component of CoA residue > result in a 4-carbon unit attached to the ACP o carries acetyl and acyl units on its terminal thiol domain (-SH) group during fatty acid synthesis o loss reaction o catalyzed by 3-ketoacyl-ACP synthase Malonyl-S-ACP + Acetyl-S-ACP > Acetoacetyl-S-ACP + ACP + CO2 * Next 3 reactions convert the 3-ketoacyl group to the corresponding saturated acyl group by a pair of reductions requiring NADPH and a dehydration steps v. Alcohol Formation o keto group is converted to an alcohol o catalyzed by 3-ketoacyl-ACP reductase o NADPH is required Acetoacetyl-S-ACP + NADPH + H+ > 3-Hydroxybutyryl-ACP + NADP+ vi. Dehydration Reaction o water molecule is removed to introduce a double bond o catalyzed by 3-hydroxyacyl-ACP dehydratase 3-Hydroxybutyryl-S-ACP > Crotonyl-S-ACP + H2O vii. Second Reduction o catalyzed by enoyl-ACP reductase o NADPH is required Crotonyl-S-ACP + NADPH + H+ > Butyryl-S-ACP + NADP+ 4. Result o production of a 4 carbon compound (fully saturated) Trans 2 |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 5 of 9  BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism 5. Elongation o butyryl-ACP reacts with another malonyl group via the reactions described above > cycle continues o repetition of the 7 steps incorporating 2 carbon unit (repeated 7x) > 16-carbon chain (still attached to ACP-SH) > process terminated > fully saturated molecule of palmitate 6. Release of Palmitate (16:0) o catalyzed by palmitoyl thioesterase (deacylase) o cleaves thioester bond Palmitoyl-S-ACP + H2O > Palmitate + ACP-SH 7. Overall Reaction for the Synthesis of Palmitate 8 Acetyl CoA + 14 NADPH + 14 H+ + 7 ATP > Palmitic Acid + 8 CoA-SH + 14 NADP+ + 7 ADP + 7 Pi + 7 H2O o all of the carbons of palmitic acid have passed through malonyl CoA except the 2 donated by the original acetyl CoA (found at the methyl group-end of the fatty acid) F. Interrelationship between Glucose Metabolism and Palmitate Synthesis 1. Glycolytic Pathway produces o pyruvate (primary source of mitochondrial acetyl CoA to be used for fatty acid synthesis) o cytosolic reducing equivalents of NADH 2. Mitochondrial OAA o produced in the 1st step in the gluconeogenic pathway 3. Acetyl CoA o produced in the mitochondria o condenses with OAA > citrate (1st step E. Major Sources of the NADPH Required for Fatty Acid Synthesis in the TCA cycle) 1. Hexose Monophosphate Pathway 4. Citrate o major supplier of NADPH o leaves the mitochondria o 2 NADPH produced per glucose molecule entering o cleaved in the cytosol to produce this pathway cytosolic acetyl CoA 2. Cytosolic NADP+-Dependent Malate Dehydrogenase 5. Cytosolic Reducing Equivalents (NADH) (Malic Enzyme) o produced during glycolysis o o contribute to the reduction of NADP+ to o source of cytosolic NADPH NADPH needed for palmitoyl CoA o malate can arise from the reduction of OAA by synthesis cytosolic NADP+-dependent malate dehydrogenase 6. Carbons of Cytosolic Acetyl CoA o cytosolic NADH can be produced during glycolysis o used to synthesize palmitate (NADPH as the source of reducing equivalents for the pathway) Trans 2 |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 6 of 9  BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism Fatty Acid Oxidase o mixed-function oxidase o requires o O2 o NADPH o humans lack the ability to introduce double bonds beyond carbons 9 to 10 > polyunsaturated linoleic and linolenic acids must be provided in the diet I. Storage of Fatty Acids as Components of TAG o fatty acids are esterified through their carboxyl groups > loss of negative charge > formation of neutral fat (if species of acylglycerol is solid at room temperature > “fat”, if liquid > “oil”) 1. Structure of TAGs o triesters of glycerol and 3 fatty acids o fatty acid on carbon 1 is usually saturated o fatty acid on carbon 2 is usually unsaturated o fatty acid on carbon 3 can be either > presence of unsaturated fatty acid(s) > decreased melting temperature G. Further Elongation of Fatty Acid Chains 1. Palmitate o 16-carbon o fully saturated fatty acid o end-product of fatty acid synthase activity o can be further elongated and/or desaturated by separate enzymic processes enzymes - found in the mitochondria and ER - can use fatty acids of various chain lengths and degrees of unsaturation as substrates 2. Function 2. Elongation Systems o fatty acids are converted to TAG o form fatty acids longer than 16-carbons by adding 2-carbon o for transport between tissues units o for storage of metabolic fuel a. Endoplasmic Reticulum System * TAGs are only slightly soluble in water > cannot form o most active stable micelles > coalesce within adipocytes > form oily droplets o adds malonyl CoA onto palmitate in a manner (major energy reserve of the body) that are nearly anhydrous similar to the action of fatty acid synthase a. Fat Deposits i. CoA - involved rather than ACP o main stores of metabolic fuel in humans in fat cells ii. Stearic Acid (adipocytes) o 18-carbon unit o very large portion of ingested fats are stored as TAG in the o common product fat droplets of adipocytes > serve long term needs of b. Mitochondrial Elongation System metabolic fuel o uses acetyl CoA units rather than malonyl CoA b. Advantages of TAG over Other Forms of Metabolic Fuels units o light weight (less dense than water) o for the synthesis of structural lipids in this o concentrated form of fuel (complete combustion to CO2 and organelle water > release 9 kcal/g as opposed to 4 kcal/g of 3. Brain - additional elongation capabilities > production of very long carbohydrates and proteins) chain fatty acids (up to 24 carbons) for brain lipid synthesis o water-insolubility > no osmotic problems to the cells H. Desaturation of Fatty Acid Chains 3. Glycerol Phosphate Synthesis o 2 most common monounsaturated fatty acids in mammals a. Glycerol Phosphate 1. Palmitoleic acid (16 : 1 : 9) o initial acceptor of fatty acids during the synthesis of TAG 2. Oleic acid (18 : 1 : 9) b. 2 Pathways o cis double bonds are introduced between carbons 9 and 10 i. Glycerol Phosphate Dehydrogenase by fatty acid oxidase in the ER o liver o adipose tissues Trans 2 |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 7 of 9  BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism ii. Glycerol Kinase a. Acylation of Glycerol o liver only i. 1st Acylation o adipocytes can only take up glucose in the o 2 routes of acylation of the 1st hydroxyl of glycerol presence of insulin (absence of insulin > ia. 1st Route adipocytes have limited capability to produce o uses DHAP (derived from glucose by the glycolytic glycerol phosphate > cannot form TAG) pathway) as the acceptor of the acyl moiety from the fatty acyl CoA o initial reaction is followed by reduction (NADPH as the electron acceptor) > lysophosphatidate o fatty acid preferentially introduced to form lysophosphatidate is saturated 4. Conversion of Free Fatty Acid to its Activated Form o fatty acid must be activated to its ib. 2nd Route activated form (attached to CoA) o gives the same product > TAG synthesis o shows the same preference for a saturated fatty o catalyzed by fatty acyl CoA acid synthetase (thiokinase) o order is reversed o reduction of DHAP > glycerol 3-phosphate occurs before acylation of the C1 hydroxyl 5. Synthesis of a Molecule of TAG from ii. 2nd Acylation Glycerol Phosphate and Fatty Acyl CoA o unsaturated fatty acyl CoA thioester is introduced to the 2-hydroxyl of lysophosphatidate o except in the human mammary gland (saturated fatty acyl CoA is used) iii. 3rd Acylation o phosphate group on C3 is removed by phosphatase o followed by addition of either a saturated or unsaturated fatty acid to the C3 hydroxyl J. Different Fates of TAGs in the Liver and Adipose Tissues 1. Adipose Tissue o esterification of fatty acids > TAG depends on ongoing carbohydrate metabolism for the formation of DHAP or glycerol 3-phosphate o lack glycerol kinase > cannot phosphorylate glycerol to form glycerol 3-phosphate o only source of glycerol 3-phosphate for TAG synthesis is from DHAP o entry of glucose into adipocyte is insulin-dependent > insulin is an essential requirement for TAG synthesis in the adipose tissue o TAG is stored in the cytosol in a nearly anhydrous form > serves as “depot fat” > ready for mobilization 2. Liver - little TAG is stored o most are - exported o packaged with o cholesterol o cholesteryl esters o phospholipid o apolipoprotein B-100 * form lipoprotein particles (VLDL) > secreted into the blood > peripheral tissues Trans 2 |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 8 of 9  BIOCHEMISTRY Fatty Acid and Triacylglycerol Metabolism III. CLINICAL ASPECTS NOTE A. Symptoms of Essential Fatty Acid Deficiency in Humans Include The essential fatty acid linoleic acid is required in the diet for at least Skin three reasons: Lesions & Impairment of Lipid Transport (a) It serves as a precursor of arachidonic acid from which o adults, no signs of essential fatty acid deficiencies have been eicosanoids are produced. reported (b) It covalently binds another fatty acid attached to cerebrosides in o infants (formula diets low in fat) and patients maintained for the skin, forming an unusual lipid (acylglucosylceramide) that helps to long periods exclusively by intravenous nutrition low in make the skin impermeable to water. This function of linoleic acid essential fatty acids show deficiency symptoms > prevented may help to explain the red, scaly dermatitis and other skin problems by an essential fatty acid intake of 1% to 2% of the total associated with a dietary deficiency of essential fatty acids. caloric requirement (c) It is the precursor of C22:6ω3, an important neuronal fatty acid. B. Abnormal Metabolism of Essential Fatty Acids Occurs in Several The other essential fatty acid, ω-linolenic acid (18:3, ω9, 12, 15), also Diseases forms eicosanoids. o may be connected with dietary insufficiency, has been noted in cystic fibrosis, acrodermatitis enteropathica, hepatorenal Adipose tissue also undergoes glyceroneogenesis, the process of syndrome, Sjögren-Larsson syndrome, multisystem neuronal synthesizing glycerol from gluconeogenic precursors in the blood, such degeneration, Crohn disease, cirrhosis and alcoholism, and as alanine, aspartate, and malate. Glyceroneogenesis occurs primarily Reye syndrome in the fasting state and is dependent on the induction of cytoplasmic o Elevated levels of very long chain polyenoic acids have been PEPCK in the adipocyte. The re-synthesis of triglycerides by adipose found in the brains of patients with Zellweger syndrome tissue during fasting modulates the release of fatty acids in the o Diets with a high P:S (polyunsaturated:saturated fatty acid) circulation. ratio reduce serum cholesterol levels and are considered to be beneficial in terms of the risk of development of coronary Fatty acids for VLDL synthesis in the liver may be obtained from the heart disease blood or they may be synthesized from glucose. In a healthy individual, C. Trans Fatty Acids Are Implicated in Various Disorders the major source of the fatty acids of VLDL triacylglycerol is excess o Small amounts of trans-unsaturated fatty acids are found in dietary glucose. In individuals with Diabetes mellitus, fatty acids ruminant fat (eg, butter fat has 2%-7%), where they arise mobilized from adipose triacylglycerols in excess of the oxidative from the action of microorganisms in the rumen, but the capacity of tissues are a major source of the fatty acids re-esterified main source in the human diet is from partially hydrogenated in liver to VLDL triacylglycerol. These individuals frequently have vegetable oils (eg, margarine). elevated levels of blood triacylglycerols. o Trans fatty acids compete with essential fatty acids and may exacerbate essential fatty acid deficiency. Moreover, they Where does the methyl group of the first acetyl COa that binds to fatty are structurally similar to saturated fatty acids and have acid synthase appear in palmitate, the final product? comparable effects in the promotion of The methyl group of acetyl COa becomes the ω-carbon (the terminal hypercholesterolemia and atherosclerosis. methyl group) of palmitate. Each new 2-carbon unit is added to the D. Prostanoids Are Potent, Biologically Active Substances carboxyl end of the growing fatty acyl chain. o Thromboxanes are synthesized in platelets and upon release cause vasoconstriction and platelet aggregation. Their Why do some alcoholics have high VLDL levels? synthesis is specifically inhibited by low-dose aspirin. In alcoholism, NADH levels in the liver are elevated. High levels of Prostacyclins (PGI2) are produced by blood vessel walls and NADH inhibit the oxidation of fatty acids. Therefore, fatty acids, are potent inhibitors of platelet aggregation. Thus, mobilized from adipose tissue, are re-esterified to glycerol in the liver, thromboxanes and prostacyclins are antagonistic. forming triacylglycerols, which are packaged into VLDL and secreted o PG3 and TX3, formed from eicosapentaenoic acid (EPA), into the blood. Elevated VLDL is frequently associated with chronic inhibit the release of arachidonate from phospholipids and alcoholism. As alcohol-induced liver disease progresses, the ability to the formation of PG2 and TX2. secrete the triacylglycerols is diminished, resulting in a fatty liver. o PGI3 is as potent an antiaggregator of platelets as PGI2, but TXA3 is a weaker aggregator than TXA2, changing the balance of activity and favoring longer clotting times. As little as 1 ng/mL of plasma prostaglandins causes contraction of smooth muscle in animals. o Potential therapeutic uses include prevention of conception, induction of labor at term, termination of pregnancy, prevention or alleviation of gastric ulcers, control of inflammation and of blood pressure, and relief of asthma REFERENCES and nasal congestion. 1. Harvey RA. Lippincott’s Illustrated Reviews: Biochemistry. o In addition, PGD2 is a potent sleep-promoting substance. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2011. Prostaglandins increase cAMP in platelets, thyroid, corpus 2. Rodwell VW., et.al. Harper’s Illustrated Biochemistry. 13th luteum, fetal bone, adenohypophysis, and lung but reduce ed. The McGraw-Hill Education, 2015. cAMP in renal tubule cells and adipose tissue. Trans 2 |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 9 of 9