BIOCHEMISTRY LIPIDS Triacylglycerol Metabolism PDF

BIOCHEMISTRY LIPIDS: Triacylglycerol Metabolism Brendo Jandoc, M.D.  fatty acids are converted to TAG Topic Outline...

BIOCHEMISTRY LIPIDS: Triacylglycerol Metabolism Brendo Jandoc, M.D.  fatty acids are converted to TAG Topic Outline  for transport between tissues  for storage of metabolic fuel - TAGs are only slightly soluble in water → cannot form stable I. Storage of Fatty Acids as Components of TAG micelles → coalesce within adipocytes → form oily droplets A. Structure and Function of TAG (major energy reserve of the body) that are nearly B. Glycerol Phosphate Synthesis anhydrous C. Conversion of Free Fatty Acid to its Activated a. Fat Deposits Form - main stores of metabolic fuel in humans in fat cells D. Synthesis of a Molecule of TAG from Glycerol (adipocytes) - very large portion of ingested fats are stored as TAG in the fat Phosphate and Fatty Acyl CoA droplets of adipocytes → serve long term needs of metabolic II. Different Fates of TAGs in the Liver and Adipose Tissues fuel III. Mobilization of Stored Fat (Lipolysis of TAG) b. b. Advantages of TAG over Other Forms of Metabolic Fuels A. Release of Fatty Acids from TAGs - light weight (less dense than water) B. Lipolysis in Other Tissues - concentrated form of fuel (complete combustion to CO2 and IV. Oxidation of Fatty Acids water → release 9 kcal/g as opposed to 4 kcal/g of A. β-Oxidation of Fatty Acids carbohydrates and proteins) - water-insolubility → no osmotic problems to the cells B. Oxidation of fatty Acids with an Odd Number of B. Glycerol Phosphate Synthesis Carbons a. Glycerol Phosphate C. Oxidation of Unsaturated Fatty Acids - initial acceptor of fatty acids during the synthesis of TAG D. Alternative Pathways for Fatty Acid Oxidation b. 2 Pathways V. Clinical Aspects i. Glycerol Phosphate Dehydrogenase VI. Specialized Fatty Acids: Prostaglandins and Related - liver Compounds - adipose tissues ii. Glycerol Kinase VII. Ketone Bodies: An Alternate Fuel for Cells - liver only I. STORAGE OF FATTY ACIDS AS COMPONENTS OF TAG - adipocytes can only take up glucose in the presence of insulin (absence of insulin→adipocytes have limited Storage of Fatty Acids as Components of TAG capability to produce glycerol phosphate→cannot form TAG) – 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”) Because TAGs are slightly soluble in water and cannot form stable micelles, they coalesce within adipocytes to form oily droplets that are nearly anhydrous. These cytosolic lipid droplets are the major energy Both liver (the primary site of TAG synthesis) and adipose tissue, reserve of the body. glycerol phosphate can be produced from glucose, using first the reactions of the glycolytic pathway to produce dihydroxyacetone A. Structure and Function of TAG phosphate 1. Structure of TAG C. Conversion of Free Fatty Acid to its Activated Form  triesters of glycerol and 3 fatty  fatty acid must be activated to acids its activated form (attached to CoA) → TAG synthesis - fatty acid on carbon 1 is  catalyzed by fatty acyl CoA usually saturated synthetase (thiokinase) - fatty acid on carbon 2 is usually unsaturated - fatty acid on carbon 3 can be either  presence of unsaturated fatty acid(s) → decreased melting temperature 2. Function ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 1 of 9  BIOCHEMISTRY CARBOHYDRATES: Complex carbohydrates D. Synthesis of a Molecule of TAG from Glycerol Phosphate and 2. Liver Fatty Acyl CoA  little TAG is stored  ACYLATION OF GLYCEROL  most are – exported i. 1st Acylation – packaged with: - 2 routes of acylation of the 1st · cholesterol hydroxyl of glycerol · cholesteryl esters a. 1st Route · phospholipid · uses DHAP (derived from · apolipoprotein B-100 → form glucose by the glycolytic lipoprotein particles (VLDL) → secreted pathway) as the acceptor of the into the blood → peripheral tissues acyl moiety from the fatty acyl CoA III. MOBILIZATION OF STORED FAT (LIPOLYSIS OF TAG) · initial reaction is followed by reduction (NADPH as the  TAGs provide concentrated stores of metabolic energy (highly electron acceptor) → reduced and largely anhydrous) lysophosphatidate  complete oxidation of fatty acids to CO2 and H2O → 9 kcal/g of · fatty acid preferentially fat introduced to form - proteins and carbohydrates: 4 kcal/g lysophosphatidate is saturated - alcohol: 7 kcal/g b. 2nd Route · gives the same product A. Release of Fatty Acids from TAGs · shows the same preference for  initiated by hydrolytic release of fatty acids and glycerol by a saturated fatty acid hormone-sensitive lipase (removes fatty acids from either · order is reversed · reduction of DHAP → glycerol carbon 1 or 3 of TAG) 3-phosphate occurs before  other lipases specific for MAG or DAG remove the remaining acylation of the C1 hydroxyl fatty acids ii. 2nd Acylation - present in excess - unsaturated fatty acyl CoA thioester is introduced to the 2- hydroxyl of lysophosphatidate - except in the human mammary gland (saturated fatty acyl CoA is used) iii. 3rd Acylation - phosphate group on C3 is  rate-limiting step of lipolysis in adipocytes - reaction catalyzed removed by phosphatase by hormone-sensitive TAG lipase - followed by addition of either a saturated or 1. Activation of Hormone-Sensitive unsaturated fatty acid to Lipase the C3 hydroxyl - activated (by covalent modification) when II. DIFFERENT FATES OF TAG IN THE LIVER AND ADIPOSE TISSUES phosphorylated by a 3’,5’- 1. Adipose Tissue cAMP-dependent protein  esterification of fatty acids → TAG depends on ongoing kinase carbohydrate metabolism for the formation of DHAP or a. Activated cAMP-Mediated Cascade glycerol 3-phosphate - fatty acid synthesis is turned  lack glycerol kinase → cannot phosphorylate glycerol to form off glycerol 3-phosphate - TAG degradation is turned on  only source of glycerol 3-phosphate for TAG synthesis is b. High Insulin and Glucose Levels from DHAP - hormone-sensitive lipase  entry of glucose into adipocyte is insulin-dependent → dephosphorylation and inactivation insulin is an essential requirement for TAG synthesis in the c. Prostaglandins adipose tissue - inhibit lipolysis by reducing  TAG is stored in the cytosol in a nearly anhydrous form → cAMP levels serves as “depot fat” → ready for mobilization ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 2 of 9  BIOCHEMISTRY CARBOHYDRATES: Complex carbohydrates 2. Fate of Glycerol 1. Fatty Acid Transport into Mitochondria - adipocytes lack glycerol kinase → cannot metabolize a. Long Chain Fatty Acid Transport into the Mitochondria glycerol - free fatty acid take-up into the cell → activated to acyl-CoA - transported through the blood to the liver → - 2 activating systems i. Endoplasmic Reticulum Fatty Acyl CoA Synthase (Thiokinase) · glycerol phosphate formation → liver TAG synthesis - activates long-chain fatty acids (12 or more carbons) · conversion to DHAP (reversal of glycerol phosphate FA + ATP + CoA Acyl CoA + PPi + AMP dehydrogenase reaction) → glycolysis or ii. Inner Mitochondrial Acyl CoA Synthases gluconeogenesis - activates fatty acids of: · medium-chain length (4-10 carbons) · short-chain length · acetate · propionate · these fatty acids freely enter the mitochondria from the cytosol b. Long Chain Fatty Acid Translocation (Carnitine Shuttle) - β-oxidation occurs in the mitochondria → long-chain fatty acids must be transported across mitochondrial inner membrane (generally impermeable to bulky polar molecules such as CoA) → specialized carrier (carnitine shuttle) in the membrane transports the acyl group from cytosol → mitochondrial matrix 3. Fate of Fatty Acids  Carnitine - free (unesterified) fatty acids → cross cell membrane of - exists in the inner mitochondrial membrane adipocyte → bind to plasma albumin → fatty acids diffuse to 1. Sources · dietary - red meat cells → oxidation for energy production · dairy products - active transport of fatty acids across membranes mediated 2. Synthesis by membrane fatty acid · in the body from - binding protein · lysine - carbon source for lipid biosynthesis · methionine - those that cannot use free fatty acids as fuel · by - liver a. Brain - impermeable blood-brain barrier · kidney b. Other nervous tissues 3. Skeletal Muscles c. RBCs - no mitochondria · contain about 97% of all carnitine in the body d. Adrenal medulla 4. Functions · receives the transferred fatty acyl group → long-chain B. Lipolysis in Other Tissues fatty acids in the mitochondrial matrix  other tissues (muscle, liver) store small amounts of TAG · allows export from the mitochondria of branched- (intracellular lipid droplets) for their own use chain acyl groups  mobilized by the same hormonal controls as are found in · trapping and excretion via the kidney of acyl groups adipocytes that cannot be metabolized by the body i. Acyl group is transferred from cytosolic CoA to carnitine by IV. OXIDATION OF FATTY ACIDS carnitine palmitoyl transferase I (CPT-I)/carnitine acyltransferase I (CAT-I) in the outer surface of the inner  The major pathway for catabolism of fatty acids is a mitochondrial membrane → acylcarnitine mitochondrial pathway called β-oxidation ii. Acylcarnitine transported across the membrane to mitochondrial matrix → acyl group transferred to A. β-Oxidation of Fatty Acids mitochondrial CoA by carnitine palmitoyl transferase II (CPT- - 2-carbon fragments are successively removed from the II)/carnitine acyltransferase II (CAT-II) in the inner surface of carboxyl end of the fatty acyl CoA → acetyl CoA the inner mitochondrial membrane - generates · NADH · FADH2 - yields acetyl CoA (substrate for the TCA cycle) - principal pathway for fatty acid catabolism - occurs in the mitochondrial matrix - involves oxidation of β-carbon toβ-keto acid ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 3 of 9  BIOCHEMISTRY CARBOHYDRATES: Complex carbohydrates c. Carnitine Shuttle Inhibitor CASE (SYSTEMIC CARNITINE DEFICIENCY)  Malonyl CoA  Presentation · inhibits carnitine acyltransferase I → inhibiting entry of acyl A 3-year-old boy was found to have an enlarged heart while being groups into the mitochondrial matrix examined for a cough. An ECG was abnormal. The boy’s development · when fatty acid synthesis is occurring in the cytosol (as appeared normal, although he was an irritable child. He was released indicated by the presence of malonyl CoA), newly made fatty and monitored. Over the next 2 years, cardiomegaly increased, and he acids cannot be transferred into the mitochondria for developed symptoms of CHF. He also began to exhibit signs of degradation weakness of skeletal muscles. A muscle biopsy showed lipid deposition d. Genetic Defects in the Carnitine Shuttle and low carnitine levels. Plasma levels of carnitine were also found to - congenital absence of carnitine acyltransferase in skeletal be below normal. muscles  Diagnosis and Treatment - defective carnitine synthesis → low carnitine – below normal carnitine levels confirmed a diagnosis of carnitine concentration deficiency - → inability to use long-chain fatty acids as a metabolic fuel – treatment was begun with daily dose of 174 mg/kg L-carnitine → accumulation of: · within 1 month · toxic amounts of free fatty acids - activity increased · branched-chain acyl groups in cells - irritability decreased i. CPT I Deficiency · after 12 months · affects the liver - cardiac problems improved · inability to use long chain fatty acids for fuel → - normal strength and exercise tolerance impaired glucose synthesis during fasting →  Discussion · severe hypoglycaemia – oral carnitine load → plasma carnitine levels increased to low- · coma normal range, urinary levels increased to 30x normal → suggests · death a defect in renal and/or gastrointestinal transport of carnitine ii. CPT II Deficiency a) Primarily in f. Short- and Medium-Chain Fatty Acid Entry into the Mitochondria - cardiac muscles - fatty acids < 12 carbons can cross the inner mitochondrial - skeletal muscles membrane without the aid of carnitine or the CPT system b) Symptoms of Carnitine Deficiency → activated to their CoA derivative by matrix enzymes → - cardiomyopathy oxidation - muscle weakness  Medium Chain Fatty Acids - myoglobinemia following exercise · plentiful in human milk iii. Treatment · oxidation not dependent on CPT-I → not - avoidance of prolonged fasts inhibited by malonyl CoA - diet – high carbohydrate – low in long chain fatty acids 2. Reactions of β-Oxidation – supplementation with medium chain fatty  sequence of 4 reactions → acids shortening of the fatty acid chain e. Carnitine Deficiency by 2 carbons i. 2 Categories a. Steps a) Systemic – oxidation that produces FADH2 - carnitine levels are reduced in all tissues – hydration b) Myopathic – oxidation that produces NADH - carnitine levels are reduced only in muscle tissue – thiolytic cleavage → acetyl CoA including the heart release ii. Congenital Deficiencies - defective tubular carnitine reabsorption i. Acyl CoA → Enoyl CoA - deficient cellular carnitine uptake - dehydrogenation reaction iii. Secondary Deficiencies catalyzed by acyl CoA - liver disease → decreased carnitine synthesis dehydrogenase - malnutrition - prosthetic group FAD - strict vegetarian diet reduced to FADH2 during - increased carnitine requirements the reaction · pregnancy ii. Enoyl CoA → 3-Hydroxyacyl · severe infections CoA · burns - hydration reaction · trauma catalyzed by enoyl CoA - hemodialysis → carnitine removal hydratase iv. Treatment - carnitine supplementation ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 4 of 9  BIOCHEMISTRY CARBOHYDRATES: Complex carbohydrates iii.3-Hydroxyacyl CoA → 3-Ketoacyl CoA 4. Respiratory Quotient - dehydrogenation reaction catalyzed by 3-hydroxyacyl  moles of CO2 produced divided by the moles of O2 consumed CoA dehydrogenase during complete oxidation of a metabolic fuel to CO2 and H2 O - NAD+ is reduced to NADH during the reaction a. Palmitate iv. 3-Ketoacyl CoA + CoA → Acetyl CoA + Tetradecanoyl CoA RQ = 16 moles CO2 produced = 0.7 - thiolytic cleavage reaction catalyzed by thiolase (β- 23 moles O2 consumed ketothiolase) b. Glucose b. Acetyl CoA C6H12O6 + 6O2 → 6CO2 + 6H2O - positive allosteric effector of pyruvate carboxylase → link RQ = 6 moles CO2 produced = 1.0 between fatty acid oxidation and gluconeogenesis 6 moles O2 consumed c. Protein = 0.83 3. Energy Yield from Fatty Acid Oxidation *Daily Energy Expenditure (DEE) i. Stoichiometry of β-Oxidation - can be determined from the oxygen consumption and the  β-Oxidation of Palmitate (16 carbons) respiratory quotient (RQ) Palmitoyl CoA + 7CoA + 7FAD + 7H2O → 8Acetyl CoA + 7FADH2 + 5. Medium-Chain Fatty Acyl CoA Dehydrogenase Deficiency 7NADH + 7H+  there are 4 fatty acyl CoA dehydrogenase species in the mitochondria with specificities for:  7 moles FADH2 → 14 moles ATP by electron transport and - short- chain length fatty acids oxidative phosphorylation - medium- chain length fatty acids  7 moles NADH → 21 moles ATP by electron transport and - long chain length fatty acids oxidative phosphorylation - very long-chain length fatty acids  autosomal recessive Palmitoyl CoA + 7CoA + 7O2 + 35Pi + 35ADP → 8Acetyl CoA + 35ATP +  one of the most common inborn errors of metabolism 42H2O  most common inborn errors of fatty acid oxidation  costs 2 moles ATP to activate free palmitate → 33 moles ATP  found in 1/40,000 births (more prevalent than phenylketonuria) per mole of palmitate for β-oxidation worldwide  causes up to 10% of cases of Sudden Infant Death Syndrome ii. Total Oxidation (SIDS) or Reye’s syndrome  acetyl CoA derived from β-oxidation of fatty acids → oxidized a. Causes the Following to O2 and H2O by the TCA cycle - decrease in fatty acid oxidation 8Acetyl CoA + 16O2 + 96Pi + 96ADP → 8CoA + 96ATP + 16CO2 + - severe hypoglycemia 104H2O b. Treatment - carbohydrate-rich diet  combined yield of ATP Palmitoyl CoA + 23O2 + 131Pi + 131ADP → 8CoA + 131ATP + 16CO2 + B. Oxidation of fatty Acids with an Odd Number of Carbons 146H2O  oxidation proceeds by the same reaction steps as that of fatty acids with an even number of carbons, until the final 3 carbons are  when starting with the free fatty acid palmitate, the ATP reached (propionyl CoA) → metabolized by 2-step pathway required for the production of palmitoyl CoA must be taken  propionyl CoA is also produced during the metabolism of certain into consideration → 2 high-energy bonds are broken down amino acids owing to the thiokinase reaction → total energy yield is 129 a. Synthesis of Methylmalonyl CoA ATP - propionyl CoA carboxylase has an absolute requirement for the coenzyme biotin - propionyl CoA → carboxylation → D-methylmalonyl CoA b. Formation of L-Methylmalonyl CoA - D-methylmalonyl CoA → L- methylmalonyl CoA by methylmalonyl CoA racemase c. Synthesis of Succinyl CoA - succinyl CoA can enter the TCA cycle - methylmalonyl CoA mutase requires a coenzyme form of vitamin B12 (deoxyadenosylcobalamin) i. Vitamin B12 Deficiency ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 5 of 9  BIOCHEMISTRY CARBOHYDRATES: Complex carbohydrates · propionate and methylmalonate are excreted in the urine ii. Methylmalonic Acidemia and Aciduria · 2 types – 1 in which the mutase is missing – 1 in which the patient is unable to convert vitamin B12 into its coenzyme form  either defects result in: · metabolic acidosis · developmental retardation C. Oxidation of Unsaturated Fatty Acids  50% of fatty acids in the human body are unsaturated  provides less energy because they are less highly reduced → fewer reducing equivalents produced  degraded by the β-oxidation pathway assisted by other 2 enzymes  double bonds in naturally occurring fatty acids are in the cis D. Alternative Pathways for Fatty Acid Oxidation configuration 1. ω-Oxidation  β-oxidation pathway deal only with trans configuration as at the – oxidation of the terminal methyl group to form ω -hydroxy fatty enoyl CoA hydratase step acid 1. Oxidation of Monounsaturated Fatty Acids – minor pathway observed with liver microsomal preparations – Δ3-cis-Δ2-Trans Enoyl CoA Isomerase - shifts the double bond to the preferred Δ2-trans 2. α-Oxidation configuration – oxidation of long-chain fatty acids to 2-hydroxy fatty acids - ex: β-oxidation of (constituents of brain lipids) followed by oxidation to a fatty · palmitoleate (16 : 1 : Δ9) acid with 1 less carbon · oleic acid (18 : 1 : Δ9) a. Phytanic Acid - hydroxylated at the α-carbon by fatty acid α-hydroxylase → product - decarboxylated → activated to CoA derivative → β-oxidation b. Normal Individuals - α-oxidation of phytanic acid removes the terminal carbonyl before β-oxidation, allowing the latter pathway to operate, 2. Oxidation of Polyunsaturated Fatty Acids as the β-carbon is – polyunsaturated fatty acids require another enzyme for - now available complete oxidation c. Refsum’s Disease (Phytanic Acid Storage Disease) - hydration of a cis-Δ2 double bond →D isomer of β- – rare hydroxyacyl CoAs (not substrates for L-β-hydroxyacyl – autosomal recessive CoA dehydrogenase) – autosomal recessive - epimerase act on the D isomer of a β-hydroxyacyl CoA → – fatty acid α-hydroxylase deficiency yield required L isomer – unable to oxidize fatty acids at the α-carbon → build-up of 3. β-Oxidation in the Peroxisome phytanic acid (derived from animal fat and cow’s milk and – very long-chain fatty acids (> 20 carbons) → preliminary β- probably originally from chlorophyll) in the: oxidation in the peroxisomes → chain shortening → · plasma mitochondrion → further oxidation · tissues – initial dehydrogenation catalyzed by FAD-containing acyl CoA i. Phytanic Acid oxidase - not a substrate for acyl CoA dehydrogenase – FADH2 produced → oxidized by molecular oxygen → H2O2 → - cannot be oxidized by the β-oxidation system because catalase → H2O the β-position – genetic defects → very long-chain fatty acid accumulation in - is blocked by a methyl group · blood - branched-chain fatty acid · tissues II. Symptoms a. Zellweger (Cerebrohepatorenal) Syndrome - retinitis pigmentosa - defect in peroxisomal biogenesis in all tissues - failing night vision b. X-Linked Adrenoleukodystrophy - peripheral neuropathy - defect in peroxisomal activation of very long-chain - cerebellar ataxia fatty acids III. Treatment - dietary restriction ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 6 of 9  BIOCHEMISTRY CARBOHYDRATES: Complex carbohydrates V. CLINICAL ASPECTS VI. SPECIALIZED FATTY ACIDS: PROSTAGLANDINS and RELATED COMPOUNDS A. Carnitine Deficiency  can occur in the newborn, especially in preterms, due to  Prostaglandins and Related Compounds (Thromboxanes, Leukotrienes) inadequate biosynthesis or renal leakage - eicosanoids  can also be caused by hemodialysis - extremely potent compounds 1. Signs and Symptoms - elicit a wide range of physiologic responses - episodic periods of hypoglycemia owing to decreased - extremely short half-life gluconeogenesis from impaired fatty acid oxidation in - produced in very small amounts the presence of increased plasma free fatty acids → lipid - formed in almost all tissues accumulation with muscular weakness - generally act locally - metabolized to inactive products at their site of synthesis 2. Treatment - not stored to any appreciable extent - supplementation with oral carnitine A. Synthesis of Prostaglandins B. Carnitine Palmitoyltransferase I Deficiency  Linoleic Acid  affects only the liver - essential fatty acid  Characteristics - dietary precursor of  decreased fatty acid oxidation prostaglandins  ketogenesis - converted to the immediate  hypoglycaemia precursors of prostaglandins (20- C. Carnitine Palmitoyltransferase II Deficiency carbon polyunsaturated fatty acids containing 3, 4, or 5 double  affects primarily the skeletal muscles (weakness and necrosis bonds) with myoglobinuria) and liver in its most severe form  Arachidonic Acid D. Oral Hypoglycemic Agent - Sulfunylurea (Glyburide, Tolbutamide) – precursor of the  inhibits carnitine palmitoyltransferase → decreased fatty acid predominant classes of oxidation prostaglandins – released from membrane- E. Long-Chain 3-Hydroxyacyl CoA Dehydrogenase Deficiency bound phospholipids by  acute fatty liver of pregnancy phospholipase A2 F. Jamaican Vomiting Sickness 1. Synthesis of PGH2 a. Oxidation and Cyclization of Arachidonic Acid → PGG2, PGH2  Hypoglycin – 1st step in the synthesis of prostaglandins – toxin from unripe fruit of akee tree – catalyzed by prostaglandin endoperoxide synthase complex – inactivate short- and medium-chain acyl CoA dehydrogenase - microsomal protein → inhibition of β-oxidation → hypoglycemia and excretion - 2 catalytic activities: of medium- and short-chain mono- and dicarboxylic acids · fatty acid cyclooxygenase (requires 2 molecules of G. Dicarboxylic Aciduria O2) 1. Characterized by · peroxidase (dependent on reduced glutathione) – excretion of C6-C10 ω-dicarboxylic acids – non-ketotic hypoglycemia b. PGH2 – precursor for a number of prostaglandins and 2. Etiology thromboxanes  deficiency of mitochondrial medium-chain acyl CoA dehydrogenase 2. Inhibition of Prostaglandin Synthesis H. Refsum’s Disease a. Cortisol  Inherited condition that causes vision loss, absence in the sense – inhibits phospholipase A2 activity → nonavailability of of smell arachidonic acid  Results from the abnormal build-up of a fatty acid called b. NSAIDs (Aspirin, Phenylbutazone, Indomethacin) Phytanic acid – inhibit prostaglandin endoperoxide synthase → prevent the I. Zellweger’s (Cerebrohepatorenal) Syndrome synthesis of parent prostaglandins (PGG2, PGH2) – do not affect the synthesis of leukotrienes  Also known as Cerebrohepatorenal syndrome i. Aspirin  Rare inherited absence of peroxisomes in all tissues accumulate - irreversible inhibitor C26-C38 polyenoic acids in brain tissues due to inability to ii. Other Drugs oxidize long-chain fatty acids in peroxisomes - reversible within approximately 48 hours ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 7 of 9  BIOCHEMISTRY CARBOHYDRATES: Complex carbohydrates B. Synthesis of Leukotrienes  Arachidonic Acid – converted to a wide variety of hydroperoxy acids by a separate pathway involving a family of lipoxygenases – neutrophils contain 5-lipoxygenase which converts arachidonic acid to 5-hydroxy-6, 8, 11, 14 eicosatetraenoic acid (5-HPETE) which is then converted to series of leukotrienes a. Preferred Energy Substrates of the C. Biologic Actions of Prostaglandins, Thromboxanes, and - heart Leukotrienes - skeletal muscle  different in each organ system - kidney  excess prostaglandin production – if blood levels of β-hydroxybutyrate and acetoacetate - pain increase sufficiently (after 20 days of starvation) → form - inflammation valuable energy substrate for the brain (may account for up - fever to 75% of brain oxidation) - nausea b. Important Sources of Energy for the Peripheral Tissues Because - vomiting – soluble in aqueous solution and do not need to be incorporated to lipoproteins or carried by albumin – produced in the liver during periods when the amount of acetyl CoA present exceeds the oxidative capacity of the liver – used in the extrahepatic tissues (skeletal muscles, cardiac muscles, renal cortex) A. Synthesis of Ketone Bodies by the Liver  synthesized in liver mitochondria → used as metabolic fuel by other tissues (liver cannot use ketone bodies as metabolic fuel)  synthesis is limited except under conditions of - high rates of fatty acid oxidation - limited carbohydrate intake - ex: fasting, starvation  flooding of liver with fatty acids → elevated hepatic acetyl CoA → pyruvate dehydrogenase inhibition; pyruvate carboxylase activation → oxaloacetate production → used by the liver for gluconeogenesis rather than for the TCA cycle acetyl CoA channelled into ketone body synthesis 1. 3-Hydroxy-3-Methylglutaryl CoA (HMG-CoA) Synthesis a. Acetoacetyl CoA Formation – 1st step – can occur by 1 of 2 processes – incomplete breakdown of fatty acid – reversal of the thiolase reaction of fatty acid oxidation b. Mitochondrial HMG-CoA Synthase – catalyzes the rate-limiting step of ketone body synthesis VII. KETONE BODIES: AN ALTERNATIVE FUEL FOR CELLS – present in significant quantities only in the liver – combines a 3rd molecule of acetyl CoA with acetoacetyl CoA 1. Liver Mitochondria → produce 3-hydroxy-3- methylglutaryl CoA (HMG-CoA) – capacity to divert any excess acetyl CoA derived from fatty c. HMG-CoA acid or pyruvate oxidation into ketone bodies – structural intermediate in the catabolism of leucine – precursor of cholesterol 2. Ketone Bodies – cleaved to produce acetoacetate and acetyl CoA – small – water-soluble 2. Ketone Body Synthesis – potential units of acetate a. HMG CoA Cleavage Yields – transported in the blood to the peripheral tissues → – acetoacetate reconverted to acetyl CoA → TCA cycle – acetyl CoA b. Acetoacetate ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 8 of 9  BIOCHEMISTRY CARBOHYDRATES: Complex carbohydrates – can be reduced to form 3-hydroxybutyrate (NADH as D. Ketoacidosis hydrogen donor) a. Starvation – can be spontaneously decarboxylated → acetone formation – ketone body production increases dramatically c. β-Hydroxybutyrate – blood levels rise only slowly to a maximum of 7 mM after 20- – formed from acetoacetate by β-hydroxybutyrate 30 days of starvation dehydrogenase when the NADH/NAD+ ratio is high (as it is – ketone bodies are the only source of fuel → consumed by the in the liver during fasting) body → no excess to accumulate → ketonuria and ketonemia d. Acetone are never high enough to precipitate ketoacidosis (ketosis – volatile biologically nonmetabolizable side product accompanied by metabolic acidosis) – formed spontaneously from a small fraction of circulating – untreated diabetic patients → blood ketone body acetoacetate → lost in the expired air from the lungs levels may be extremely high → capable of producing  Untreated DM life-threatening ketoacidosis – odor of acetone is apparent on the patient’s fruity b. Ketonuria (high output in the urine) accompanies ketonemia breath (in this condition, ketone body production can (high blood ketone body levels) → ketosis be extremely high) E. Excessive Production of Ketone Bodies in Diabetes Mellitus B. Utilization of Ketone Bodies by the Peripheral Tissues 1. Rate of Ketone Body Formation > Rate of Use  ketone bodies are constantly produced by the liver at low levels – increased blood levels (ketonemia) → increased urinary levels – the liver cannot reconvert acetoacetate to acetoacetyl CoA (ketonuria) → ketosis → cannot use them as fuels – seen in - starvation  production becomes more significant during starvation (when - most often in cases of uncontrolled type I (insulin- ketone bodies are much more needed to provide energy to the dependent) diabetes mellitus peripheral tissues) - high fatty acid degradation → excessive acetyl CoA → NAD+ depletion 1. β-Hydroxybutyrate Dehydrogenase increased NADH pool – oxidizes β-hydroxybutyrate to acetoacetate → slowing of TCA cycle → acetyl CoAs forced to ketone body formation 2. Activation – occurs by the formation of the CoA thioester of 2. Diabetic Patients with Ketosis acetoacetate – urinary excretion of ketone bodies may be as high as 5000 mg/24 – CoA provided by succinyl CoA hours – catalyzed by succinyl CoA: acetoacetate CoA – blood concentration may reach 90 mg/dL (< 3 mg/dL in normal transferase (thiophorase) individuals) – reversible reaction – elevated ketone body concentration in the blood → acidemia 3. Thiolase - carboxyl group of a ketone body has a pKa of 4 → losses – cleavage of acetoacetyl CoA to 2 acetyl CoAs → proton (H+) as it circulates in the blood → lowers blood oxidation by the TCA cycle pH → acidosis (ketoacidosis) – urinary excretion of glucose and ketone bodies (osmotic diuresis) → dehydration C. Energy Yield from Oxidation of Ketone Bodies - conversion of β-hydroxybutyrate to acetoacetate → yields NADH → 3 ATP molecules by electron transport and oxidative phosphorylation - each acetyl CoA → yields 12 ATP molecules via TCA cycle, electron transport, and oxidative phosphorylation - activation requires → 1 mole ATP - acetoacetate oxidation → 2 acetyl CoAs → 24 moles ATP - β-hydroxybutyrate oxidation → yield NADH → 3 moles ATP 26 moles ATP ABACO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 9 of 9