Fatty Acid Metabolism Lecture Presentation PDF

Dr. Emanuel F.Cummings Reader in Biochemistry Molecular Medicine and Genetics Fatty Acid Metabolism TGs Are Highly Concentrated Energy Stores 9 Kcal/g VS 4 Kcal/g for protein/carbohydrates. Anhydrous storage in adipose VS hydrated glycogen in liver/muscle A typical 70kg man would have fu...

Dr. Emanuel F.Cummings Reader in Biochemistry Molecular Medicine and Genetics Fatty Acid Metabolism TGs Are Highly Concentrated Energy Stores 9 Kcal/g VS 4 Kcal/g for protein/carbohydrates. Anhydrous storage in adipose VS hydrated glycogen in liver/muscle A typical 70kg man would have fuel reserves: 100,000 kcal in TGs, 25,000 kcal in protein (mostly in muscle), 600 kcal in glycogen 40 kcal in glucose. TGs constitute about 11 kg of his total body weight. If the 11kg TGs to be stored in Glycogen form, his total body weight would be 55kg greater (11+55 kg) + 59. Storing energy in TGs saves 55Kg of body weight. Glycogen & Glucose provide energy for short-term (a day or so), while TGs support the body with energy for several weeks. 2  Dietar Bile salt y TGs Other lipids & proteins micelles H 2O Pancreati c Lipase Chylomicrons Lymp FAs h syste TGs m Monoglyceroles Intestinal Intestinal lumen mucosa Monoglyceroles FAs lipoprote in lipases Storage in TGs adipose -oxidation in tissue muscle 3 The Utilization of Fatty Acids as Fuel Requires Three Stages of Processing 1. The lipids must be mobilized: TGs are degraded to FAs and glycerol They are released from the adipose tissue and transported to the energy-requiring tissues. 2. At these tissues, the fatty acids must be activated and transported into mitochondria for degradation. 3. The fatty acids are broken down step-by-step into acetyl CoA, which is then processed in the citric acid cycle. 6 1. Triacylglycerols Are Hydrolyzed byAMP- Regulated Lipases epinephrine, norepinephrine, glucagon, adrenocorticotropic hormone 8 Formation of Free Fatty Acid Glycerol formed by lipolysis is absorbed by the liver where it enters glycolysis or gluconeogenesis. phosphatase 11 TGs Are Highly Concentrated Energy Stores 9 Kcal/g VS 4 Kcal/g for protein/carbohydrates. Anhydrous storage in adipose VS hydrated glycogen in liver/muscle A typical 70kg man would have fuel reserves: 100,000 kcal in TGs, 25,000 kcal in protein (mostly in muscle), 600 kcal in glycogen 40 kcal in glucose. TGs constitute about 11 kg of his total body weight. If the 11kg TGs to be stored in Glycogen form, his total body weight would be 55kg greater (11+55 kg) + 59. Storing energy in TGs saves 55Kg of body weight. Glycogen & Glucose provide energy for short-term (a day or so), while TGs support the body with energy for several weeks. 14 2. Fatty Acids Are Linked to CoA Before They Are Oxidized Fatty acids are oxidized in mitochondria. They are activated before they enter the mitochondrial matrix. ATP drives the formation of a thioester linkage between the carboxyl group of a FA and the sulfhydryl group of CoA. This activation reaction takes place on the outer mitochondrial membrane, where it is catalyzed by Acyl CoA synthase (also called fatty acid thiokinase). 15 Activation of FA Transport of FA Into Mitochondria Beta Oxidation 3. Fatty Acid Oxidation Through a sequence of 4 reactions: 1. Oxidation by FAD 2. Hydration by H2O 3. Oxidation by NAD+ 4. Thiolysis by CoA 20 Step Reaction Enzyme 1 Fatty acid + CoA + ATP Acyl CoA synthetase [also called fatty acid acyl CoA + AMP + PPi thiokinase and fatty acid:CoA ligase (AMP)] 2 Carnitine + acyl CoA Carnitine acyltransferase (also called acyl carnitine + CoA carnitine palmitoyl transferase) 3 Acyl CoA + E-FAD Acyl CoA dehydrogenases (several isozymes trans- 2 -enoyl CoA + E-FADH2 having different chain-length specificity) 4 trans-2 -Enoyl CoA +H2O Enoyl CoA hydratase (also called crotonase L-3-hydroxyacyl CoA or 3-hydroxyacyl CoA hydrolyase) 5 L-3-Hydroxyacyl CoA + NAD+ L-3-Hydroxyacyl CoA dehydrogenase 3-ketoacyl CoA + NADH + H+ 6 3-ketoacyl CoA + CoA -Ketothiolase (also called thiolase) acetyl CoA + acyl CoA (shortened by C2) 23  Humans Cannot Convert Fatty Acids into Glucose Acetyl CoA cannot be converted into pyruvate or oxaloacetate in humans. Oxaloacetate is regenerated, but it is not formed de novo when the acetyl unit of acetyl CoA is oxidized by the citric acid cycle. In contrast, plants have two additional enzymes enabling them to convert the carbon atoms of acetyl CoA into oxaloacetate. 24 Fats burn in the flame of carbohydrates The entry of acetyl CoA into the citric acid cycle depends on the availability of oxaloacetate for the formation of citrate. Oxaloacetate is normally formed from pyruvate, the product of glycolysis, by pyruvate carboxylase The concentration of oxaloacetate is lowered if carbohydrate is unavailable or improperly utilized. 25 In fasting or diabetes Oxaloacetate is consumed to form glucose by the gluconeogenesis. Under these conditions, acetyl CoA is diverted to the formation of acetoacetate and D-3-hydroxybutyrate. Acetoacetate, D-3-hydroxybutyrate, and acetone are often referred to as ketone bodies. 26 Acyl-CoA Dehydrogenase Deficiency Acyl-CoA Dehydrogenase Deficiency A group of inherited diseases that impair B-oxidation result from deficiencies in acyl-CoA dehydrogenases. The enzymes affected may belong to one of four categories: Very long-chain acyl-CoA dehydrogenase (VLCAD) Long-chain acyl-CoA dehydrogenase (LCAD) Medium-chain acyl-CoA dehydrogenase (MCAD) Short-chain acyl-CoA dehydrogenase (SCAD). Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency An Autosomal recessive disorder that prevents your body from breaking down certain fats and converting them into energy. As a result, the level of glucose in our blood can drop dangerously low. MCAD deficiency is present from birth. In the U.S., most states screen for MCAD deficiency at birth. If MCAD deficiency is diagnosed and treated early The disorder can be managed through diet and lifestyle actions.  In rare cases, the disorder is not diagnosed until adulthood. In the first years of life this deficiency will become apparent following a prolonged fasting period If Left untreated, it can lead to seizures, lethargy ,breathing difficulties, vomiting coma and death Viral infections also can cause MCAD deficiency- related reactions. Excessive urinary excretion of medium-chain dicarboxylic acids as well as their glycine and carnitine esters is diagnostic of this condition Sudden Infant Death Syndrome. Sudden death in infants has been linked deficiency of Acyl CoA Deficiency, due to imbalance between glucose and FA metabolism , This enzyme deficiency has been implicated in Jamaican Vomiting sickness, where the victims suffer from violent vomiting coma, severe , hypoglycaemia and even death. This condition resulted from eating the unripe ackee fruit. The unripe ackee contains HYPOGLYCIN A and B a unusual amino acid that is metabolized to Methylenecyclopropylacetal which inhibits Acyl CoA dehydrogenase. Ripened fruit -Hypoglycin A and B- ripened levels of less than 0.1 ppm, in unripe it can be over 1000 ppm Treatment Treatment of toxicity: Use activated charcoal and gastric lavage; give intravenous fluids and dextrose, Use anti-emetics to suppress vomiting, give benzodiazepines to suppress seizures  Propionyl CoA Carboxylase Deficiency Propionic Acidemia , ketoacidosis, developmental abnormalities Methyl malonic aciduria Defective formation of adenosyl B12 with deficient mutase activity –mental retardation Alpha Oxidation Fatty acids are oxidized by removing 1 carbon at a time from the carboxyl end This process is important in Brain Phytanic Acic Phytanic acid (or 3,7,11,15-tetramethyl hexadecanoic acid) is a branched chain fatty acid that humans can obtain through the consumption of dairy products, animal fats, and certain fish. Western diets are estimated to provide 50-100 mg of phytanic acid per day. In a study conducted in Oxford, individuals who consumed meat had, on average, a 6.7-fold higher geometric mean plasma phytanic acid concentration than vegetarians Refum’s Disease Refsum disease, also known as classic or adult Refsum disease, heredopathia atactica polyneuritiformis, phytanic acid oxidase deficiency and phytanic acid storage disease, An autosomal recessive neurological disease that results from the over- accumulation of phytanic acid in cells and tissues. It is named after Norwegian neurologist Sigvald Bernhard Refsum Refsum disease icauses vision loss, absence of the sense of smell (anosmia), and a variety of other signs and symptoms. The vision loss associated with Refsum disease is caused by an eye disorder called retinitis pigmentosa. This disorder affects the retina, the light-sensitive layer at the back of the eye. Vision loss occurs as the light-sensing cells of the retina gradually deteriorate.  The first sign of retinitis pigmentosa is usually a loss of night vision, which often becomes apparent in childhood. Over a period of years, the disease disrupts side (peripheral) vision and may eventually lead to blindness. The disease result from the abnormal build up of phytanic acid. That is obtained from the diet, particularly from beef and dairy products. It is normally broken down through a process called alpha-oxidation, which occurs in cell structures called peroxisomes. These sac-like compartments contain enzymes that process many different substances, such as fatty acids and certain toxic compounds. Mutations in either the PHYH or PEX7 gene disrupt the usual functions of peroxisomes, including the breakdown of phytanic acid. As a result, this substance builds up in the body's tissues. Regulation of Fatty Acid Synthesis Availability of Substrates – abundant CHO Acetyl CoA carboxylase – key enzyme stimulated by citrate and inhibited by palmitoyl CoA the end product. Insulin favors lipogenesis Glucagon inhibits lipogenesis Ketone Bodies If the body is deficient in oxaloacetate (due to fasting, diabetes, starvation), acetyl CoA from the Beta -oxdiation pathway cannot enter the citric acid cycle. (Oxaloacetate is diverted to gluconeogenesis). Acetyl CoA is diverted to form acetoacetate, D-3- hydroxybutarate and acetone. These are the three compounds that are often referred to as ketone bodies. ( Liver is the main site for synthesis) Ketone Body Oxidation: Long-term starvation or ketoacidosis Tissues that can use ketones as "fuel": brain, muscle, kidney, intestine Ketone bodies production in the liver Biosynthesis of Ketone Bodies Synthesis do Novo of Fatty Acids Transport of AcetyCoA- Citrate Shuttle System Formation of Malonyl CoA Elongation  Synthesis typically continues until a C16 palmitoyl group is formed. (The process is often called palmitate synthesis.) 3. Palmitate is released from palmitoyl-ACP by a thioesterase: Clinical Correlation 1. Deficiencies in Carnitine: Deficiencies in carnitine lead to an inability to transport fatty acids into the mitochondria for oxidation. This can occur in newborns and particularly in pre- term infants. Carnitine deficiencies also are found in patients undergoing hemodialysis or exhibiting organic aciduria. Carnitine deficiencies may manifest systemic symptomology or may be limited to only muscles. Symptoms can range from mild occasional muscle cramping to severe weakness or even death. Treatment is by oral carnitine administration.  2. Carnitine Palmitoyltransferase I (CPT I) Deficiency: Deficiencies in this enzyme affect primarily the liver and lead to reduced fatty acid oxidation and ketogenesis. Carnitine Palmitoylransferase II (CPT II) deficiency: results in recurrent muscle pain and fatigue and myoglobinuria following strenuous exercise. Carnitine acyltransferases may also be inhibited by sulfonylurea drugs such as tolbutamide and glyburide. Integration Metabolism