Regulation Of Energy Metabolism (Part 3) PDF

TOPIC 2 – REGULATION OF ENERGY METABOLISM (PART 3) Sumathy Arumugam  INTRODUCTION Gluconeogenesis is GLUCO – glucose; NEO – new; GENESIS – creation. Gluconeogenesis is a biochemical term that describes the sy...

TOPIC 2 – REGULATION OF ENERGY METABOLISM (PART 3) Sumathy Arumugam  INTRODUCTION Gluconeogenesis is GLUCO – glucose; NEO – new; GENESIS – creation. Gluconeogenesis is a biochemical term that describes the synthesis of glucose from substances which are not carbohydrates. Gluconeogenesis is the formation of new glucose molecules in the body as opposed to glucose that is broken down from the long storage molecule glycogen. Gluconeogenesis is the opposite process of glycolysis, which is the breakdown of glucose molecules into their components. It takes place mostly in the liver, though it can also happen in smaller amounts in the kidney and small intestine.  LEARNING OUTCOMES On successful completion of the lesson, the student will be able to: identify the function of gluconeogenesis; describe the pathway of gluconeogenesis.  FUNCTIONS Human bodies produce glucose to maintain healthy blood sugar levels. Glucose levels in the blood must be maintained because it is used by cells to make the energy molecule adenosine triphosphate (ATP). Gluconeogenesis occurs during times when a person has not eaten in a while, such as during a period of starvation. Without food intake, blood sugar levels become low.  FUNCTIONS (CONT.) During this time, the body does not have an excess of carbohydrates from food that it can break down into glucose, so it uses other molecules for the process of gluconeogenesis such as amino acids, lactate, pyruvate and glycerol instead. Once glucose is produced through gluconeogenesis in the liver, it is then released into the bloodstream, where it can travel to cells of other parts of the body so that it may be used for energy. The process of gluconeogenesis is sometimes referred to endogenous glucose production (EGP) because it requires the input of energy.  PATHWAY 1. Gluconeogenesis begins in either the mitochondria or cytoplasm of the liver or kidney. First, two pyruvate molecules are carboxylated to form oxaloacetate. One ATP (energy) molecule is needed for this. 2. Oxaloacetate is reduced to malate by NADH so that it can be transported out of the mitochondria. 3. Malate is oxidized back to oxaloacetate once it is out of the mitochondria. 4. Oxaloacetate forms phosphoenolpyruvate using the enzyme PEPCK.  PATHWAY (CONT.) 5. Phosphoenolpyruvate is changed to fructose-1,6-biphosphate, and then to fructose-6-phosphate. ATP is also used during this process, which is essentially glycolysis in reverse. 6. Fructose-6-phosphate becomes glucose-6-phosphate with the enzyme phosphoglucoisomerase. 7. Glucose is formed from glucose-6-phosphate in the cell’s endoplasmic reticulum via the enzyme glucose-6-phosphatase. To form glucose, a phosphate group is removed, and glucose-6-phosphate and ATP becomes glucose and ADP. PATHWAY (CONT.) PATHWAY (CONT.)  SUMMARY During a prolonged fast or vigorous exercise, glycogen stores become depleted, and glucose must be synthesized de novo (new) in order to maintain blood glucose levels. Gluconeogenesis is the pathway by which glucose is formed from non-hexose precursors such as glycerol, lactate, pyruvate, and glucogenic amino acids.  SUMMARY (CONT.) Gluconeogenesis is essentially the reversal of glycolysis. However, to bypass the three highly exergonic (and essentially irreversible) steps of glycolysis, gluconeogenesis utilizes four unique enzymes. The enzymes unique to gluconeogenesis are pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Because these enzymes are not present in all cell types, gluconeogenesis can only occur in specific tissues. In humans, gluconeogenesis takes place primarily in the liver and to a lesser extent, the renal cortex.  INTRODUCTION Fructose is an abundant sugar in the diet. This dietary monosaccharide is present naturally in fruits and vegetables, either as free fructose or as part of the disaccharide sucrose and as its polymer inulin. Sucrose (table sugar) is a disaccharide which when hydrolyzed yields fructose and glucose.  LEARNING OUTCOMES On successful completion of the lesson, the student will be able to: describe the metabolism of fructose: Fructolysis Metabolism of fructose to DHAP and glyceraldehyde Synthesis of glycogen from DHAP and glyceraldehyde 3- phosphate Synthesis of triglyceride from DHAP and glyceraldehyde 3- phosphate  METABOLISM All three dietary monosaccharides are transported into the liver by the GLUT2 transporter. Fructose and galactose are phosphorylated in the liver by fructokinase (Km= 0.5 mM) and galactokinase (Km = 0.8 mM), respectively. By contrast, glucose tends to pass through the liver (Km of hepatic glucokinase = 10 mM) and can be metabolized anywhere in the body. Uptake of fructose by the liver is not regulated by insulin. However, insulin is capable of increasing the abundance and functional activity of GLUT5 in skeletal muscle cells. METABOLISM (CONT.) Intestinal sugar transport proteins  FRUCTOLYSIS The initial catabolism of fructose is referred to as fructolysis, in analogy with glycolysis, the catabolism of glucose. In fructolysis, the enzyme fructokinase initially produces fructose 1-phosphate, which is split by aldolase B to produce the trioses dihydroxyacetone phosphate (DHAP) and glyceraldehyde. Unlike glycolysis, in fructolysis the triose glyceraldehyde lacks a phosphate group. A third enzyme, triokinase, is therefore required to phosphorylate glyceraldehyde, producing glyceraldehyde 3-phosphate. The resulting trioses are identical to those obtained in glycolysis and can enter the gluconeogenic pathway for glucose or glycogen synthesis or be further catabolized through the lower glycolytic pathway to pyruvate.  METABOLISM OF FRUCTOSE TO DHAP AND GLYCERALDEHYDE The first step in the metabolism of fructose is the phosphorylation of fructose to fructose 1-phosphate by fructokinase, thus trapping fructose for metabolism in the liver. Fructose 1-phosphate then undergoes hydrolysis by aldolase B to form DHAP and glyceraldehydes; DHAP can either be isomerized to glyceraldehyde 3-phosphate by triosephosphate isomerase or undergo reduction to glycerol 3-phosphate by glycerol 3-phosphate dehydrogenase. The glyceraldehyde produced may also be converted to glyceraldehyde 3- phosphate by glyceraldehyde kinase or further converted to glycerol 3-phosphate by glycerol 3-phosphate dehydrogenase. The metabolism of fructose at this point yields intermediates in the gluconeogenic pathway leading to glycogen synthesis as well as fatty acid and triglyceride synthesis.  SYNTHESIS OF GLYCOGEN FROM DHAP AND GLYCERALDEHYDE 3- PHOSPHATE The resultant glyceraldehyde formed by aldolase B then undergoes phosphorylation to glyceraldehyde 3-phosphate. Increased concentrations of DHAP and glyceraldehyde 3-phosphate in the liver drive the gluconeogenic pathway toward glucose and subsequent glycogen synthesis. It appears that fructose is a better substrate for glycogen synthesis than glucose and that glycogen replenishment takes precedence over triglyceride formation. Once liver glycogen is replenished, the intermediates of fructose metabolism are primarily directed toward triglyceride synthesis. Metabolic conversion of fructose to glycogen in the liver  SYNTHESIS OF TRIGLYCERIDE FROM DHAP AND GLYCERALDEHYDE 3- PHOSPHATE Carbons from dietary fructose are found in both the free fatty acid and glycerol moieties of plasma triglycerides. High fructose consumption can lead to excess pyruvate production, causing a buildup of Krebs cycle intermediates. Accumulated citrate can be transported from the mitochondria into the cytosol of hepatocytes, converted to acetyl CoA by citrate lyase and directed toward fatty acid synthesis. In addition, DHAP can be converted to glycerol 3-phosphate, providing the glycerol backbone for the triglyceride molecule. Triglycerides are incorporated into very-low-density lipoproteins (VLDL), which are released from the liver destined toward peripheral tissues for storage in both fat and muscle cells. Metabolic conversion of fructose to triglyceride in the liver  SUMMARY Fructose is a monosaccharide, the simplest form of carbohydrate. As the name implies, mono (one) saccharides (sugar) contain only one sugar group; thus, they cannot be broken down any further. Unlike glucose, fructose does not stimulate a substantial insulin release. Fructose is transported into cells via a different transporter than glucose.  SUMMARY (CONT.) While glucose can be utilized (metabolized) by just about every cell in the human body, fructose cannot. Fructose needs to be processed and stored in the liver as a back-up energy source called glycogen. Once the liver's storage capacity is filled, then excess fructose is converted by the liver into various products; one main product is triglycerides. Triglycerides are further converted by the liver into very low-density lipoproteins (VLDL), which are released for storage in fat cells and muscle.  INTRODUCTION In biochemistry, a fatty acid is a carboxylic acid with a long aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually not found in organisms, but instead as three main classes of esters: triglycerides, phospholipids and cholesteryl esters. In any of these forms, fatty acids are both important dietary sources of fuel and they are important structural components for cells.  LEARNING OUTCOMES On successful completion of the lesson, the student will be able to: explain the types of fatty acids; describe the metabolism of fatty acids as a fuel source; identify the functions of fatty acids.  TYPES Length of fatty acids Fatty acids differ by length, often categorized as short to very long. Short-chain fatty acids (SCFA) are fatty acids with aliphatic tails of five or fewer carbons (e.g. butyric acid). Medium-chain fatty acids (MCFA) are fatty acids with aliphatic tails of 6 to 12 carbons, which can form medium-chain triglycerides. Long-chain fatty acids (LCFA) are fatty acids with aliphatic tails of 13 to 21 carbons. Very long chain fatty acids (VLCFA) are fatty acids with aliphatic tails of 22 or more carbons.  TYPES (CONT.) Saturated fatty acids Saturated fatty acids have no C=C double bonds. They have the same formula CH3(CH2)nCOOH, with variations in "n". An important saturated fatty acid is stearic acid (n = 16), which when neutralized with lye is the most common form of soap.  TYPES (CONT.) Unsaturated fatty acids Unsaturated fatty acids have one or more C=C double bonds. The C=C double bonds can give either cis or trans isomers. cis A cis configuration means that the two hydrogen atoms adjacent to the double bond stick out on the same side of the chain. The rigidity of the double bond freezes its conformation and in the case of the cis isomer, causes the chain to bend and restricts the conformational freedom of the fatty acid. The more double bonds the chain has in the cis configuration, the less flexibility it has.  TYPES (CONT.) Unsaturated fatty acids (cont.) cis (cont.) When a chain has many cis bonds, it becomes quite curved in its most accessible conformations. For example, oleic acid, with one double bond, has a "kink" in it, whereas linoleic acid, with two double bonds, has a more pronounced bend. α-Linolenic acid, with three double bonds, favors a hooked shape. The effect of this is that, in restricted environments, such as when fatty acids are part of a phospholipid in a lipid bilayer or triglycerides in lipid droplets, cis bonds limit the ability of fatty acids to be closely packed and therefore can affect the melting temperature of the membrane or of the fat.  TYPES (CONT.) Unsaturated fatty acids (cont.) trans A trans configuration, by contrast, means that the adjacent two hydrogen atoms lie on opposite sides of the chain. As a result, they do not cause the chain to bend much and their shape is similar to straight saturated fatty acids.  TYPES (CONT.) Unsaturated fatty acids (cont.) In most naturally occurring unsaturated fatty acids, each double bond has three n carbon atoms after it, for some n and all are cis bonds. Most fatty acids in the trans configuration (trans fats) are not found in nature and are the result of human processing (e.g., hydrogenation). The differences in geometry between the various types of unsaturated fatty acids, as well as between saturated and unsaturated fatty acids, play an important role in biological processes and in the construction of biological structures (such as cell membranes).  TYPES (CONT.) Unsaturated fatty acids (cont.)  TYPES (CONT.) Saturated & Unsaturated Fatty acids  TYPES (CONT.) Nonessential and Essential Fatty Acids The body is capable of synthesizing most of the fatty acids it needs from food. These fatty acids are known as nonessential fatty acids. However, there are some fatty acids that the body cannot synthesize and these are called essential fatty acids. It is important to note that nonessential fatty acids does not mean unimportant; the classification is based solely on the ability of the body to synthesize the fatty acid.  TYPES (CONT.) Nonessential and Essential Fatty Acids (cont.) Essential fatty acids must be obtained from food. They fall into two categories - omega-3 and omega-6. The 3 and 6 refer to the position of the first carbon double bond and the omega refers to the methyl end of the chain. Omega-3 and omega-6 fatty acids are precursors to important compounds called eicosanoids.  TYPES (CONT.) Nonessential and Essential Fatty Acids (cont.) Eicosanoids are powerful hormones that control many other hormones and important body functions, such as the central nervous system and the immune system. Eicosanoids derived from omega-6 fatty acids are known to increase blood pressure, immune response and inflammation. In contrast, eicosanoids derived from omega-3 fatty acids are known to have heart-healthy effects. Given the contrasting effects of the omega-3 and omega-6 fatty acids, a proper dietary balance between the two must be achieved to ensure optimal health benefits.  TYPES (CONT.) Nonessential and Essential Fatty Acids (cont.) Image by Allison Calabrese / CC BY 4.0  THE METABOLISM OF FATTY ACIDS AS A FUEL SOURCE The metabolism of fatty acids involves the uptake of free fatty acids by cells via fatty acid-binding proteins which transport the fatty acids intracellularly from the plasma membrane. The free fatty acids are then activated via acyl-CoA and transported to: 1) the mitochondria or peroxisomes to be converted into ATP and heat as a form of energy; 2) facilitate gene expression via binding to transcription factors; or 3) the endoplasmic reticulum for esterification into various classes of lipids that can be used as energy storage.  THE METABOLISM OF FATTY ACIDS AS A FUEL SOURCE (CONT.) When used as an energy source, fatty acids are released from triacylglycerol and processed into two-carbon molecules identical to those formed during the breakdown of glucose. Moreover, the two-carbon molecules generated from the breakdown of both fatty acids and glucose are used to generate energy via the same pathways. Glucose can also be converted into fatty acids under conditions of excess glucose or energy within a cell. THE METABOLISM OF FATTY ACIDS AS A FUEL SOURCE (CONT.)  FUNCTIONS Fatty acids have important roles in: 1) signal-transduction pathways; 2) cellular fuel sources; 3) the composition of hormones and lipids; 4) the modification of proteins; and 5) energy storage within adipose tissue (specialized fat cells) in the form of triacylglycerols.  SUMMARY Fatty acids, both free and as part of complex lipids, play a number of key roles in metabolism – major metabolic fuel (storage and transport of energy), as essential components of all membranes and as gene regulators. If the carbon-to-carbon bonds are all single, the acid is saturated; if any of the bonds is double or triple, the acid is unsaturated and is more reactive. Fatty acids have a wide range of commercial applications. For example, they are used not only in the production of numerous food products but also in soaps, detergents and cosmetics.  SUB-TOPICS The brain and energy metabolism* Glucagon and insulin Creatine phosphate Creatinine Glycogen Gluconeogenesis Fructose Fatty acids The Krebs cycles* Fermentative and aerobic metabolism*