Carbohydrate Metabolism Part 1 PDF

Carbohydrate Metabolism Part1 Carbohydrate CARBOHYDRATES ARE THE MOST ABUNDANT ORGANIC MOLECULES ON EARTH. They are the main structural component of plants and they provide food energy in the form of starch and sugars. In fact, carbohydrates provide half or more of the food energ...

Carbohydrate Metabolism Part1 Carbohydrate CARBOHYDRATES ARE THE MOST ABUNDANT ORGANIC MOLECULES ON EARTH. They are the main structural component of plants and they provide food energy in the form of starch and sugars. In fact, carbohydrates provide half or more of the food energy consumed by humans worldwide. Carbohydrates also act as metabolic intermediates, as constituents of RNA and DNA, as structural elements of cells and tissues, and as energy storage molecules in the body. The functional diversity of carbohydrates is due to their structural diversity. Carbohydrate Carbohydrates are constructed from carbon, oxygen, and hydrogen atoms that occur in a proportion that approximates that of a “hydrate of carbon,” (C‒H2O)n, accounting for the term carbohydrate. Carbohydrates are usually categorized into simple carbohydrates and complex carbohydrates. Simple carbohydrates include monosaccharides and disaccharides. Complex carbohydrates include oligosaccharides containing 3–10 saccharide units and polysaccharides containing more than 10 units. Carbohydrate Complex Carbohydrate 3.2 COMPLEX CARBOHYDRATES Complex carbohydrates are polymers of saccharide units linked together by glycosidic bonds. By convention, oligosaccharides contain 3–10 saccharide units and polysaccharides contain more than 10 units, usually thousands of units. The type of saccharide present in complex carbohydrates can vary, although glucose is the most abundant. Complex carbohydrates are a major component of the human diet. In the body, oligosaccharides are usually conjugated to proteins and lipids associated with cell membranes. When present on the cell surface, the conjugated oligosaccharides act as important modulators of cell function. Complex Carbohydrate Small Intestine Several structures that contribute to the surface area include: Large circular folds of the mucosa, called the folds of Kerckring, that protrude into the lumen of the small intestine Finger-like projections, called villi, that project out into the lumen of the intestine and consist of hundreds of intestinal cells called enterocytes (these cells are also referred to as absorptive, epithelial, and/or mucosal cells) along with blood capillaries and a lacteal (lymphatic vessel) for transport of nutrients out of the enterocytes. Microvilli, hairlike extensions of the plasma membrane of the enterocytes that make up the villi. The enterocyte membrane bordering the lumen is referred to as the enterocyte’s brush border (also called apical) membrane. Complex Carbohydrate Complex Carbohydrate 3.4 ABSORPTION AND TRANSPORT For dietary monosaccharides to be absorbed into the bloodstream, they must twice cross the plasma membrane of enterocytes. The monosaccharides first enter the cell on the brush border (apical) side, then exit on the basolateral side that faces a network of capillaries connected to the hepatic portal vein. In this way, the newly absorbed sugars are delivered directly to the liver where they will be metabolized according to the body’s needs. The movement of molecules across cell membranes, including those of enterocytes, is a highly regulated process. 3.4 ABSORPTION AND TRANSPORT Membrane Transport Cellular membranes are basically impermeable to molecules, yet normal cell function depends on the ability of molecules to cross these membranes. Two major In the case of monosaccharides, crossing membranes is mediated by specialized transport proteins integrated in the cell membrane. families of monosaccharide transporters have been identified in humans: the energy-dependent sodium glucose cotransporters (SGLTs) and the facilitated diffusion glucose transporters (GLUTs). The distribution of SGLTs and GLUTs throughout the body is tissue-specific, each having different regulatory properties and substrate specificity. 3.4 ABSORPTION AND TRANSPORT SGLTs Of the seven isoforms identified so far, SGLT1 and SGLT2 are known to play prominent roles in monosaccharide transport. The function of SGLTs is coupled with sodium cotransport and ATP hydrolysis. Their activity is therefore dependent on cellular energy and exemplifies active transport. SGLT1 is expressed mainly in the brush border membrane of enterocytes where its primary role is the absorption of dietary glucose and galactose. GLUTs Fourteen members of the GLUT family have been identified in humans. GLUTs are distributed throughout the body and function to transport glucose and other molecules by facilitated diffusion. Each GLUT is an integral protein, penetrating and spanning the lipid bilayer of the plasma membrane. 3.4 ABSORPTION AND TRANSPORT GLUT1 was the first GLUT identified and is the most ubiquitously expressed glucose transporter. It allows glucose to cross the blood–brain barrier and supplies glucose to the developing central nervous system during embryogenesis. GLUT1 is responsible for the supply of glucose to erythrocytes, endothelial cells of the brain, and most fetal tissue. Its importance is evident in GLUT1 deficiency syndrome in which patients experience seizures beginning in early infancy due to insufficient glucose supply to the brain. Treatment includes strict adherence to a ketogenic diet that raises levels of ketone bodies in the blood to be used as fuel for the brain and other tissues. 3.4 ABSORPTION AND TRANSPORT GLUT2 is a low-affinity, high-capacity transporter with predominant expression in the β-cells of the pancreas, liver, small intestine, and kidney. GLUT2 is involved in the transport of most monosaccharides from enterocytes into the portal blood via the basolateral membrane. And when the concentration of glucose in the intestinal lumen is high, it can transport glucose and fructose into the enterocyte through the brush border. The rate of transport is highly dependent upon the blood glucose concentration. In the pancreas, GLUT2 appears to be the sensitive indicator of blood glucose levels and is involved in the release of insulin from the β-cells. GLUT3 is a high-affinity glucose transporter with predominant expression in tissues such as the brain and neurons that are highly dependent on glucose as a fuel. It is also expressed in cells and tissues that have a high requirement for glucose such as spermatozoa, the placenta, and preimplantation embryos. 3.4 ABSORPTION AND TRANSPORT GLUT4 is the primary means by which insulin regulates the cellular uptake of blood glucose in muscle and adipose tissue. Other cells and tissues such as the liver, kidneys, erythrocytes, and brain do not express GLUT4 and therefore are not dependent upon insulin for glucose uptake. One of the actions of insulin is to cause the translocation of GLUT4 from intracellular storage vesicles to the plasma membrane. GLUT5 is highly specific for fructose and does not recognize glucose. It is expressed primarily in the small intestine and to a lesser degree in the kidney, brain, skeletal muscle, and adipose tissue. Its main function is to transport dietary fructose across the brush border membrane of enterocytes 3.5 MAINTENANCE OF BLOOD GLUCOSE CONCENTRATION Maintaining normal blood glucose concentration is an important homeostatic function, requiring the coordinated effort of the small intestine, liver, kidneys, skeletal muscle, and adipose tissue. Regulation is the net effect of the organs’ metabolic processes that remove glucose from or return glucose to the blood. These pathways are hormonally influenced, primarily by the antagonistic pancreatic hormones insulin and glucagon and to a lesser extent by the glucocorticoid hormones of the adrenal cortex. 3.5 MAINTENANCE OF BLOOD GLUCOSE CONCENTRATION The rise in blood glucose following the ingestion of carbohydrate, for example, triggers the release of insulin while reducing the secretion of glucagon. Insulin is the main hormone that lowers blood glucose levels and is the primary anabolic hormone. Insulin stimulates the cellular uptake of glucose, amino acids, and lipid, leading to their conversion to storage forms in muscle and adipose tissue. The storage form of glucose, glycogen, is synthesized through the process called glycogenesis. Glucagon, the primary catabolic hormone having opposite effects on insulin, increases the breakdown of liver glycogen by a process called glycogenolysis. Additional mechanisms to increase blood glucose levels include an increase in the secretion of glucocorticoid hormones, primarily cortisol. Glucocorticoids cause increased activity of hepatic gluconeogenesis, a process of glucose synthesis. 3.5 MAINTENANCE OF BLOOD GLUCOSE CONCENTRATION Role of Insulin Insulin and GLUT4 play extremely important roles in the uptake of glucose in muscle and adipose tissue, especially following a carbohydrate-rich meal. The sequence of events involving insulin and GLUT4 are critical to normalizing blood glucose and thus preventing hyperglycemia. When blood glucose levels raise after eating, insulin is released by the β-cells of the pancreas into the bloodstream. The circulating insulin binds with specific insulin receptors on cell membranes of muscle and adipose tissue. Insulin binding causes GLUT4 to translocate to the cell surface, where it can remove glucose from the blood.  GLUT4 is an insulin-responsive transporter that is synthesized on the ribosomes of the rough endoplasmic reticulum and then transferred to the Golgi apparatus, where it is packaged into GLUT4 storage vesicles (GSVs). Binding of insulin to its receptor causes the GSV to translocate to the cell membrane. In insulin-resistant states or at low insulin levels, the GLUT4 stays in the GSVs and its presence in the cell membrane is reduced. Interestingly, exercise causes similar translocation of GLUT4 from the GSVs to the cell membrane, as well as increased GLUT4 expression. 3.6 INTEGRATED METABOLISM IN TISSUES The metabolic fate of the monosaccharides, especially glucose, depends to a great extent on the body’s energy needs. The metabolic pathways of carbohydrate metabolism are listed below. Glycogenesis: The synthesis of glycogen Glycogenolysis: The breakdown of glycogen Glycolysis: The oxidation of glucose to pyruvate Gluconeogenesis: The synthesis of glucose from noncarbohydrate sources Pentose phosphate pathway (hexose monophosphate shunt): The production of five-carbon monosaccharides (pentoses) and nicotinamide adenine dinucleotide phosphate (NADPH) Tricarboxylic acid (TCA) cycle: The oxidation of acetyl- CoA to yield CO2 and high-energy electrons.  Glycogenesis The term glycogenesis refers to the pathway by which glucose is converted into its storage form glycogen—a process vital to ensuring a reserve of quick energy. The major sites of glycogen synthesis and storage are the liver and skeletal muscle, while a small amount of glycogen is found in the kidneys and heart, among other tissues. Liver glycogen can be broken down to glucose and reenter the bloodstream. Therefore, it plays an important role in maintaining blood glucose homeostasis. The other major site of glycogen storage is skeletal muscle. Although the concentration of glycogen in the liver is greater, muscle stores account for most of the body’s glycogen because the muscle makes up a much greater portion of the body’s weight. The liver can store approximately 100 g of glycogen, whereas muscle can store about 500 g (Figure 3.15). The glycogen stores in muscle are an energy source within that muscle fiber and cannot directly contribute to blood glucose levels. Why?  Glycogenesis Glucose is first phosphorylated upon entering the cell, producing glucose-6-phosphate. In muscle and other non-hepatic cells, the enzyme catalyzing this phosphate transfer from ATP is hexokinase, a mixture of hexokinase isozymes type 1 and 2. Muscle hexokinase is an allosteric enzyme that is negatively modulated by the product of the reaction, glucose-6-phosphate. This means that when the muscle cell has adequate glucose- 6-phosphate, the entry of additional glucose into the cell is slowed. Muscle hexokinase has a low Km, which means it can function at maximum velocity when blood glucose levels are at normal (fasting) levels.  Glycogenesis Glucose phosphorylation in the liver is catalyzed primarily by a hexokinase isozyme called glucokinase (sometimes called hexokinase 4). Although the reaction product, glucose-6-phosphate, is the same as in other tissues, interesting differences distinguish glucokinase from hexokinase. For example, muscle hexokinase is allosterically inhibited by glucose-6-phosphate, whereas liver glucokinase is not. This characteristic allows excess glucose entering the liver cell to be phosphorylated quickly and encourages glucose entry when blood glucose levels are elevated. Also, glucokinase has a much higher Km than hexokinase, meaning that it can convert glucose to its phosphorylated form at a higher velocity should the blood concentration of glucose rise significantly, particularly after a carbohydrate-rich meal.  Glycogenesis Phosphorylation of glucose effectively decreases the free glucose concentration in the cell, which enhances more blood glucose into the liver cell due to the concentration gradient that is created. The main glucose transporter in the liver, GLUT2, has a high capacity and is not dependent on insulin. Therefore, the liver has the capacity to reduce blood glucose concentration as long as the cellular free glucose concentration remains lower than the blood.  Glycogenesis Unlike GLUT2, glucokinase is inducible by insulin. Glucokinase activity is below normal in people with type 1 diabetes mellitus because they have very low insulin levels, and glucokinase is therefore not induced. In type 2 diabetes, glucokinase becomes resistant to the effects of insulin. In either case, the low glucokinase activity contributes to the liver cell’s inability to rapidly take up and metabolize glucose. After glucose-6-phosphate is produced, the next step in glycogenesis is to move the phosphate group from C-6 of the glucose molecule to C-1 in a reaction catalyzed by the enzyme phosphoglucomutase. Nucleoside triphosphates other than ATP sometimes function as activating substances in intermediary metabolism.  Glycogenesis In the next reaction of glycogenesis, energy derived from the hydrolysis of the a-b-phosphate anhydride bond of uridine triphosphate (UTP to UMP) allows the resulting uridine monophosphate to be coupled to the glucose-1-phosphate to form uridine diphosphate-glucose (UDP-glucose). The reaction is catalyzed by UDP-glucose pyrophosphorylase. Attachment of glucose, as UDP-glucose, to the growing glycogen molecule is catalyzed by glycogen synthase.  Glycogenesis Glycogen synthase can add UDP-glucose only to polysaccharide chains containing at least four glucose units. This requires some short glycogen “primer” molecules of only a few glucose units. The initial glycogen primer is formed by a protein called glycogenin. Glycogen synthase takes over once the glucose chain reaches a sufficient length  Glycogenesis Glycogen synthase exists in an active (dephosphorylated) form and a less active (phosphorylated) form. Insulin facilitates glycogen synthesis by stimulating the dephosphorylation of glycogen synthase. The glycogen synthase reaction is the primary target of insulin’s stimulatory effect on glycogenesis. When six or seven glucose molecules are added to the glycogen chain, the branching enzyme transfers them to a hydroxyl group at C-6. Glycogen synthase cannot form the a(1-6) bonds of the branch points. This action is left to the branching enzyme, also called amylo(1-4→1-6)-transglycosylase, which transfers a seven-residue oligosaccharide segment from the end of the main glycogen chain to a C-6 hydroxyl group.  Glycogenesis Branching within the glycogen molecule is important because it increases the molecule’s solubility and compactness. Branching also makes available many nonreducing ends of chains from which glucose residues can be cleaved rapidly and used for energy, in the process known as glycogenolysis. The overall pathway of glycogenesis, like most synthetic pathways, consumes energy because an ATP and a UTP are consumed for each molecule of glucose introduced.  Glycogenesis Dietary carbohydrate is not the only source of glucose used in glycogen synthesis. Newly synthesized glucose via gluconeogenesis provides another source of glucose-6-phosphate that can be used for glycogen synthesis in the liver, even when there is an abundance of glucose following a carbohydrate-rich meal. As discussed in detail later in this chapter, gluconeogenesis produces glucose-6-phosphate from noncarbohydrate sources including lactate, a by-product of glycolysis in red blood cells and muscle. While it may seem paradoxical for both gluconeogenesis and glycogenesis to function simultaneously, gluconeogenesis provides about one-third of the glucose-6-phosphate used for glycogen synthesis in the liver. Glycogenesis Glycogenesis Glycogenolysis The potential energy of glycogen is contained within the glucose residues that make up its structure. In accordance with the body’s energy demands, the residues can be systematically cleaved one at a time from the nonreducing ends of the glycogen branches and routed through energy-releasing pathways. The breakdown of glycogen into individual glucose units, in the form of glucose-1-phosphate, is called glycogenolysis and is catalyzed by the enzyme glycogen phosphorylase. Glycogenolysis Although glycogen phosphorylase cleaves a(1-4) glycosidic bonds, it cannot hydrolyze a(1-6) bonds. Phosphorylase acts repetitively along linear portions of the glycogen molecule until it reaches a point four glucose residues away from an a(1-6) branch point. Here the degradation process stops, resuming only after another enzyme, called the debranching enzyme, cleaves the a(1-6) bond at the branch point. Glycogenolysis At times of heightened glycogenolytic activity, the formation of increased amounts of glucose-1-phosphate shifts the phosphoglucomutase reaction toward the production of the 6-phosphate isomer. In the liver (and, to some extent, the kidneys), glucose-6-phosphate can become free glucose or enter into the oxidative pathway for glucose (glycolysis). The conversion of glucose-6-phosphate to free glucose requires the action of glucose-6-phosphatase. This enzyme is not expressed in muscle cells or adipocytes. Therefore, free glucose can be formed only from liver or kidney glycogen and transported through the bloodstream to other tissues for oxidation. Glycogenolysis Glycogenolysis Like its counterpart glycogenesis, glycogenolysis is highly regulated. Its catalyzing enzyme, glycogen phosphorylase, is regulated by both covalent and allosteric mechanisms. The regulation is different for the phosphorylation isozymes in muscle than in liver. The muscle and liver isozymes fulfill different physiological purposes: In muscle, the glucose is released from glycogen to provide glucose for energy within the cell, whereas in the liver the glucose is released to provide blood glucose. As phosphorylase is activated for glycogen phosphorylation, glycogen synthase is inhibited.