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Metabolism of carbohydrates
- 1. Metabolism of Carbohydrates Medicalstudent: Phuoc Nguyen Trong YB – K113 - HMU
- 2. Origins of glucidein the body Exogenous • major and important • GI to circulation: Glucose, Fructose, Galactose. Endogenous • Gluconeogenis from a.a and glycerol: Liver • Cori cycle: From Lactat: Liver • Glycogenolysis
- 4. After absorption fromthe intestinal tract, much of the fructose and almost all the galactose are rapidly converted into glucose in the liver. Therefore, little fructose and galactose are present in the circulating blood. Glucose thus becomes the fnal common pathway for the transport of almost all carbohydrates to the tissue cells.
- 6. Transport of GlucoseThrough the Cell Membrane - The transport of glucose through the membranes of most tissue cells is quite different from that which occurs through the gastrointestinal membrane or through the epithelium of the renal tubules. In both cases, the glucose is transported by the mechanism of active sodium-glucose co- transport, in which active transport of sodium provides energy for absorbing glucose against a concentration difference. This sodium-glucose co- transport mechanism functions only in certain special epithelial cells that are specifcally adapted for active absorption of glucose. - At other cell membranes, glucose is transported only from higher concentration toward lower concentration by facilitated diffusion, made possible by the special binding properties of
- 8. Phosphorylation of Glucose -Immediately upon entry into the cells, glucose combines with a phosphate radical in accordance with the following reaction: Glucose → G6P - This phosphorylation is promoted mainly by the enzyme glucokinase in the liver and by hexokinase in most other cells. - The phosphorylation of glucose is almost completely irreversible except in liver cells, renal tubular epithelial cells, and intestinal epithelial cells; in these cells, another enzyme, glucose phosphatase, is also available, and when activated, it can reverse the reaction. - In most tissues of the body, phosphorylation serves to capture the glucose in the cell. That is, because of its almost instantaneous binding with phosphate, the glucose
- 9. Glycogen Is Storedin the Liver and Muscle - After absorption into a cell, glucose can be used immediately for release of energy to the cell, or it can be stored in the form of glycogen, which is a large polymer of glucose - All cells of the body are capable of storing at least some glycogen, but certain cells can store large amounts, especially liver cells, which can store up to 5 to 8 percent of their weight as glycogen, and muscle cells, which can store up to 1 to 3 percent glycogen. - This conversion of monosaccharides into a highmolecular-weight precipitated compound (glycogen) makes it possible to store large quantities of carbohydrates without signifcantly altering the osmotic pressure of the intracellular fluids. High concentrations of low-molecularweight soluble
- 10. After absorption intoa cell, glucose ( G6P) can: be used immediately for release of energy to the cell. ( Glycolysis) be stored in the form of glycogen, which is a large polymer of glucose ( Glycogenesis) Significant situation: Gluconogenesis: Glycogenolysis: AFTER ALL
- 12. Glycolysis The enzymesof this pathway are found in most living species and are located in the cytosol. The glycolytic pathway is active in all differentiated cell types in multicellular organisms. In some mammalian cells (such as those in the retina and some brain cells), it is the only ATP-producing pathway.
- 13. The tenreactions of glycolysis . They can be divided into two stages: the hexose stage and the triose stage . ATP is consumed in the hexose stage and generated in the triose stage. producing ATP (Steps 7 and 10). utilization of ATP (Steps 1 and 3) NADH (Step 6)
- 14. Step 1- Hexokinase the γ-phosphoryl group of ATP is transferred to the oxygen atom at C-6 of glucose producing glucose 6-phosphate and ADP irreversible reaction.
- 15. Step 1- Hexokinase Isozymes of hexokinase occur in many eukaryotic cells. Ex: 4 hexokinase isozymes have been isolated from mammalian liver. These isozymes catalyze the same reaction but have different Km values for glucose. In eukaryotes, glucose is taken up and secreted by passive transport using GLUT. The concentration of glucose in the blood and the cell cytoplasm is usually below the Km of glucokinase for glucose At these low concentrations the other hexokinase isozymes catalyze the phosphorylation of glucose. With high glucose levels, glucokinase is active. glucokinase is never saturated with glucose, the liver can respond to large increases in blood glucose by phosphorylating it for entry into glycolysis or the glycogen synthesis pathway.
- 17. Step 2 -phosphoglucose isomerase (PGI) catalyzes the conversion of G6-P (an aldose) to F6P (a ketose ) Glucose 6-phosphate isomerase is highly stereospecific Reverse reaction
- 18. Step 3 -Phosphofructokinase-1 ( PFK – 1) transfer of a phosphoryl group from ATP to the C1-hydroxyl group of F6P irreversible reaction. The PFK-1 catalyzed reaction is the first committed step of glycolysis PFK-1 is one of the classic allosteric enzymes The activity of the mammalian enzyme is regulated by AMP and citrate
- 19. Step 4 -Aldolase There are two distinct classes of aldolases: class I enzymes are found in plants and animals; class II enzymes are more common in bacteria, fungi, and protists. • Manyspecies have both types of enzyme. • Class I and class II aldolases are unrelated. The enzymes have very different structures and sequences in spite of the fact that they catalyze the same reaction. • The two classes of aldolase have slightly different mechanisms. Class I aldolases involve formation of a covalent Schiff base between lysine and pyruvate derivatives (Section 6.3) and class II aldolases use a metal ion cofactor.
- 20. Step 5 -Triose Phosphate Isomerase ( TPI) Of the two molecules produced by the splitting of fructose 1,6-bisphosphate, only glyceraldehyde 3-phosphate is a substrate for the next reaction in the glycolytic pathway The other product, dihydroxyacetone phosphate, is converted to glyceraldehyde 3-phosphate in a near-equilibrium reaction catalyzed by TPI.
- 21. Step 6 -Glyceraldehyde3-Phosphate Dehydrogenase The recovery of energy from triose phosphates begins with the reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase The NADH formed is reoxidized, either by the membrane-associated electron transport chain or in other reactions where NADH serves as a reducing agent, such as the
- 24. Step 7 -PhosphoglycerateKinase
- 25. Step 8 -PhosphoglycerateMutase catalyzes the near-equilibrium interconversion of 3-PG and 2-PG. Two different types of phosphoglycerate mutase enzymes: The first type of enzyme is called cofactor- independent PGM, or iPGM The second type of phosphoglycerate mutase is called cofactor-dependent
- 26. Step 9 -Enolase The systematic name of enolase is 2- phosphoglycerate dehydratase. Enolase requires Mg for activity. Two magnesium ions participate in this reaction.
- 27. Step 10 -Pyruvate Kinase irreversible reaction Pyruvate kinase is regulated both by allosteric modulators and by covalent modification. In addition, expression of the pyruvate kinase gene in mammals is regulated by various hormones and nutrients Because pyruvate kinase is regulated, the concentration of phosphoenolpyruvate is maintained at a high enough level to drive ATP
- 29. The Fate ofPyruvate
- 30. Metabolism of Pyruvateto Ethanol Many bacteria, and some eukaryotes, are capable of surviving in the absence of oxygen. They convert pyruvate to a variety of compounds that are secreted. Ethanol is one of these compounds convert pyruvate to ethanol and CO2 and oxidize NADH to NAD . Two reactions are required pyruvate decarboxylase & Alcohol dehydrogenase
- 31. Reduction of Pyruvateto Lactate This reaction is common in anaerobic bacteria and also in mammals. The net effect is to maintain flux in the glycolytic pathway and the production of ATP.
- 33. Regulation of Glycolysis The regulation of glycolysis has been examined more thoroughly than that of any other pathway
- 34. Other Sugars CanEnter Glycolysis
- 35. Gluconeogenesis Four key enzymesin the gluconeogenic pathway bypass irreversible steps in glycolysis
- 36. Pyruvate Carboxylase Thereaction is coupled to the hydrolysis of one molecule of ATP Pyruvate carboxylase is a large, complex, enzyme composed of four identical subunits a biotin-containing mitochondrial enzyme activated by acetyl CoA Oxaloacetate can enter the citric acid cycle or serve as a precursor for glucose biosynthesis much of the oxaloacetate that is made is not used for gluconeogenesis. it replenishes the pool of citric acid cycle intermediates that serve as precursors to the biosynthesis of amino acids and lipids
- 37. Phosphoenolpyruvate Carboxykinase twodifferent versions The enzyme found in bacteria, protists, fungi, and plants uses ATP as the phosphoryl group donor in the decarboxylation reaction. The animal version uses GTP is common in most eukaryotes, including humans
- 38. Fructose 1,6-bisphosphatase inhibitedby AMP and by the regulatory molecule fructose 2,6-bisphosphate Stimulated by Citrat
- 39. Glucose 6-phosphatase Althoughwe present glucose as the final product of gluconeogenesis, this is not true in all species. In most cases, the biosynthetic pathway ends with glucose 6-phosphate. In mammals, glucose is an important end product of gluconeogenesis since it serves as an energy source for glycolysis in many tissues. Glucose is made in the cells of the liver, kidneys, and small intestine and exported to the bloodstream
- 40. Precursors for Gluconeogenesis themajor gluconeogenic precursors in mammals: lactate most amino acids, especially alanine. Glycerol, which is produced from the hydrolysis of triacylglycerols. Glycerol enters the pathway after conversion to dihydroxyacetone phosphate. Precursors arising in nongluconeogenic tissues must first be transported to the liver to be substrates for gluconeogenesis.
- 41. Lactate - theCori cycle Glycolysis generates large amounts of lactate in active muscle and red blood cells => enters the bloodstream and travels to the liver where it is converted to pyruvate by the action of lactate dehydrogenase. Glucose produced by the liver enters the bloodstream for delivery to peripheral tissues, including muscle and red blood cells. The conversion of lactate to glucose requires energy, most of which is derived from the oxidation of fatty acids in the live.
- 42. Amino Acids –the Glucose – Alanin cycle The carbon skeletons of most amino acids are catabolized to pyruvate or intermediates of the citric acid cycle. Pyruvate can also accept an amino group from an a-amino acid, such as glutamate, forming alanine by the process of transamination. Alanine travels to the liver, where it undergoes transamination with a- ketoglutarate to re-form pyruvate for gluconeogenesis. => Amino acids become a major source of carbon for gluconeogenesis during fasting when
- 43. Glycerol The catabolismof triacylglycerols produces glycerol and acetyl CoA Glycerol -> glycerol 3-phosphate -> dihydroxyacetone phosphat -> gluconeogenesis
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- 48. Glycogenesis requires a preexistingfragment of glycogen or a primer glycoprotein (glycogenin) plus the activated glucose donor UDP-glucose
- 49. Glycogenesis Phosphoglucomutase UDP-glucose pyrophosphorylase Glycogen synthase
- 50. Glycogenesis There areusually two branches per chain and each chain is 8–14 residues in length. The molecule has about 12 layers of chains
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Editor's Notes
- #14 The main energy gain in glycolysis is due to production of NADH molecules.
- #15 Cells need to maintain a relatively high concentration of glucose 6-phosphate and a low internal concentration of glucose. the reverse reaction is inhibited by glucose 6-phosphate.
- #16 - Hexokinases I, II, and III have Km values of about 10-6 to 10-4 M - whereas hexokinase IV, also called glucokinase, has a much higher Km value for glucose (about 10-2 M) - Hexokinases and glucokinases can be found in bacteria but they play a minor role in glycolysis because, unlike the situation in eukaryotic cells, the bacterial enzymes rare
- #18 in the reverse reaction catalyzed by this enzyme fructose 6-phosphate (in which C-2 is not chiral) is converted almost exclusively to glucose 6-phosphate. Only traces of mannose 6-phosphate, the C-2 epimer of glucose 6-phosphate, are formed.
- #19 The PFK-1 catalyzed reaction is the first committed step of glycolysis because some substrates other than glucose can enter the glycolytic pathway by direct conversion to fructose 6-phosphate, thus bypassing the steps catalyzed by hexokinase and glucose 6-phosphate isomerase (Section 11.6C). (The metabolically irreversible reaction catalyzed by hexokinase is not the first committed step.) Another reason for regulating PFK-1 activity has to do with the competing glycolysis and gluconeogenesis pathways (Figure 11.1). PFK-1 activity must be inhibited when glucose is being synthesized. - PFK-1 has the suffix “1” because there is a second phosphofructokinase that catalyzes the synthesis of fructose 2,6-bisphosphate instead of fructose 1,6-bisphosphate. This second enzyme, which we will encounter later in this chapter, is known as PFK-2.
- #20 Aldolases evolved originally as enzymes that could catalyze the synthesis of fructose 1,6-bisphosphate. This reaction occurred at the end of a biosynthesis pathway leading from pyruvate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. - Keep in mind that the glucose biosynthesis pathway (gluconeogenesis) evolved first. It was only after glucose became readily available that pathways for its degradation evolved Triose phosphate isomerase, like glucose 6-phosphate isomerase, catalyzes an aldose-to-ketose conversion Dihydroxyacetone phosphate (DHAP) is derived from C-1 to C-3 of fructose 1,6-bisphosphate, and glyceraldehyde 3-phosphate (GAP) is derived from C-4 to C-6
- #21 As glyceraldehyde 3-phosphate is consumed in Step 6, its steady state concentration is maintained by flux from dihydroxyacetone phosphate. In this way, two molecules of glyceraldehyde 3-phosphate are supplied to glycolysis for each molecule of fructose 1,6-bisphosphate split Triose phosphate isomerase catalyzes a stereospecific reaction so that only the D isomer of glyceraldehyde 3-phosphate is formed. Note that carbons 1, 2, and 3 of one molecule of glyceraldehyde 3-phosphate are derived from carbons 4, 5, and 6 of glucose, whereas carbons 1, 2, and 3 of the second molecule of glyceraldehyde 3-phosphate (converted from dihydroxyacetone phosphate) originate as carbons 3, 2, and 1 of glucose
- #22 Thus, this step of glycolysis is the main energy-producing step in the entire pathway The concentration of NAD in most cells is low. Thus, it is essential to replenish it by reoxidizing NADH or glycolysis will stop at this step The methemoglobin reductase system and the pathway for synthesizing 2,3-bisphosphoglycerate (2,3-BPG) are ancillary pathways that emanate from this reaction An important function of glycolysis in red blood cells is the production of 2,3-bisphosphoglycerate, an allosteric inhibitor of the oxygenation of hemoglobin Erythrocytes contain bisphosphoglycerate mutase. This enzyme catalyzes the transfer of a phosphoryl group from C-1 to C-2 of 1,3-bisphosphoglycerate, to form 2,3-bisphosphoglycerate
- #23 Thus, this step of glycolysis is the main energy-producing step in the entire pathway The concentration of NAD in most cells is low. Thus, it is essential to replenish it by reoxidizing NADH or glycolysis will stop at this step
- #24 Arsenate competes with phosphate for its binding site in glyceraldehyde 3-phosphate dehydrogenase. s the energy-rich thioacyl–enzyme intermediate. However, arsenate produces an unstable analog of 1,3-bisphosphoglycerate, called 1-arseno-3-phosphoglycerate, which is rapidly hydrolyzed on contact with water. This nonenzymatic hydrolysis produces 3-phosphoglycerate In the presence of arsenate, glycolysis can proceed from 3-phosphoglycerate, but the ATP-producing reaction involving 1,3-bisphosphoglycerate is bypassed. As a result, there is no net formation of ATP from glycolysis.
- #25 This reaction is the first ATP-generating step of glycolysis. It operates at substrate and product concentrations that are close to the equilibrium concentrations. This is not surprising since the reverse reaction is important in gluconeogenesis, where ATP is utilized. Flux can proceed easily in either direction
- #26 (dPGM) belongs to a family of enzymes that include acid phosphatases and fructose 2,6-bisphosphatase. It is the major form of phosphoglycerate mutase in fungi, some bacteria, and most animals. (iPGM) belongs to the alkaline phosphatase family of enzymes. This version of phosphoglycerate mutase is found in plants and some bacteria
- #29 During glycolysis, NAD is reduced to NADH at the glyceraldehyde 3-phosphate dehydrogenase reaction (Step 6). In order for glycolysis to operate continuously, the cell must be able to regenerate NAD => Under aerobic conditions, NADH can be oxidized by the membrane-associated electron transport system (Chapter 14), which requires molecular oxygen. Under anaerobic conditions, the synthesis of ethanol or lactate consumes NADH and regenerates the NAD essential for continued glycolysis
- #30 Pyruvate can be converted to acetyl CoA and acetyl CoA can be used in a number of metabolic pathways. In one important pathway it is completely oxidized to CO2 in the citric acid cycle - Pyruvate can be carboxylated to produce oxaloacetate. Oxaloacetate is one of the citric acid cycle intermediates but it is also an intermediate in the synthesis of glucose. The fate of pyruvate as a precursor in gluconeogenesis In some species, pyruvate can be reduced to ethanol, which is then excreted from cells. This reaction normally takes place under anaerobic conditions where entry of acetyl CoA into the citric acid cycle is unfavorable In some species, pyruvate can be reduced to lactate. Lactate can be transported to cells that convert it back to pyruvate for entry into one of the other pathways. This is also an anaerobic pathway. In all species, pyruvate can be converted to alanine
- #37 - The pyruvate carboxylase reaction plays an important role in fixing carbon dioxide in bacteria and some eukaryotes. -
- #38 However, many species of bacteria can convert pyruvate directly to phosphoenolpyruvate in an ATP-dependent reaction catalyzed by phosphoenolpyruvate synthetase
- #39 The two enzymes that catalyze the interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate are reciprocally controlled by the concentration of fructose 2,6-bisphosphate
- #40 Although we present glucose as the final product of gluconeogenesis, this is not true in all species. In most cases, the biosynthetic pathway ends with glucose 6-phosphate. This product is an activated form of glucose. In these cells, glucose 6-phosphatase is bound to the endoplasmic reticulum with its active site in the lumen. The enzyme is part of a complex that includes a glucose 6-phosphate transporter (G6PT) and a phosphate transporter. G6PT moves glucose 6-phosphate from the cytosol to the interior of the ER where it is hydrolyzed to glucose and inorganic phosphate. Phosphate is returned to the cytosol and glucose is transported to the cell surface (and the bloodstream) via the secretory pathway. Glucose 6-phosphatase is found only in cells from the liver, kidneys, and small intestine, so only these tissues can synthesize free glucose. Cells of tissues that lack glucose 6-phosphatase retain glucose 6-phosphate for internal carbohydrate metabolism. Defects in the activities of glucose 6-phosphatase or glucose 6-phosphate transporter cause von Gierke disease
- #43 Lactate provides approximately one third of the carbon skeletons used in gluconeogenesis
- #48 -Glycogen is an important storage polysaccharide in bacteria, protists, fungi and animals. Large glycogen particles can be easily seen in the cytoplasm of these organisms. Most of the glycogen in vertebrates is found in muscle and liver cells. - Muscle glycogen appears in electron micrographs as cytosolic granules with a diameter of 10 to 40 nm, about the size of ribosomes. Glycogen particles in liver cells are about three times larger. The glycogen particles in bacteria are smaller. -
- #49 - (UDP-glucose), which is the activated form of glucose
- #50 (UDP-glucose), which is the activated form of glucose The glycogen synthase reaction is the major regulatory step of glycogen synthesi
- #51 There are usually two branches per chain and each chain is 8–14 residues in length. The molecule has about 12 layers of chains
- #52 entails the initial breakdown of glycogen to glucose 1-phosphate and free glucose in a ratio of about 10:1 Glycogen phosphorylase sequentially removes glucose units from the ends of all chains but stops four glucose units from each branch point - he fate of glucose 6-phosphate derived from glycogenolysis differs in muscle and liver. +
- #53 High insulin (low glucagon), typical of the fed state, promotes glycogen synthase activity leading to glycogen synthesis. High glucagon (low insulin), typical of the fasting state, activates adenylate cyclase, leading to sequential activation of protein kinase A, phosphorylase kinase, and phosphorylase in the liver, and inactivates glycogen synthase (phosphorylation inhibits the enzyme), leading to glycogen degradation in the liver Epinephrine, unlike glucagon, enhances glycogenolysis in muscle (b-adrenergic) and liver (a1-adrenergic).