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- 2. CARBOHYDRATE METABOLISM DR JAYESH POST GRADUATE STUDENT DEPARTMENT OF ORAL AND MAXILLOFACIAL SURGERY
- 3. INTRODUCTION TO CARBOHYDRATES CARBOHYDRATES AT A GLANCE CLASSIFICATION OF CARBOHYDRATES METABOLISM CATABOLISM DIGESTION AT A GLANCE ABSORPTION OF GLUCOSE GLUCOSE METABOLISM GLYCOLYSIS AND STEPS IN GLYCOLYSIS IMPORTANCE OF LACTATE ENERGETICS OF GLYCOLYSIS FATE OF LACTATE BPG PATHWAY PYRUVATE AND ITS FATE ACETYL CoA AND ITS IMPORTANCE CITRIC ACID CYCLE AND ITS IMPORTANCE AND DEFECTS OF THE CYCLE ELECTRON TRANSPORT CHAIN HEXOSE MONOPHOSPHATE SHUNT PATHWAY GLYCOGEN METABOLISM ERRORS ASSOCIATED WITH CARBOHYDRATE METABOLISM CONCLUSION BIBLIOGRAPHY CONTENTS
- 4. 1. Carbohydrates are the main sources of energy in the body. Brain cells and RBCs are almost wholly dependent on carbohydrates as the energy source. Energy production from carbohydrates will be 4 k calories/g (16 k Joules/g). 2. Storage form of energy (starch and glycogen). 3. Excess carbohydrate is converted to fat. 4. Glycoproteins and glycolipids are components of cell membranes and receptors. 5. Structural basis of many organisms: Cellulose of plants; exoskeleton of insects, cell wall of microorganisms, mucopolysaccharides as ground substance in higher organisms. CARBOHYDRATES AT A GLANCE
- 5. -The general molecular formula of carbohydrate is Cn(H2O)n -Carbohydrates are polyhydroxy aldehydes or ketones or compounds which yield these on hydrolysis
- 8. Thousands of chemical reactions are taking place insdie a cell in a organised , well coordinated manner, all these reactions are collectively called as METABOLISM Its purpose is to 1. Obtain energy 2. Synthesis of various bio molecules 3. Various metabolic pathways are taking place which are regulate by a. Thru allosteric enzymes. Affected by effector molecule b. Hormones c. DNA 1. Metabolism is of 2 types A. Catabolism- energy rich molecules aredegraded to simpler molecules B. Anabolism – synthesis of complex molecules from precursor molecules METABOLISM
- 9. Has 3 stages 1. Primary metabolism – occurs in GI tract. Converts macromolecules to smaller molecuels 2. Secondary/intermediatory – the products are absorbed and then catabolised to smaller components which in mitochondria form NADH of FADH which takes part in electron transport chain 3. Tertiary/ internal/cellular respiration – ETC where the energy is released CATABOLISM
- 10. -Carbohydrates in the food are complex molecules, -Cooking makes the molecules simpler . -The digestion starts in the oral cavity where saliva(salivary alpha amylase) acts on the complex molecules. It hydrolyses them to form monosaccharides -Gastric hydrochloric acid neutralizes the salivary amylase -pancreas alpha amylase cleaves random alpha 1-4 glycosidic links to form random subunits like maltose, isomaltose, etc - In Intestin there are enzymes like maltase, isomaltase etc which then break these molcules to monosaccharides BEGINING OF DIGESTION
- 13. Monosaccharides are only absorbed from the intestine. Galactose >glucose > fructose is the order of absorption ABSORPTION
- 14. From lumen to intestinal wall A. By sodium dependent Glucose Transporter 1 (SGluT-1) ABSORPTION OF GLUCOSE
- 15. B. Into the blood The intestinal cells have a different mechanism on membrane facing capillaries. By mechanism called glucose transporter type 2 (GLuT2) Sodium independent system. Also called as uniport system Ping pong mechanism
- 16. SUMMARY TILL NOW
- 17. GLUT4
- 19. Preferred source of energy with blood and brain exclusively depending on it Minimal glucose is always required for proper functioning of body Fasting glucose is 70 – 110 mg/dl IMPORTANCE OF GLUCOSE
- 20. Glycolysis= glyks+lysis Sweet splitting ( embden-meyerhof pathway ) Def- in the pathway glucose is converted to pyruvate (aerobic condition) or lactate(anaerobic condition), along with the production of energy . *It occurs in all the cells cytoplasm* METABOLISM OF GLUCOSE
- 21. • In all the cells • Only source of energy for erythrocytes • During strenous exercise glycolysis provides energy by anaerobic glycolysis • 1° step for complete oxidation • Gives the basic carbon skeleton for synthesis of amino acids and faty acids in body • Most reactions are reversible GLYCOLYSIS
- 23. Glucose phosphorylated to glucose 6 phosphate Enzyme hexokinase a key glycolytic enzyme Glucokinase is found in liver which is under influence of insulin Once phosphorylated the glucose 6 phosphate cant go out and its final fate is written . STEP 1
- 24. 1. Glycolysis 2. Glucose 3. Glycogen 4. Shunt pathway GLUCOSE 6 PHOSPHATE FATES
- 25. Glucose 6 phosphate is isomerised to fructose 6 phosphate Enzyme isomerase STEP 2
- 26. Fructose 6 phosphate -> fructose 1,6 bis phosphate Enzyme phosphofructokinase STEP 3
- 27. glyceraldehyde 3 phosphate aldolase triose phosphate isomerase Fructose 1,6 bisphosphate dihydroxyacetone phosphate Both the molecules are isomers Net result we have 2 molecules of Glyceraldehyde 3 phosphate STEP 4
- 28. Glyceraldehyde 3 phosphate is dehyrogenated and phosphorylated It forms 1,3 bis phosphoglycerate with the help of a NAD+ and iP Enzyme is glyceraldehyde 3 phosphate dehydrogenase Product has a high energy bond STEP 5
- 29. One ATP molecule is generated 1,3 bisphosphoglycerate forms an ATP Bisphophoglycerate is the enzyme here STEP 6
- 30. 3 phosphoglycerate is isomerised to 2 phosphoglycerate Enzyme is phosphoglucomutase STEP 7
- 31. 2 phosphoglycerate is converted to phosphoenol pyruvate Enzyme is enolase STEP 8
- 32. Phosphoenol pyruvate is dephosphorylated to pyruvate Enzyme is pyruvate kinase STEP 9
- 33. In anaerobic conditions Pyruvate converted to lactate Enzyme lactate dehyrpgenase STEP 10
- 34. REGULATION
- 35. In step 5 NAD is a limiting coenzyme as it forms NADH+ and gets reduced Reverse can be done by oxidative phosphorylation During anaerobic conditions when pyruvate is converted to lactate NAD is formed Thus regenerating it for the 5° step IMPORTANCE OF LACTATE
- 37. In aerobic condition ENERGY YIELDS
- 38. ENERGY YIELD IN ANAEROBIC CONDITION
- 39. Under anaerobic conditions lactate is produced The lactate is then again converted back to glucose by CORI’S cycle in the liver FATE OF LACTATE
- 40. Def :- It is the process by which glucose molecules are produced from non-carbohydrate precursors. These include lactate, glucogenic amino acids, glycerol part of fat and propionyl CoA derived from odd chain fatty acids GLUCONEOGENESIS
- 41. Irreversible steps in Corresponding key glycolysis gluconeogenic enzymes 1.Pyruvate kinase (Step 9) Pyruvate carboxylase; 2.Phosphoenol pyruvate carboxy kinase 3.Phosphofructokinase (Step 3) Fructose-1,6- bisphosphatase 4.Hexokinase (Step 1) Glucose-6- phosphatase
- 42. Pyruvate to Phosphoenol pyruvate is a irreversible reaction STEP 1
- 43. Malate-Aspartate Shuttle. MDH = malate dehydrogenase. AST = Aspartate amino transferase. Glu= Glutamic acid. AKG = alpha keto glutaric acid MALATE ASPARTATE SHUTTLE
- 44. In the cytoplasm, PEPCK enzyme then converts oxaloacetate to phosphoenol pyruvate by removing a molecule of CO2 PHOSPHOENOL PYRUVATE CARBOXY KINASE
- 45. The phosphoenol pyruvate undergoes further reactions catalyzed by the glycolytic enzymes to form fructose-1,6-bisphosphate PARTIAL REVERSAL OF GLYCOLYSIS
- 46. Fructose 1,6-bis-phosphate is then acted upon by fructose 1,6-bisphosphatase to form fructose -6-phosphate. This will bypass the step of PFK Reaction ie step 3 of the glycolysis Fructose-1,6-bisphosphatase Fructose-1,6- ––––––––––––––––→ Fructose-6- bisphosphate phosphate + Pi FRUCTOSE-1,6-BISPHOSPHATASE
- 47. The glucose 6-phosphate is hydrolysed to free glucose by glucose-6-phosphatase. Glucose-6-phosphate + H2O -----→ Glucose + Pi GLUCOSE-6-PHOSPHATASE REACTION
- 48. 1. Only liver can replenish blood glucose 2. During starvation gluconeogenesis maintains the blood glucose level. Energy requirement Lactate Glucogenic amino acids(Alanine, glutamic acid, aspartic acid, etc) Glycerol SIGNIFICANCE OF GLUCONEOGENESIS SUBSTRATES
- 49. RAPAPORT-LEUBRING CYCLE BPG PATHWAY In erythrocytes Enzyme is bisphosphoglycerate mutase
- 50. • Reduces affinity of the Hb to o2 so it helps unloading the oxygen • In hypoxic condition also it helps to unload the o2 SIGNIFICANCE
- 51. Pyruvate Carboxylase Fructose-1,6-bisphosphatase ATP Hormonal Regulation of Gluconeogenesis REGULATION
- 53. PYRUVATE
- 55. Pyruvate is formed in cytoplasm The acetyl coa is metabolised in the mitochondria The process of pyruvate entering the mitochondria and formation of acetyl coa is done by process oxidative decarobxylation It has 5 co enzyme and 3 apo enzyme PYRUVATE DEHYDROGENASE COMPLEX
- 57. MECHANISM
- 59. Only step which forms the acetyl coa Compeltely irreversible This step commits the molecule to the electron transport chain Acetyl CoA can be used to form fatty acids IMPORTANCE
- 60. DEFICIENCY
- 61. ACETYL COA
- 64. HISTORY
- 65. Final common pathway that oxidises acetyl CoA to CO2 Source or reduced coenzymesthat provide substrate for respiratory chain Acts as link between catabolic and anabolic pathways Precursor of amino acid synthesis FUNCTIONS
- 67. THE CYCLE
- 69. Formation of citric acid Enzyme is citrate synthatase Is irreversible STEP 1
- 70. Formation of isocitrate Enzyme is acotinase STEP 2
- 71. Formation of alpha keto glutarate Enzyme is isocitrate dehydrogenase STEP 3
- 72. Formation of succnyl coA Enzyme alpha ketoglutartedehydrogenase STEP 4
- 73. The next stage is a substrate level phosphorylation Enzyme here is succinate thiokinase STEP 5
- 74. Formation of fumarate Enzyme is a flavoprotein STEP 6
- 75. Addition of water to form malate from fumarate Enzyme is fumarase STEP 7
- 76. Regeneration of oxaloacetate Enzyme is malate dehydrogenase NADH is formed from NAD which is utilized in ETC STEP 8
- 77. IN SHORT
- 78. 1. generation of 2 molcules of CO2 2. Generation of 10/12 ATP molecules 3. Final pathway in oxidation of all major food SIGNIFICANCE OF TCA CYCLE
- 79. 4. Integration of all major metabolic pathways Carbohydrate- acetyl CoA enter the pathway Fats->fatthy acids-> beta oxidation->Acetyl CoA Ketogenic amino acids ->Acetyl CoA 5. Fats need oxaloacetate for breaking down to produce energy and oxaloacetate is produced via pyruvate 6. Excess glucose is stored as neutral fat but fat cant be changed to glucose Because pyruvate to acetyl CoA is absolutely irreversible
- 80. 7. No net synthesis of carbohydratez as the pyruvate cant be formed fromacetyl CoA 8. Amino acids can enter the cycle for energy production
- 81. DEFECTS
- 83. 1. Citrate and citrate synthatase- ATP acts as allosteric inhibitor . It stop the citrate synthatase. Citrate also allosteriaclly inhibits PPK to stop formation of acetyl CoA 2. ATP is inversely related to the speed of TCA cycle. More the ATP slower is the cycle and less the ATP faster is the TCA cycle 3. Hypoxia stops the ETC leading to accumulation of NADH and FADH leading to stopping of the TCA REGULATION OF THE TCA
- 84. METABOLIC DEFECTS ASSOCIATED WITH TCA CYCLE
- 87. ALSO CALLED AS RESPORATORY CHAIN Is the final stage where the production of energy takes place Also called as tertiary or internal metabolism total energy by one molecule glucose 2850KJ/mol ELECTRON TRANSPORT CHAIN
- 88. It occurs in the membrane of the mitochondria
- 90. TRANSPORT OF REDUCING EQUIVALENTS THRU RESPIRATORY CHAIN
- 92. ATP generation, old and new values ATP generation by Old value Presently NADH 3 2.5 FADH 2 1.5 Glucose 38 32 Acetyl CoA 12 10 Palmitate 129 106
- 94. The glucose molecule instead of going thru normal path is shunted to this pathway hence called Instead of bisphosphate intermediate there are monophosphate Also the reaction involves pentose phosphate intermediate Hence its called hexose monophosphate shunt pathway AN INTRODUCTION
- 95. The pathway has 2 phases a. Oxidative b. Non oxidative The pathway is used to metabolise upto 10% glucose daily and RBC and liver utilize it upto 30% to produce energy PATHWAY is a major source for 1. Production of NADH 2. Pentose sugars for production of nucleic acids
- 96. Glucose 6 phosphate is oxidized forming 2 NADPH 1 pentosephosphate 1 molecule of CO2 OXIDATIVE PATHWAY
- 97. Pentose phosphate is converted to inermediate in glycolysis NON OXIDATIVE PHASE
- 98. One molecule of NADPH is formed Emzyme is Glucose 6 phosphate dehydrogenase A. OXIDATIVE PHASE 1° STEP
- 99. Lactone is hydrolysed Enzyme is dehydrogenase STEP 2
- 100. Oxidative step couples with dehydrogenase 6 phospho glucanatedehyrdogenase 2° NADPH is formed STEP 3
- 101. Isomerization Ribulose 5 phosphate is isomerized to ribose 5 phosphate Or epimerised to xyluslose 5 phosphate B. NON OXIDATIVE PHASE STEP 4
- 103. Transaldolase reaction 3 C unit from sedoheptulose 7 phosphate to glyceraldehyde 3 phosphate It forms fructose 6 phosphate Donor is ketose and acceptor is aldehyde STEP 6
- 104. Second transketolase reaction Another reaction where xylulose 5 P and erythrose 4 p react 2 C are removed from Xylulose and added erythrose 4 Phosphate to form fructose 6 phosphate and a glyceraldehyde 3 p STEP 7
- 105. Finally 2 glyceraldehyde 3 phosphate combine and form afructose 6 phosphate STEP 8
- 106. HMP pathaway can be summarised as 6 glucose 6 phosphate+ 12 NADp+ +7 H2O-----> 5 G6P +12 NADPH + 12 H+ iP This pathway is not utilized for ATP production SUMMARY
- 107. IMPORTANCE OF THE PATHWAY
- 108. Glycogen synthesis and metabolism consists of 2 different pathways 1. Glycogenesis STEP 1 Activation of glucose GLYCOGEN METABOLISM
- 109. Glycogen synthesis Enzyme is glycogen sythatase STEP 2
- 111. GLYCOGEN DEGRADATION STEP 1. GLYCOGEN PHOSPHORYLASE
- 112. Step 2 debranching Step 3 phosphofructokinase Step 4 glucose 6 phosphatase in liver
- 113. i. In muscle, the energy yield from one glucose residue derived from glycogen is 3 ATP molecules, because no ATP is required for initial phosphorylation of glucose (step 1 of glycolysis). ii. If glycolysis starts from free glucose only 2 ATPs are produced. ENERGETICS
- 114. i. The synthetic and degradative pathways are reciprocally regulated to prevent futile cycles. ii. The phosphorylated form of glycogen phosphorylase is active; but glycogen synthase becomes inactive on phosphorylation. The covalently modified phosphorylase is active even without AMP. Active (dephosphorylated) glycogen synthase is responsive to the action of glucose-6- phosphate. Covalent modification modulates the effect of allosteric regulators. The hormonal control by covalent modification and allosteric regulation are interrelated. iii. These hormones act through a second messenger, cyclic AMP iv. The covalent modification of glycogen phosphorylase and synthase is by a cyclic AMP mediated cascade. Specific protein kinases bring about phosphorylation and protein phosphatases cause dephosphorylation REGULATION
- 115. It is a balance between synthesis and degradation of glcogen GLYCOGEN METABOLISM IN SUMMARY
- 116. ERRORS ASSOCIATED WITH CARBOHYDRATE METABOLISM
- 117. 1. PRINCIPLES OF BIOCHEMISTRY :- LEHNINGER 2. HARPER'S ILLUSTRATED BIOCHEMISTRY - ROBERT K. MURRAY, DARRYL K. GRANNER, PETER A. MAYES, VICTOR W. RODWELL 3. DM VASUDEVAN - TEXTBOOK OF BIOCHEMISTRY FOR MEDICAL STUDENTS, 6TH EDITION.PDF BIBLIOGRAPHY
Notas del editor
- Polysaccharides having only one type of monosaccharide units are called homopolysaccharides and those having different monosaccharide units are heteropolysaccharides
- A membrane bound carrier protein is involved which carries glucose with sodium. Sodium is then expelled by sodium pump with utilization of energy in diarrohoea the ORS solution has sodium and glucose. Presence of glucose allows the uptake of sodium to replinish body sodium
- Glut2 opens up first on one side. It absorved the glucose molecule . When fixed it open on the uinner side towards the capillaries.
- Glut2 is also involved in absorption of glucose from blood to cells. Example in liver, pancreas and kidney, it helps pancreas to monitor glucose level
- Is a major glucose transporter in adipose tissues and skeletal muscles. Is under control of insulin In Type 2 diabetes the Glut 2 is reduced . Leading to insulin resistance Insulin- lets glut 4 come out of vesicles to increase transport into adipose and muscle. This is done via insulin receptors- tyrosine kinase receptors- 1. receptor dimerizes, 2. tyrosine kinase activity- terminal phosphate of ATP, sticks the phosphate onto tyrosines. Autophosphorylates itself. Attracts IRS1, which attracts SH2 proteins- such as PI3 Kinase. PI3 kinase is activated in response to the insulin- this is the dominant protein that is responsible for opening the vesicle. Insulin effects brain and erythrocytes are insulin independent Insulin dependent tissues: Liver, muscles, adipocytes. Don't usually see pathology in insulin dependent tissues in diabetics. You see pathology in insulin independent tissues, for example, cataracts, renal problems. Extra glucose for an extended period of time starts to latch onto amino groups of proteins, such as hemoglobin, forming HbA1C
- Louis pasteur demostrated fermantation of glucose to alcohol Von euler chelpin demonstrated hexokinase enzyme in 1915 Other enzymes where identified rapidly also Otto warburg crystallized the enzymes of glycolytic pathway
- Step 1 3 and 9 are irreversible hence are the limiting steps While steps 5 6 9 produce the ATP Steps 5 and 10 produce the nad
- A ATP is used here to add a iP to the glucose molecule. This is a irreversible step
- PFK is a induciable regulatory enzyme. Its activated by ATP. Its irreversible but can be circuvented by fructose 1,6 bisphosphate in gluconeogenesis
- Since the backward reaction is a aldol condesation the enzyme is called aldolase This stage is called as splitting phase
- Di phosphate- when 2 phosphate groups are linked together and then attached to parent cpompuned Bisphosphate- when phosphoric acid group is present at 2 different sites of a compound
- Example of substrate level phosphorylation(ie energy is trapped directly without the ETC)
- One water molecule is removed. High energy phosphate bond is produced Mg++ is needed for the reaction . Fluoride removes the mg++ and can effectively block the glycolysis at this step. Hence when blood is taken for glucose estimation fluoride is added to prevent the utilization of glucose by rbc
- One atp is generated Example of substrate level phosphorylation The enzyme is a key enzyme
- In aerobic condition pyruvate enters citric acid cycle In anaerobic conditon it forms lactate which enters coris cycle
- Although most of the reactions of glycolysis are reversible, three are markedly exergonic and must therefore be considered physiologically irreversible. These reactions, catalyzed by hexokinase (and glucokinase), phosphofructokinase, and pyruvate kinase, are the major sites of regulation of glycolysis. Cells that are capable of reversing the glycolytic pathway (gluconeogenesis) have different enzymes that catalyze reactions which effectively reverse these irreversible reactions.
- Under new calculations the ATP yield is 32 instead of 38 2 NADH in step 5 can enter the ETC and compelte the oxidation providing 3 ATP each So when oxygen is plenty the net gain is 8
- When oxygen supply is insufficient, typically during intense muscular activity, energy must be released through anaerobic metabolism. Lactic acid fermentation converts pyruvate to lactate by lactate dehydrogenase. Most important, fermentation regenerates NAD+, maintaining the NAD+ concentration so that additional glycolysis reactions can occur. The fermentation step oxidizes the NADH produced by glycolysis back to NAD+, transferring two electrons from NADH to reduce pyruvate into lactate. Refer to the main articles on glycolysis and fermentation for the details. Instead of accumulating inside the muscle cells, lactate produced by anaerobic fermentation is taken up by the liver. This initiates the other half of the Cori cycle. In the liver, gluconeogenesis occurs. The cycle's importance is based on the prevention of lactic acidosis in the muscle under anaerobic conditions. However, normally before this happens the lactic acid is moved out of the muscles and into the liver.[3] The cycle is also important in producing ATP, an energy source, during muscle activity. The Cori cycle functions more efficiently when muscle activity has ceased. This allows the oxygen debt to be repaid such that the Krebs cycle and electron transport chain can produce energy at peak efficiency.[3] The drug metformin can precipitate lactic acidosis in patients with renal failure because metformin inhibits the cori cycle. Normally, the excess lactate would be cleared by the kidneys, but in patients with renal failure, the kidneys cannot handle the excess lactic acid.
- Gluconeogenesis occurs mainly in the liver, and to a lesser extent in the renal cortex. The pathway is partly mitochondrial and partly cytoplasmic. 3. Key Gluconeogenic Enzymes 1. Pyruvate carboxylase 2. Phosphoenol pyruvate carboxy kinase 3. Fructose-1-6-bisphosphatase 4. Glucose-6-phosphatase Gluconeogenesis involves several enzymes of glycolysis, but it is not a reversal of glycolysis. The irreversible steps in glycolysis are circumvented by four enzymes which are designated as the key enzymes of gluconeogenesis
- Pyruvate in the cytoplasm enters the mitochondria. Then, carboxylation of pyruvate to oxaloacetate is catalysed by a mitochondrial enzyme, pyruvate carboxylase (Fig. 9.24). It needs the co-enzymes biotin and Atp
- Malate Aspartate Shuttle The carboxylation of pyruvate (previous reaction) takes place in mitochondria. So, oxaloacetate is generated inside the mitochondria. This oxaloacetate has to be transported from mitochondria to cytosol, because further reactions of gluconeogenesis are taking place in cytosol. This is achieved by the malate aspartate shuttle. Oxaloacetate is first converted to malate, which traverses the membrane and reaches cytoplasm. Malate is then re-converted to oxaloacetate. Malate dehydrogenase is present in both mitochondria and cytoplasm. (Fig. 9.25). Oxaloacetate may also be transported as aspartate formed by transamination of oxaloacetate. When alanine is the substrate for gluconeogenesis, the malate shuttle predominantly operates, because NADH is also required in the cytoplasm for the gluconeogenesis to continue. When lactate is the substrate for gluconeogenesis, the aspartate shuttle operates, because sufficient NADH is available in the cytoplasm by the LDH reaction.
- present in kidney and intestinal mucosa to a lesser extent, but is absent in muscle.
- 1. Only liver can replenish blood glucose through gluconeogenesis, because glucose-6- phosphatase is present mainly in liver. So liver plays the major role in maintaining the blood glucose level. 2. During starvation gluconeogenesis maintains the blood glucose level. The stored glycogen is depleted within the first 12-18 hours of fasting. On prolonged starvation, the gluconeogenesis is speeded up and protein catabolism provides the substrates, namely glucogenic amino acids. 3. Energy Requirement: The reactions catalyzed by pyruvate carboxylase, phosphoenol pyruvate carboxy kinase and phospho glycerate kinase require one ATP each; so 3 ATPs are used by 1 pyruvate residue to produce one-half molecule of glucose; or 6 ATPs are required to generate one glucose molecule.
- is a metabolic pathway in mature erythrocytes involving the formation of 2,3-bisphosphoglycerate (2,3-BPG), which regulates oxygen release from hemoglobin and delivery to tissues. 2,3-BPG, the reaction product of the Luebering-Rapoport pathway was first described and isolated in 1925 by the Austrian biochemist Samuel Mitja Rapoport and his technical assistant Janet Luebering In the erythrocytes of many mammals, the reaction catalyzed by phosphoglycerate kinase may be bypassed by a process that effectively dissipates as heat the free energy associated with the high-energy phosphate of 1,3-bisphosphoglycerate (Figure 17–4). Bisphosphoglycerate mutase catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate, which is converted to 3-phosphoglycerate by 2,3-bisphosphoglycerate phosphatase (and possibly also phosphoglycerate mutase). This alternative pathway involves no net yield of ATP from glycolysis. However, it does serve to provide 2,3-bisphosphoglycerate, which binds to hemoglobin, decreasing its affinity for oxygen and so making oxygen more readily available to tissues (
- It is an allosteric enzyme. Acetyl CoA is an activator of pyruvate carboxylase so that generation of oxaloacetate is favored when acetyl CoA level is sufficiently high Fructose-1,6-bisphosphatase Citrate is an activator while fructose-2,6-bisphosphate and AMP are inhibitors. All these three effectors have an exactly opposite effect on the phospho fructo kinase (PFK 3. ATP Gluconeogenesis is enhanced by ATP. 4. Hormonal Regulation of Gluconeogenesis i. The hormones glucagon and gluco corticoids increase gluconeogenesis (Fig. 9.33). ii. Glucocorticoids induce the synthesis of hepatic amino transferases thereby providing substrate for gluconeogenesis. iii. The high glucagon-insulin ratio also favors induction of synthesis of gluconeogenicenzymes (PEPCK, Fructose-1,6-bisphosphatase and glucose-6-phosphatase). iv. At the same time, synthesis of glycolytic enzymes HK, PFK and PK are depressed. v. Insulin inhibits the process
- Clinical Significance of Pyruvate 1. Pyruvate carboxylase deficiency. It is seen as an inborn error of metabolism, where mental retardation is manifested. Its incidence is 1 in 25,000 births. Lactic acidosis is noticed. 2. Malignant hyperthermia. This may occur when halothane is given as an anesthetic to certain persons. The ryanodine receptor, a calcium-release channel is defective, leading to inappropriate release of calcium from sarcoplasmic reticulum. This results in uncontrolled heat generation, damage of muscle cells, ATP depletion, lactic acidosis and rhabdomyolysis. CPK is markedly elevated. This defect is seen in 1 per 50,000 population. 3. Ethanol (Ethyl alcohol). It inhibits gluconeogenesis. During the metabolism of ethanol the level of cytoplasmic NADH is raised. Thus, the Pyruvate → Malate → Oxaloacetate reactions are reversed. So, excessive ingestion of alcohol results in hypoglycemia. Lactate also accumulates as NADH level is high (Chapter 10).
- Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that convert pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle
- The citric acid cycle – also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle[1][2] – is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetyl-CoA derived fromcarbohydrates, fats and proteins into carbon dioxide and chemical energy in the form of guanosine triphosphate (GTP). In addition, the cycle provides precursors of certain amino acids as well as the reducing agent NADH that is used in numerous other biochemical reactions
- Several of the components and reactions of the citric acid cycle were established in the 1930s by the research of the Nobel laureate Albert Szent-Györgyi, for which he received the Nobel Prize in 1937 for his discoveries pertaining to fumaric acid, a key component of the cycle.[5] The citric acid cycle itself was finally identified in 1937 by Hans Adolf Krebs while at the University of Sheffield, for which he received the Nobel Prize for Physiology or Medicine in 1953.[6]
- The citric acid cycle begins with the transfer of a two-carbon acetyl group from acetyl-CoA to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).
- Is a 2 step process. 1° water molecule us removed to form a cis aconitate And the the water is again added to form isocitrate This process shifts the hydroxyl group
- Is also a 2 step process A nadh2 is formed here which is utilised in electron transport chain to produce atp Also a molecule of CO2 is formed here where the isocitrate undergoes oxidative decarboxylation to release a carbon dioxide
- This step a high energy molecule is created by thio ester bond of the acetyl CoA A gdp is utilized here to form a GTP which then transfer the high energy iP to the ATP
- Succinate is dehyrogenated releasing a H+ ion. This ion is accepted by FAD to form FADH2 FADH 2 is then utilized in the ETC to form ATPS Malonate stops the reaction at this stage
- Four of the B vitamins are essential in the citric acid cycle and therefore in energy-yielding metabolism: (1) riboflavin, in the form of flavin adenine dinucleotide (FAD), a cofactor in the α-ketoglutarate dehydrogenase complex and in succinate dehydrogenase; (2) niacin, in the form of nicotinamide adenine dinucleotide (NAD), the coenzyme for three dehydrogenases in the cycle— isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase; (3) thiamin (vitamin B1), as thiamin diphosphate, the coenzyme for decarboxylation in the α-ketoglutarate dehydrogenase reaction; and (4) pantothenic acid, as part of coenzyme A, the cofactor attached to “active” carboxylic acid residues such as acetyl-CoA and succinyl-CoA. THE CITRIC ACID CYCLE PLAYS A PIVOTAL ROLE IN METABOLISM The citric acid cycle is not only a pathway for oxidation of two-carbon units—it is also a major pathway for interconversion of metabolites arising from transamination and deamination of amino acids. It also provides the substrates for amino acid synthesis by transamination, as well as for gluconeogenesis and fatty acid synthesis. Because it functions in both oxidative and synthetic processes, it is amphibolic
- TWELVE ATP ARE FORMED PER TURN OF THE CITRIC ACID CYCLE As a result of oxidations catalyzed by the dehydrogenases of the citric acid cycle, three molecules of NADH and one of FADH2 are produced for each molecule of acetyl-CoA catabolized in one turn of the cycle. These reducing equivalents are transferred to the respiratory chain (Figure 16–2), where reoxidation of each NADH results in formation of 3 ATP and reoxidation of FADH2 in formation of 2 ATP. In addition, 1 ATP (or GTP) is formed by substrate-level phosphorylation catalyzed by succinate thiokinase.
- Allosteric inhibition is non competitive inhibition where the molecule is not structurly related to the enzyme and binds at some other site than the enzyme binding site and causing inhibition of reaction by changing the site
- This is a rate limiting step
- Oxidative step coupled with decarboxylation. 6 phosphogluconic acid is dehydrogenated to 3 keto 6 phospho glucobnate. This transient compund spontaneously decarboxylates to form ribose 5 phosphate Co2 is derieved from cooh
- In thiamine deficiency the stage is slowed to stopped
- This pathway is activated in liver, adipose tissue , adrenal cortex, testis and ovaries,RBC and lens of eys In these organs NADPH is needed for lipid or steroid synthesis Also the enzyme glutathione reductase is regenerated in with the help of NADPH produced here. Glutathione reductase is a key enzyme in free radical removal from body. So it protects the DNA RNA and cell membrane from activity of free radicals. By keeping the glutathione in a reduced state which helps it captuyre the free radicals Helps to detoxify toxins with help of cytochrome P450 in liver Helpos to mainatin transparecny of lens
- UDP glucose is formed from glucose-1-phosphate and UTP (uridine triphosphate) by the enzyme UDPglucose pyrophosphorylase.
- The glucose moiety from UDP-glucose is transferred to a glycogen primer (glycogenin) molecule. The primer is essential to accept the glycosyl unit. The primer is made up of a protein-carbohydrate complex. It is a dimeric protein, having two identical monomers. An oligosaccharide chain of 7 glucose units is added to each monomer. Glycogen synthase In the next step, activated glucose units are sequentially added by the enzyme glycogen synthase (Fig. 9.37). The glucose unit is added to the nonreducing (outer) end of the glycogen primer to form an alpha-1,4 glycosidic linkage and UDP is liberated.
- i. The glycogen synthase can add glucose units only in alpha-1,4 linkage. A branching enzyme is needed to create the alpha-1,6 linkages. ii. When the chain is lengthened to 11 - 12 glucose residues, the branching enzyme will transfer a block of 6 to 8 glucose residues from this chain to another site on the growing molecule. The enzyme amylo-[1,4]→[1,6]- transglucosidase (branching enzyme) forms this alpha-1,6 linkage (Fig. 9.37). iii. To this newly created branch, further glucose units can be added in alpha-1,4 linkage by glycogen synthase.
- glucose-1-phosphate from glycogen (phosphorolysis) (Fig. 9.34). It contains pyridoxal phosphate (PLP) as a prosthetic group. The alpha-1,4 linkages in the glycogen are cleaved. ii. It removes glucose units one at a time. Enzyme sequentially hydrolyses alpha-1,4 glycosidic linkages, till it reaches a glucose residue, 3-4 glucose units away from a branch point (Fig. 9.35). It cannot attack the 1,6 linkage at branch point. iii. If glycogen phosphorylase alone acts on a glycogen molecule, the final product is a highly branched molecule; it is called limit dextrin
- i. Then a block of 3 glucose residues (trisaccharide unit) are transferred from thebranching point to another branch. This enzyme is alpha-1,4 → alpha-1,4 glucan transferase. ii. Now the branch point is free. Then alpha- 1,6- glucosidase (debranching enzyme) can hydrolyse the remaining glucosyl unit held in alpha-1,6 linkage at the branch point (Fig. 9.35). iii. This glucose residue is released as free glucose. At this stage, the ratio of glucose-1- phosphate to free glucose is about 8:1. iv. The transferase and alpha-1,6-glucosidase will together convert the branch point to a linear one. With the removal of the branch point, phosphorylase enzyme can proceed with its action. branching point to another branch. This enzyme is alpha-1,4 → alpha-1,4 glucan transferase. ii. Now the branch point is free. Then alpha- 1,6- glucosidase (debranching enzyme) can hydrolyse the remaining glucosyl unit held in alpha-1,6 linkage at the branch point (Fig. 9.35). iii. This glucose residue is released as free glucose. At this stage, the ratio of glucose-1- phosphate to free glucose is about 8:1. iv. The transferase and alpha-1,6-glucosidase will together convert the branch point to a linear one. With the removal of the branch point, phosphorylase enzyme can proceed with its action. 3. Phosphogluco mutase Phosphorylase reaction produces glucose-1- phosphate while debranching enzyme releases glucose. The glucose-1-phosphate is converted to glucose-6-phosphate by phosphoglucomutase (Fig. 9.36). 4. Glucose-6-phosphatase in Liver Next, hepatic glucose-6-phosphatase hydrolyses glucose-6-phosphate to glucose. The free glucose is released to the blood stream.
- Type I GSD Dr. Edgar Von Gierke described this disease 1929 after autopsy of two children "Hepatonephromegaly glykogenica" High glycogen content in liver and kidney with normal structure Von Gierke disease is characterized by Hepatonephromegaly Severe fasting hypoglycemia Lactic acidemia Hyperuricemia Hyperlipidemia Progressive renal disease Treatment possible: regular administration of uncooked corn starch or nocturnal gastric glucose infusions Type 2 by dr Johanne pompe. Due to defective maltase enzyme Defective glycogen degradation by lysozymes leading toaccumulation in heart muscle and liver and can lead to rupture of lysozymes Type 3 has deficiency of debranching enzyme. Cori disease is clinically characterized by muscular weakness, hypotonia and cardiomyopathy Type 4 i charecterised by long chains with less branching The abnormal glycogen structure in Anderson disease leads to scarring by the attack of the body's immune system Infantile hypotonia Infantile liver cirrhosis Death by 5 years of age