Metabolic pathways governing to catbohydrate.pptx

METABOLIC PATHWAYS OF CARBOHYDRATES

1. Lecture -2: METABOLIC PATHWAYS GOVERNING CARBOHYDRATE 1 By: Dr. Preeti Dixit, Prarambh Health & Academic Consultancy Course Title: Advanced Human Nutrition and Metabolism

2. CONTENTS - Classification of carbohydrates - Functions of carbohydrates - What is metabolism? Major metabolic pathways of carbohydrates - Introduction about each pathway - Step of reactions in every metabolic pathway - Clinical Aspects 2 Prarambh Health & Academic Consultancy

3. INTRODUCTION 3 Prarambh Health & Academic Consultancy

4. CARBOHYDRATE: Most abundant organic molecule on earth. Carbohydrates are defined as aldehyde or keto derivatives of polyhydric alcohols. For example: Glycerol on oxidation is converted to D- glyceraldehyde , which is a carbohydrate derived from the trihydric alcohol (glycerol). All carbohydrates have the general formula C n H 2 n O n [or it can be re-written as C n (H 2 O) n ] . 4 Prarambh Health & Academic Consultancy

5. CLASSIFICATION OF CARBOHYDRATE 5 Prarambh Health & Academic Consultancy

6. Biomedical Importance Of Glucose Glucose is a major carbohydrate It is a major fuel of tissues It is converted into other carbohydrates Glycogen for storage. Ribose in nucleic acids. Galactose in lactose of milk. They form glycoproteins & proteoglycans They are present in some lipoproteins (LDL) . Present in plasma membrane:glycocalyx . Glycophorin is a major intergral membrane glycoprotein of human erythrocytes. 6 Prarambh Health & Academic Consultancy

7. Metabolism 7 Thousands of chemical reactions are taking place inside a cell in an organized, well co- ordinated and purposeful manner; all these reactions are called as METABOLISM. TYPES OF METABOLIC PATHWAY: Catabolic Pathway Anabolic Pathway Amphibolic Pathway STAGES AND PHASES OF METABOLISM: Primary Secondary Tertiary Prarambh Health & Academic Consultancy

8. Major Pathways of Carbohydrate Metabolism 8 Prarambh Health & Academic Consultancy

9. 9 Prarambh Health & Academic Consultancy

10. Prarambh Health & Academic Consultancy 10

11. Prarambh Health & Academic Consultancy 11

12. Prarambh Health & Academic Consultancy 12

13. Glycolysis Prarambh Health & Academic Consultancy 13

14. Glycolysis Embden -Meyerhof pathway (or) E.M.Pathway 14 Definition: Glycolysis is defined as the sequence of reactions converting glucose (or glycogen) to pyruvate or lactate, with the production of ATP

15. Prarambh Health & Academic Consultancy 15

16. 16 Salient features: Takes place in all cells of the body. Enzymes present in “ cytosomal fraction” of the cell. Lactate – end product – anaerobic condition. Pyruvate (finally oxidized to CO2 & H2O) – end product of aerobic condition. Tissues lacking mitochondria – major pathway – ATP synthesis. Very essential for brain – dependent on glucose for energy. Central metabolic pathway Reversal of glycolysis – results in gluconeogenesis . Prarambh Health & Academic Consultancy

17. Reactions of Glycolysis Energy Investment phase (or) priming phase 2) Splitting phase 3) Energy generation phase 17 Prarambh Health & Academic Consultancy

18. 18

19. 19

20. 20 Prarambh Health & Academic Consultancy

21. Prarambh Health & Academic Consultancy 21

22. Prarambh Health & Academic Consultancy 22

23. Prarambh Health & Academic Consultancy 23

24. Prarambh Health & Academic Consultancy 24

25. Prarambh Health & Academic Consultancy 25

26. Prarambh Health & Academic Consultancy 26

27. 2. Breakdown of Pyruvate to Acetyl-Coenzyme A Prarambh Health & Academic Consultancy 27

28. Lecture -3: METABOLIC PATHWAYS GOVERNING CARBOHYDRATE: Krebs Cycle and ETC 28 By: Dr. Preeti Dixit, Prarambh Health & Academic Consultancy Course Title: Advanced Human Nutrition and Metabolism

29. Prarambh Health & Academic Consultancy 29

30. 30

31. Prarambh Health & Academic Consultancy 31

32. Prarambh Health & Academic Consultancy 32

33. Prarambh Health & Academic Consultancy 33

34. Prarambh Health & Academic Consultancy 34

35. 3. Citric Acid Cycle Prarambh Health & Academic Consultancy 35

36. CITRIC ACID CYCLE KREBS CYCLE / TRICARBOXYLIC ACID/ TCA CYCLE 36 Essentially, it involves the oxidation of acetyl-CoA to CO 2 and H 2 O. This Cycle utilizes about two-thirds of the total oxygen consumed by the body. Prarambh Health & Academic Consultancy

37. 37 Prarambh Health & Academic Consultancy

38. Reactions of citric acid cycle Formation of citrate : Condensation of acetyl CoA and oxaloacetate  catalysed by citrate synthase . 2) & 3) Citrate is isomerized to isocitrate  aconitase (two steps). 4) & 5) Formation of ᾀ - ketoglutarate : enzyme isocitrate dehydrogenase . 6) Conversion of ᾀ - ketoglutarate to succinyl CoA : through oxidative decarboxylation , catalysed by ᾀ - ketoglutarate dehydrogenase complex. 38

39. 7) Formation of succinate : enzyme succinate thiokinase GTP + ADP  ATP + GDP (nucleoside diphosphate kinase ) 8) Conversion of succinate to fumarase : enzyme succinate dehydrogenase 9) Formation of malate : enzyme fumarase 10) Conversion of malate to oxaloacetate : enzyme malate dehydrogenase. 39 Prarambh Health & Academic Consultancy

40. 40

41. 41 TCA cycle is strictly aerobic in contrast to glycolysis . Total of 12 ATP are produced from one acetyl CoA :- During the process of oxidation of acetyl CoA via citric acid cycle  3 NADH & 1 FADH2. Oxidation of 3 NADH by electron transport chain coupled with oxidative phosphorylation results in 9 ATP, FADH2  2 ATP. One substrate level phosphorylation . Prarambh Health & Academic Consultancy

42. 4. Electron Transport Chain Prarambh Health & Academic Consultancy 42

43. 43

44. Prarambh Health & Academic Consultancy 44

45. Prarambh Health & Academic Consultancy 45

46. 46

47. Prarambh Health & Academic Consultancy 47

48. Prarambh Health & Academic Consultancy 48

49. Prarambh Health & Academic Consultancy 49

50. Prarambh Health & Academic Consultancy 50

51. Prarambh Health & Academic Consultancy 51

52. Prarambh Health & Academic Consultancy 52

53. Prarambh Health & Academic Consultancy 53

54. Lecture -4: METABOLIC PATHWAYS GOVERNING CARBOHYDRATE: Gluconeogenesis, Glycogenesis, Glycogenolysis 54 By: Dr. Preeti Dixit, Prarambh Health & Academic Consultancy Course Title: Advanced Human Nutrition and Metabolism

55. Glycogenesis Prarambh Health & Academic Consultancy 55

56. GLYCOGEN METABOLISM 56 Glycogen is a storage form of glucose in animals. Stored mostly in liver (6-8%) and muscle (1-2%) Due to muscle mass the quantity of glycogen in muscle = 250g and liver =75g Stored as granules in the cytosol . Functions : Liver glycogen – maintain the blood glucose level Muscle glycogen – serves as fuel reserve Prarambh Health & Academic Consultancy

57. GLYCOGENESIS 57 Synthesis of glycogen from glucose. Takes place in cytosol . Requires UTP and ATP besides glucose. Steps in synthesis : Synthesis of UDP- glucose Requirement of primer to initiate glycogenesis Glycogen synthesis by glycogen synthase Formation of branches in glycogen Prarambh Health & Academic Consultancy

58. Prarambh Health & Academic Consultancy 58

59. 59 Glucose → Glucose-6-phosphate (G6P) Enzyme: Hexokinase (M) / Glucokinase (L) ATP - ADP Glucose-6-phosphate → Glucose-1-phosphate (G1P) Enzyme: Phosphoglucomutase Glucose-1-phosphate → UDP-glucose Enzyme: UDP-glucose pyrophosphorylase UTP - iPP UDP-glucose → Glycogen (elongation) Enzyme: Glycogen synthase (adds glucose units via α-1,4 linkages) Branch formation Enzyme: Branching enzyme (forms α-1,6 linkages) 🔑 Key Regulation: Activated by insulin Inhibited by glucagon and epinephrine 🧪 Steps of Glycogenesis:

60. Prarambh Health & Academic Consultancy 60

61. Prarambh Health & Academic Consultancy 61

62. Prarambh Health & Academic Consultancy 62

63. Prarambh Health & Academic Consultancy 63

64. Prarambh Health & Academic Consultancy 64

65. 65 Feature Glycolysis Glycogenesis Definition Breakdown of glucose to pyruvate for energy Formation of glycogen from glucose Purpose / Function To generate ATP (energy) from glucose To store excess glucose in the form of glycogen Site of Occurrence Cytoplasm of all cells (mainly liver, muscle) Cytoplasm of liver and muscles Starting Molecule Glucose Glucose-6-phosphate → Glucose-1-phosphate End Products 2 Pyruvate + 2 ATP + 2 NADH Glycogen (branched polymer) Key Steps / Reactions 10 enzyme-catalyzed reactions (energy investment & payoff phases) Glucose → G6P → G1P → UDP-glucose → Glycogen Main Enzymes Involved Hexokinase/Glucokinase, PFK-1, Pyruvate kinase Glycogen synthase, Branching enzyme Hormonal Regulation ⬆️ Insulin (stimulates) ⬇️ Glucagon, Epinephrine (inhibit) ⬆️ Insulin (stimulates) ⬇️ Glucagon, Epinephrine (inhibit) ATP / Energy Change Net Gain: +2 ATP per glucose (4 produced – 2 used) Energy Used: 1 ATP + 1 UTP per glucose added Anaerobic / Aerobic Conditions Occurs in both: • Aerobic → Pyruvate → Acetyl-CoA • Anaerobic → Lactate Occurs under fed state (aerobic) Physiological Role Provides immediate energy Stores energy for future Example Condition if Defective Pyruvate kinase deficiency → hemolytic anemia Glycogen synthase deficiency → low glycogen stores

66. Glycogenolysis Prarambh Health & Academic Consultancy 66

67. Prarambh Health & Academic Consultancy 67

68. Glycogen Glycogen is a polysaccharide of glucose that serves as a form of energy storage in fungi and animals. The polysaccharide structure of glucose shows the primary storage form of glucose in the body. Glycogen is made and stored in the cells of liver and muscles that are hydrated with the four parts of water. It acts as the secondary long-term energy storage. Muscle glycogen is quickly converted into glucose by muscle cells and liver glycogen that converts into glucose for use throughout the body which includes the central nervous system. Prarambh Health & Academic Consultancy 68

69. Prarambh Health & Academic Consultancy 69

70. Prarambh Health & Academic Consultancy 70

71. Prarambh Health & Academic Consultancy 71

72. GLUCONEOGENESIS Prarambh Health & Academic Consultancy 72

73. GLUCONEOGENESIS 73 Prarambh Health & Academic Consultancy

74. Importance of Gluconeogenesis 74 Prarambh Health & Academic Consultancy

75. Reaction of Gluconeogenesis 75 Glucose

76. Prarambh Health & Academic Consultancy 76

77. Lecture -5: METABOLIC PATHWAYS GOVERNING CARBOHYDRATE: Regulation of Glycolysis and Gluconeogenesis; Hexoamine Pathway 77 By: Dr. Preeti Dixit, Prarambh Health & Academic Consultancy Course Title: Advanced Human Nutrition and Metabolism

78. ROLE OF HORMONES IN CARBOHYDRATE METABOLISM 78 Prarambh Health & Academic Consultancy

79. Regulation of Blood glucose Postabsorptive state : Blood glucose is 4.5- 5.5mmol/L. After carbohydrate meal : 6.5-7.2mmol/L During fasting : 3.3-3.9mmol/L 79 Prarambh Health & Academic Consultancy

80. Metabolic & hormonal mechanisms regulate blood glucose level Maintenance of stable levels of glucose in blood is by Liver. Extrahepatic tissues. Hormones . 80 Prarambh Health & Academic Consultancy

81. Regulation of blood glucose levels Insulin 81 Prarambh Health & Academic Consultancy

82. Role of glucagon 82

83. Role of thyroid hormone 83 It stimulates glycogenolysis & gluconeogenesis . Hypothyroid Fasting blood glucose is lowered. Patients have decreased ability to utilise glucose. Patients are less sensitive to insulin than normal or hyperthyroid patients. Hyperthyroid Fasting blood glucose is elevated Patients utilise glucose at normal or increased rate Prarambh Health & Academic Consultancy

84. Glucocorticoids Glucocorticoids are antagonistic to insulin. Inhibit the utilisation of glucose in extrahepatic tissues. Increased gluconeogenesis . 84 Prarambh Health & Academic Consultancy

85. Epinephrine Secreted by adrenal medulla. It stimulates glycogenolysis in liver & muscle. It diminishes the release of insulin from pancreas. 85 Prarambh Health & Academic Consultancy

86. Other Hormones Anterior pituitary hormones Growth hormone : Elevates blood glucose level & antagonizes action of insulin. Growth hormone is stimulated by hypoglycemia (decreases glucose uptake in tissues) Chronic administration of growth hormone leads to diabetes due to B cell exhaustion. 86 Prarambh Health & Academic Consultancy

87. SEX HORMONES Estrogens cause increased liberation of insulin. Testosterone decrease blood sugar level. 87 Prarambh Health & Academic Consultancy

88. SUMMARY OF CARBOHYDRATE METABOLISM 88 Prarambh Health & Academic Consultancy

89. Role of the Hexosamine Biosynthetic Pathway (HBP) in Insulin Resistance Prarambh Health & Academic Consultancy 89

90. Overview of the Hexosamine Biosynthetic Pathway The HBP is a minor branch of glucose metabolism, using about 2–5% of glucose entering the cell. Its main role is nutrient sensing and protein modification (O-GlcNAcylation) — a process that influences gene expression and cell signaling. Prarambh Health & Academic Consultancy 90

91. Major Steps of the HBP: Glucose → Glucose-6-Phosphate (via Hexokinase) Glucose-6-Phosphate → Fructose-6-Phosphate (via Phosphoglucose isomerase) Fructose-6-Phosphate + Glutamine → Glucosamine-6-Phosphate (via Glutamine:Fructose-6-Phosphate Amidotransferase , or GFAT ) → This is the rate-limiting enzyme. Glucosamine-6-Phosphate → UDP-N-Acetylglucosamine (UDP- GlcNAc ) (final product of HBP) ➡️ UDP- GlcNAc is used for O-GlcNAcylation — the attachment of GlcNAc to proteins. Prarambh Health & Academic Consultancy 91

92. Prarambh Health & Academic Consultancy 92

93. Role of HBP in Cellular Function UDP- GlcNAc modifies proteins by O-linked N-acetylglucosamine (O- GlcNAc ) addition. This modification is reversible and similar to phosphorylation. It regulates many proteins involved in: Insulin signaling (especially insulin receptor substrate proteins) Glucose transporter (GLUT4) translocation Transcription factors and inflammatory responses Prarambh Health & Academic Consultancy 93

94. How Excess Nutrients Affect the HBP When there’s too much glucose, fatty acids, or nutrients , the HBP activity increases because more Fructose-6-phosphate and Glutamine are available to fuel the pathway. Consequences: Elevated levels of UDP- GlcNAc Increased O-GlcNAcylation of key proteins Changes in gene expression that mimic chronic nutrient excess Prarambh Health & Academic Consultancy 94

95. Prarambh Health & Academic Consultancy 95

96. Mechanism of Insulin Resistance Mechanistic Explanation: Increased UDP- GlcNAc → more O- GlcNAc on proteins Excess glucose = excess HBP activity. UDP- GlcNAc modifies insulin signaling proteins . O-GlcNAcylation of insulin signaling pathway: IRS-1 (Insulin Receptor Substrate 1) and Akt (Protein Kinase B) become excessively O- GlcNAcylated . This interferes with normal phosphorylation , which is needed for proper insulin signal transduction. Reduced GLUT4 Translocation: Less glucose uptake into muscle and fat cells → insulin resistance . Inflammation & ER stress: HBP also activates NF- κ B and other stress pathways, worsening insulin resistance. Prarambh Health & Academic Consultancy 96

97. Prarambh Health & Academic Consultancy 97 When HBP is Normal When HBP is Overactive Maintains balanced protein modification Excess UDP-GlcNAc accumulates Supports healthy insulin signaling Interferes with insulin receptor & IRS-1 Promotes proper glucose uptake Decreases GLUT4 movement → less glucose uptake Normal gene expression Activates stress and inflammation genes Simplified Summary

98. Clinical and Research Insights In Diabetes and Obesity: Chronic high glucose → sustained HBP activation → persistent insulin resistance . Animal models show that inhibiting GFAT or O- GlcNAc transferase (OGT) can improve insulin sensitivity . In Therapeutics: Nutrient sensing via HBP could be a target for diabetes treatment . Drugs modulating GFAT or O- GlcNAc enzymes are being studied. Prarambh Health & Academic Consultancy 98

99. Key Takeaways: The HBP acts as a nutrient sensor . Excessive nutrient flow → excessive protein O-GlcNAcylation → disrupted insulin signaling . HBP overactivity is a major molecular link between overnutrition and insulin resistance . Prarambh Health & Academic Consultancy 99

100. HEXOSE MONOPHOSPHATE SHUNT 100 HMP Shunt/ Pentose Phosphate Pathway/ Phosphogluconate Pathway Prarambh Health & Academic Consultancy

101. 101 Prarambh Health & Academic Consultancy

102. Reactions of the HMP Shunt Pathway 102 Prarambh Health & Academic Consultancy

103. URONIC ACID PATHWAY (Or) Glucoronic acis pathway 103 Prarambh Health & Academic Consultancy

104. Alternative oxidative pathway for glucose. synthesis of glucorinc acid,pentoses and vitamin (ascorbic acid). Normal carbohydrate metabolism ,phosphate esters are involved – but in uronic acid pathway free sugars and sugar acids are involved. Steps of reactions : Formation of UDP- glucoronate Conversion of UDP- glucoronate to L- gulonate Synthesis of ascorbic acid in some animals Oxidation of L- gulonate 104 Prarambh Health & Academic Consultancy

105. 105 Prarambh Health & Academic Consultancy

106. Clinical Aspects Effects of drugs : increases the pathway to achieve more synthesis of glucaronate from glucose . - barbital,chloro-butanol etc. Essential pentosuria : deficiency of xylitol-dehydrogenase Rare genetic disorder Asymptomatic Excrete large amount of L- xylulose in urine No ill-effects 106 Prarambh Health & Academic Consultancy

107. METABOLISM OF GALACTOSE 107 Prarambh Health & Academic Consultancy

108. 108 Disaccharide lactose present in milk – principle source of of galactose . Lactase of intestinal mucosal cells hydrolyses lactose to galactose and glucose. Within cell galactose is produced by lysosomal degradation of glycoproteins and glycolipids . CLINICAL ASPECTS : - Classical galactosemia : deficiency of galactose-1-phosphate uridyltransferase . Increase in galactose level. - Galactokinase deficiency : Responsible for galactosemia and galactosuria . - Clinical symptoms : loss of weight in infants, hepatosplenomegaly , jaundice, mental retardation , cataract etc. - Treatment : removal of galactose and lactose from diet. Prarambh Health & Academic Consultancy

109. METABOLISM OF FRUCTOSE 109 Sorbitol / Polyol Pathway: Conversion of glucose to fructose via sorbitol . Glucose to Sorbitol reduction by enzyme aldolase (NADPH). Sorbitol is then oxidized to fructose by sorbitol dehydrogenase and NAD + . Fructose is preferred carbohydrate for energy needs of sperm cells due to the presence of sorbitol pathway. Pathway is absent in liver. Directly related to glucose : higher in uncontrolled diabetes. Prarambh Health & Academic Consultancy

110. METABOLISM OF AMINO SUGARS 110 When the hydroxyl group of the sugar is replaced by the amino group, the resultant compound is an amino sugar. Eg . Glucosamine,galactosamine,mannosamine,sialic acid etc. Essential components of glycoproteins , glycosaminoglycans , glycolipids . Found in some antibiotics. 20% of glucose utilized for the synthesis of amino sugars – connective tissues. Prarambh Health & Academic Consultancy

111. Electron transport chain reactions Electron transport chain is a series of protein complexes located in the inner membrane of mitochondria . 111 Prarambh Health & Academic Consultancy

112. REFERENCES 1) Biochemistry – U.Satyanarayana-3 rd Ed. 2) Textbook of Biochemistry- D.M.Vasudevan -14 th Ed. 3) Textbook of Medical Biochemistry – M.N.Chattergy – 17 th Ed. 4) Text book of Physiology – Ganong – 24 th Ed. 5) Text book of Oral Pathology – Shafers - 7 th Ed. 6) Principles & practice of Medicine-Davidson – 21 st Ed. 112 Prarambh Health & Academic Consultancy