CHO METABOL-1.ppt
- 1. 1 CARBOHYDRATE METABOLISM Main pathways: 1. Glycolysis ( Embden- Meyerhof Pathway). 2. Tricarboxylic Acid Cycle (Kreb’s Citric Acid Cycle). 3. Glycogenesis and Glycogenolysis( Glycogen Metabolism). 4. Gluconeogenesis (Glucose formation from non-sugars. 5. Hexose Monophosphate Shunt ( pentose oxidateve pathway. 6. Uronic Acid Pathway ( Glucuronic Acid Pathway ). 7. Galactose and Fructose Metabolism & interconversions. 8. Glycogen Storage Diseases( Inherited Disorders ).
- 2. 2 GLYCOLYSIS: Two phases: Aerobic Phase & Anaerobic Phase Glycolysis occurs in three stages: Priming stage ( Phosphorylation ). 2. Splitting stage ( converts into 2 molecules ). 3. Oxidoreduction-phosphorylation stage ( ATP formation in E.T.C ). Oxidation of glucose or glycogen to pyruvate and lactate.
- 3. 3
- 4. 4 Glucokinase Hexokinase 1. Specific, can phosphorylase glucose only. 2. Physiologically more labile. 3. Found only in liver. 4. Not inhibited by glucose-6-P. 5. Km is high, has low affinity for glucose 6. Increased by glucose meal or insulin. 1. Non specific, can phosphrylase any hexose. 2. It is more stable enzyme. 3. Found almost in all tissues. 4. Allosteric inhibition by glucose- 6-P 5. Km is low, has high affinity for glucose. 6. No change with glucose feeding/meal.
- 5. 5 Biomedical importance of glycolysis 1. This pathway is virtually meant for energy. 2. In sk. muscles, provides energy even in the absence of O2 3. Heart muscle has poor glycolytic activity in ischaemia. 4. In cancer cells, glycolysis is high, lactacidosis occurs which may be favourable for cancer therapy. 5. Hexokinase & pyruvate kinase deficiency can produce hemolytic anemia.
- 6. 6 Energy yield per Glucose Molecule Oxidation A. Aerobic phase of Glycolysis: ATP production Reaction catalyzed by -1 ATP -1 ATP +6 ATP +2 ATP +2ATP Stage I: 1. Hexokinase/Glucokinase reaction 2. Phosphofructoskinase-1 reaction Stage II: 3. Glyceraldehyde-3-P dehydrogenase 2NADH in ETC. 4. Phosphoglycerate kinase substrate level Stage III: 5. Pyruvate kinase ( substrate level ) 10-2=8 ATP Net Gain
- 7. 7 B. Anaerobic phase of Glycolysis: Pyruvate LDH Lactatic Acid NAD + NADH+H+ 4 - 2 = 2 ATP
- 8. 8 Regulation of Glycolysis Depends upon the following factors: 1. Blood Glucose level. 2. Enzymatic change. 3. Hormonal control. 1. Glucose level: • Can decrease the activity of enzymes. • Can increase the activity of enzymes. • Key enzymes are: – Glucokinase. – Phosphofructokinase-I. – Pyruvate kinase.
- 9. 9 2. Enzyme changes: • May be covalent modification by reversible Phosphorylation, ↑ or ↓ glycolysis: • Allosteric Modification: • cAMP level • Protein kinase level Feedback control by: • Inhibition of enzyme by citrate & ATP • Activation of enzymes by AMP conc. 3. Hormonal control: • Insulin: ↓ glucose level ( Hypoglycemic ) •Glucagon: ↑ glucose level ( hyperglycemic ) •Epinephrine: ↑ glucose level ( hyperglycemic ) •Glucorticoids: ↑ glucose by gluconeogenesis
- 10. 10
- 11. 11 Formation and Fate of Pyruvate Formation of pyruvate: • From Oxidation of Glucose ( Glycolysis ). •From Lactic acid by Oxidation ( LDH ). •Transaminate of Alanine ( GPT/ALT ). •Glucogenic amino acids-pyruvate forming. •Decarboxylation of Malic acid & OAA. Fate of Pyruvic Acid •Forms Lactic Acid by reduction (LDH) anaerobically. •Forms Acetyl CoA by oxidative decarboxylation ( Aerobic ). •Forms Alanine by transamination ( GPT/ALT ). •Forms Glucose by gluconeogenesis. •Forms Malic Acid to OAA ( Oxaloacetic Acid ). •Forms Oxaloacetic acid ( OAA ) by CO2 fixation reaction.
- 12. 12
- 13. 13 TCA CYCLE
- 14. 14 Biomedical importance of TCA cycle 1. Final common pathway for CHO, proteins & fats through formation of 2- carbon unit acetyl – CoA. 2. Has catabolic role, energy rich cycle, acetyl CoA is oxidized to CO2 & H2O producing energy. 3. It is amphibolic in nature, has anabolic role as well, synthesis of FA, cholesterol, steroids, AA, heme, glucose and ketone bodies is correlated with this cycle.
- 15. 15 Regulation of TCA Cycle •Energy level through ECT/ Oxidative Phosphorylation •Key Enzymes control: - Citrate Synthetase -Isocitrate dehydrogenase ( ICD ) -2-oxo- glutarate dehydrogenase Their inhibition or activation depends upon ATP, ADP & NAD,NADH.
- 16. 16 Glycogen Metabolism • Glycogenesis •Glycogenolysis • Glycogen is the storage form of glucose. • Why the glucose is not store itself in body? Possible Reasons 1. Being insoluble it exerts no osmotic pressure. 2. Does not disturb the intracellular fluid (ICF) content. 3. Does not diffuse from its storage sites. 4. Has higher energy level than corresponding wt. of glucose. 5. Readily broken under influence of hormones and enzymes.
- 17. 17 Storage Capacity of Glycogen in Normal Adult Man( 70kg ) Normal weight of the organ Amount Organ 1800 gm 4-6%= 72-180 gm Liver 35 kg 0.7%=245 gm Sk. Muscles Total volume= 10 literes 0.1% = 10 gm EC Glucose Total = 325-360
- 18. 18 GLYCOGENESIS Formation of glycogen from glucose
- 19. 19 Regulation of glycogenesis • Glycogen synthase- key regulatory enzyme. - Active from GS “ a “ ( GS-I ). -Inactive from GS “ b “ (GS-D). • cAMP dependant protein kinase. • Glycogen conc. ( feedback control ).
- 20. 20 Stimulation of Glycogenesis 1. Insulin increases the pathway. 2. Glucocorticoids: 2-3 hrs after administration. 3. Glucose higher concentration ↑ synthesis. Inhibition of Glycogenesis 1. Increase conc. of glycogen (feedback inhibition). 2. Increased conc. Of cAMP inhibition protein phosphatase-I.
- 21. 21 GLYCOGENOLYSIS Breakdown of glycogen to glucose
- 22. 22 Regulation of glycogenolysis • cAMP dependant protein kinase. • Phosphorylase – key regulatory enzyme. • Hormones like Glucagon & Catecholamines. • Calmodulin, Ca ++ dependant regulatory protein. 6 / بوعلي ح 2/3/1424
- 23. 23 HEXOSE MONOPHOSPHATE (HMP) SHUNT An alternate Pathway for oxidation of glucose It is called by various names: •Hexose Monophosphate Shunt or Pathway. •Pentose - Phosphate Pathway (PP-Pathway). •Pentose Oxidative Pathway (Pentose Cycle). •Phosphogluconate Pathway (Dicken Pathway).
- 24. 24
- 25. 25
- 26. 26 Biomedical Importance of HMP Shunt • Various tissues can utilize glucose readily by this shunt when anaerobic glycolysis is blocked by specific inhibitors as “ lodo-acetic acid” • Provides NADPH which is required for various reductive synthesis in metabolic pathways i.e. Fatty Acids, steroids & cholesterol. • Provides pentoses required for nucleic acids (RNA & DNA) synthesis. • Deficiency of G6PD enzyme leads to hemolytic anemia, which has great clinical importance. • Not meant for energy, but multicyclic process in which 3 molecules of Gl-6-P enter, producing 3 moles of CO2 & 3 moles of 5-C residues which rearrange to give 2 moles of Fr.6.p & one mole of Glyceraldehyde -3-P.
- 27. 27 Difference of EM Pathway and HMP Shunt HM Pathway EM Pathway 1. Occurs in certain spec. tissue 2. Multicyclic process 3. NADPH2 is produced 4. Not meant for energy (ATP) 5. CO2 is produced 1. Occurs almost in all tissues 2. Not a multicycle process 3. NADH2 is produced 4. ATP is required and produced 5. CO2 is never formed
- 28. 28 GLUCONEOGENESIS Formation of glucose or glycogen from non carbohydrate sources. Sources/substrates •Glucogenic Amino Acids •Lactate and Pyruvate •Glycerol from lipolysis of fat •Propionyl-CoA & Prop ionic Acid •Odd- Chain Fatly Acids. Sites/tissues i. Liver ii. Kidneys iii. Heart iv. Intestine No Gluconeogenesis in sk. muscles
- 29. 29
- 30. 30
- 31. 31 Biomedical importance I. Gluconeogenesis meets the requirements of glucose in body when Carbohydrates are not sufficiently available. Certain “basal level” of glucose is even needed for specific uses: • Source of energy for nervous tissues & RBCs • For maintaining level of intermediates of TCA cycle • Precursor of milk sugar (lactose) in lactating mammary glands in females • Source of glyceride-glycerol-P for adipose tissues • Only fuel for sk. muscle in anaerobic conditions.
- 32. 32 2. Gluconeogenic mechanisms are required to clear the products of metabolism of other tissues from blood e.g. •Lactic acid produced by muscles & RBCs •Glycerol produced by fat lipolysis in adipose
- 33. 33 • Carbohydrate diet • Insulin/Glucagon ratio • Steroid Hormone (Cortisol) • Fatty acid oxidation ↑ it • Energy requirements of body - pyruvate carboxylase (PC) - PEPCK - Fr. 1,6 bisphoshatase - Gl-6-phosphatase Regulation of Gluconeogenesis • Key Enzymes are:
- 34. 34 GALACTOSE METABOLISM 1. Conversion to glucose 2. Conversion to lactose 3. Enters into glycolysis 4. Enters into HMP Shunt 5. Galactosemia disorder
- 35. 35 FRUCTOSE METABOLISM 1. Conversion to glucose 2. Conversion to sucrose 3. Enters into glycolysis 4. Conversion to fat (TAG) 5. Converts to sorbitol in diabetes mellitus 6. Fructosuria can occur
- 36. 36 Biomedical importance • Fructose is easily metabolized in body • Fructose is good source of energy • Sperms utilize fructose for energy • Excess dietary fructose harmful ↑TAG • In diabetics, through sorbitol pathway causes development of cataract in eyes • Heriditary fructose intolerance occurs in deficiency of aldolase- B enzyme
- 37. 37 URONIC ACID PATHWAY Alternate pathway for glucose oxidation
- 38. 38 Biomedical Importance • In this pathway energy is not produced • Produces D- glucuronic acid which detoxifies foreign chemicals & synthesizes MPS • Inherited deficiency of enzyme in this pathway produces “essential pentosuria” • Pathway synthesizes vitamin C in birds, dogs etc. but not in humans/primates & guinea pigs
- 39. 39
- 40. 40 Inherited Disorders GLYCOGEN STORAGE DISEASES Clinical Features Deficient Enzyme Name of Disease Type Liver, kidney & intestine affected. Hypoglycemia, ketosis, lactacidosis, Uric acid↑, cholesterol↑, hepatomegaly and growth stunted (dwarfism). GL.6.P Phosphatase Von Gierke’s Disease I Liver, heart & smooth muscles involved. Cardiomegaly, muscle hypotonia, muscle weakness, No hypoglycemia. Early death occurs. Acid Maltase (in lysosomes) Pompe’s Disease II Liver, heart & muscles involved. Hypoglycemia, acidosis, myopathy, and hepatomegaly. Debranching Enzyme Limit Dextrinosis (Forbe’s Disease) III Liver, heart, muscle & R.E. system involved. Hepatosplenomegaly, acites and liver cirrhosis (hepatic failure). Branching Enzyme Amylopectinosis (Andersen’s Disease) IV Sk.muscles involved. Muscle pains on exercise. Weakness and stiffness of muscles are also observed. Muscle phosphorylase Mac Adle’s Disease V Liver & leukocytes are involved. Hypoglycemia, acidosis & hepatomegaly have also been noted. Liver phosphorylase Her’s Disease VI
- 41. 41
- 42. 42