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Dental Biochemistry 1- (6)




    Carbohydrates Metabolism
             Part I



1
Glucose metabolism
Importance of Glucose:
1. Glucose is the preferred source of energy for most
   of the body tissues. Brain cells derive energy
   mainly from glucose.
2. When glucose metabolism is deranged, life-
   threatening conditions may occur. A minimum
   amount of glucose is always required for normal
   functioning.
3. Normal fasting plasma glucose level is 70 to 110
   mg/dl. After a heavy carbohydrate meal, in a
   normal person, this level is below 150 mg/dl.
  2
Glucose is used in
• Oxidation:
The pathways for oxidation of glucose are classified
into two main groups:
      A. The major pathways which are mainly for
energy production:
        1. Glycolysis.
        2. Citric acid cycle (CAC).
  B. The minor pathways for oxidation which are not
for energy production:
        1. Hexose monophosphate shunt (HMS).
        2. Uronic acid pathway.
  3
• II. Conversion to biologically active
  substances as:
 1. Galactose: which is essential for formation of
lactose, glycolipids, mucopolysaccharides, ...etc.
 2. Fructose: needed for nutrition of sperms.
 3. Amino sugars.
 4. Non-essential amino acids.
 5. Fatty acids.
 6. Ribose-5-P.
 7. Glucuronic acid.
  4
• III. Storage of glucose:
 1. As glycogen in the liver and muscles mainly.
 2. As triglycerides (TG), mainly in adipose tissues.

• IV. Excretion of glucose in urine:
  When blood glucose level exceeds a certain limit
(renal sugar threshold), it will pass to urine. This
will occur when blood glucose level is above 180
mg/dl and this is known as glucosuria.


5
Glycolysis
      (Embden-Meyerhof Pathway)
Importance of the pathway
• In this pathway glucose is converted to pyruvate
  (aerobic condition) or lactate (anaeroboic
  condition), along with production of a small
  quantity of energy.
• All the reaction steps take place in the cytoplasm. It
  is the only pathway that is taking place in all the
  cells of the body.
• Glycolysis is the only source of energy in
  erythrocytes.
  6
7
8
Importance of glycolysis
•     I-Energy production :
•       1. Under aerobic conditions:
        Glucose ------→ 2 Pyruvate + 8 ATP.
    For tissues that have mitochondria, glycolysis
    is considered a preparatory step for complete
    oxidation via citric acid cycle since pyruvate is
    transported into the mitochondria to provide
    oxaloacetate or active acetate where it is
    oxidized by CAC for more energy.
    9
• The hydrogens of NADH produced by
  glycolysis are transported to the mitochondria
  mainly to be oxidized by electron transport
  chain (ETC).

• 2. Under anaerobic conditions:

 Glucose ------→ 2 lactate + 2 ATP
 Pyruvate is reduced to lactate in a reversible
  reaction catalyzed by lactate dehydrogenase
  (LDH).
  10
• This occurs in muscles during severe exercise
  (hypoxic conditions) and in tissues that lack
  mitochondria as RBCs and lens.
11
Cori’s cycle or lactic acid cycle
• In an actively contracting muscle, only about
  8% of the pyruvate is utilized by the citric acid
  cycle, and the remaining molecules are
  therefore reduced to lactate.
• The lactic acid thus, generated should not be
  allowed to accumulate in the muscle tissues.
• The muscle cramps, often associated with
  strenuous muscular exercise, are through to
  be due to lactate accumulation.

12
• This lactate diffuses into the blood. During exercise,
  blood lactate level is increased appreciably.
• Lactate then reaches liver, where it is oxidized to
  pyruvate.
• It is then taken up through gluconeogenesis
  pathway, and becomes glucose which can enter into
  blood and then taken to muscle.
• This cycle is called Cori’s cycle, by which the Lactate
  is efficiently reutilized by the body.
• Carl Cori and Gerty Cori were awarded Nobel prize
  in 1947.
  13
14
Regulation of glycolysis
       Hormonal regulation of glycolysis:
• a) Glucagon : is secreted in hypoglycemia or in
   carbohydrate deficiency. It affects liver cells mainly
   as follows:
  It acts as inhibitors for glycolytic key enzymes
   (glucokinase,PFK-1, pyruvate kinase).

• b) Insulin: It is secreted in hyperglycemia and after
  carbohydrates feeding, it causes:
  Stimulation of glycolytic key enzymes.
  15
Enzyme regulation

• The key irreversible regulatory Enzymes
  are:
  - Hexokinase (glucokinase),
  - Phosphofructokinase (PFK-1)
  - Pyruvate kinase.




  16
Inhibitors of glycolysis:
1- 2- deoxyglucose inhibits
  hexokinase.
2- Mercury and iodoacetate inhibit
  glyceraldehyde-3-P dehydrogenase.
3- Fluoride inhibits enolase by removal
  of Mg2+ as Mg fluoride.

17
Pyruvate as a junction point
 Pyruvate occupies an important junction
  between various metabolic pathways. It may be
  decarboxylated to acetyl-CoA which enters the
  TCA cycle, or may be utilized for fatty acid
  synthesis.
 Pyruvate may be carboxylated to oxaloacetate
  which is used for gluconeogenesis.
 Pyruvate dehydrogenase step is the committed
  step towards oxidation of glucose.
 18
19
Citric acid cycle (CAC)
  or Tricarboxylic Acid Cycle (TCA)
             or Krebs Cycle
Definition:
     It is a series of reactions in mitochondria, that
     brings about the catabolism of acetyl residues,
     liberating hydrogen equivalents which upon
     oxidation, leads to the release of energy.




20
21
Functions of the Citric Acid Cycle
1. It is the final common oxidation pathway that
          oxidises acetyl CoA to CO2.
2.        Energy production, every one mole of acetyl- CoA
          produces 12 moles of ATP.
3.        It is the source of reduced coenzymes that provide
          the substrate for the respiratory chain.
4.        It acts as a link between catabolic and anabolic
          pathway (amphibolic role).
5.        It provides precursors for synthesis of amino acids
          and nucleotides.
6.        Components of the cycle have direct or indirect
          controlling effects on key enzymes of other
          pathways.
     22
Total ATP produced from complete oxidation of
 one molecule of glucose during glycolysis,
 oxidative decarboxylation and CAC :
Glycolysis G           →             2PA          8 ATP
Oxidative decarboxylation 2PA → 2 acetyl CoA      6 ATP
                        (2 NADH + H+ ×3)
Oxidation of 2 acetyl CoA in CAC → (12 ATP ×2) 24 ATP
                                               -------------------

                                               38 ATP


23
Inhibitors of CAC
1- Fluorocitrate inhibits aconitase.
2- Mercury and arsenite inhibit pyruvate and α–
  ketoglutarate dehydrogenase complex.
3- Malonic acid inhibits succinic acid
   dehydrogenase.




24
Gluconeogenesis
• i. It is the process by which new glucose is
  synthesized from noncarbohydrate precursors like
  lactate, glycerol and glucogenic amino acids.
• ii. It occurs mainly in the liver.
• iii. Gluconeogenesis involves several enzymes of
  glycolysis, but it is not a reversal of glycolysis.



  25
26

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Lec 6 level 3-de (carbohydrate metabolism i)

  • 1. Dental Biochemistry 1- (6) Carbohydrates Metabolism Part I 1
  • 2. Glucose metabolism Importance of Glucose: 1. Glucose is the preferred source of energy for most of the body tissues. Brain cells derive energy mainly from glucose. 2. When glucose metabolism is deranged, life- threatening conditions may occur. A minimum amount of glucose is always required for normal functioning. 3. Normal fasting plasma glucose level is 70 to 110 mg/dl. After a heavy carbohydrate meal, in a normal person, this level is below 150 mg/dl. 2
  • 3. Glucose is used in • Oxidation: The pathways for oxidation of glucose are classified into two main groups: A. The major pathways which are mainly for energy production: 1. Glycolysis. 2. Citric acid cycle (CAC). B. The minor pathways for oxidation which are not for energy production: 1. Hexose monophosphate shunt (HMS). 2. Uronic acid pathway. 3
  • 4. • II. Conversion to biologically active substances as: 1. Galactose: which is essential for formation of lactose, glycolipids, mucopolysaccharides, ...etc. 2. Fructose: needed for nutrition of sperms. 3. Amino sugars. 4. Non-essential amino acids. 5. Fatty acids. 6. Ribose-5-P. 7. Glucuronic acid. 4
  • 5. • III. Storage of glucose: 1. As glycogen in the liver and muscles mainly. 2. As triglycerides (TG), mainly in adipose tissues. • IV. Excretion of glucose in urine: When blood glucose level exceeds a certain limit (renal sugar threshold), it will pass to urine. This will occur when blood glucose level is above 180 mg/dl and this is known as glucosuria. 5
  • 6. Glycolysis (Embden-Meyerhof Pathway) Importance of the pathway • In this pathway glucose is converted to pyruvate (aerobic condition) or lactate (anaeroboic condition), along with production of a small quantity of energy. • All the reaction steps take place in the cytoplasm. It is the only pathway that is taking place in all the cells of the body. • Glycolysis is the only source of energy in erythrocytes. 6
  • 7. 7
  • 8. 8
  • 9. Importance of glycolysis • I-Energy production : • 1. Under aerobic conditions: Glucose ------→ 2 Pyruvate + 8 ATP. For tissues that have mitochondria, glycolysis is considered a preparatory step for complete oxidation via citric acid cycle since pyruvate is transported into the mitochondria to provide oxaloacetate or active acetate where it is oxidized by CAC for more energy. 9
  • 10. • The hydrogens of NADH produced by glycolysis are transported to the mitochondria mainly to be oxidized by electron transport chain (ETC). • 2. Under anaerobic conditions: Glucose ------→ 2 lactate + 2 ATP Pyruvate is reduced to lactate in a reversible reaction catalyzed by lactate dehydrogenase (LDH). 10
  • 11. • This occurs in muscles during severe exercise (hypoxic conditions) and in tissues that lack mitochondria as RBCs and lens. 11
  • 12. Cori’s cycle or lactic acid cycle • In an actively contracting muscle, only about 8% of the pyruvate is utilized by the citric acid cycle, and the remaining molecules are therefore reduced to lactate. • The lactic acid thus, generated should not be allowed to accumulate in the muscle tissues. • The muscle cramps, often associated with strenuous muscular exercise, are through to be due to lactate accumulation. 12
  • 13. • This lactate diffuses into the blood. During exercise, blood lactate level is increased appreciably. • Lactate then reaches liver, where it is oxidized to pyruvate. • It is then taken up through gluconeogenesis pathway, and becomes glucose which can enter into blood and then taken to muscle. • This cycle is called Cori’s cycle, by which the Lactate is efficiently reutilized by the body. • Carl Cori and Gerty Cori were awarded Nobel prize in 1947. 13
  • 14. 14
  • 15. Regulation of glycolysis Hormonal regulation of glycolysis: • a) Glucagon : is secreted in hypoglycemia or in carbohydrate deficiency. It affects liver cells mainly as follows: It acts as inhibitors for glycolytic key enzymes (glucokinase,PFK-1, pyruvate kinase). • b) Insulin: It is secreted in hyperglycemia and after carbohydrates feeding, it causes: Stimulation of glycolytic key enzymes. 15
  • 16. Enzyme regulation • The key irreversible regulatory Enzymes are: - Hexokinase (glucokinase), - Phosphofructokinase (PFK-1) - Pyruvate kinase. 16
  • 17. Inhibitors of glycolysis: 1- 2- deoxyglucose inhibits hexokinase. 2- Mercury and iodoacetate inhibit glyceraldehyde-3-P dehydrogenase. 3- Fluoride inhibits enolase by removal of Mg2+ as Mg fluoride. 17
  • 18. Pyruvate as a junction point  Pyruvate occupies an important junction between various metabolic pathways. It may be decarboxylated to acetyl-CoA which enters the TCA cycle, or may be utilized for fatty acid synthesis.  Pyruvate may be carboxylated to oxaloacetate which is used for gluconeogenesis.  Pyruvate dehydrogenase step is the committed step towards oxidation of glucose. 18
  • 19. 19
  • 20. Citric acid cycle (CAC) or Tricarboxylic Acid Cycle (TCA) or Krebs Cycle Definition: It is a series of reactions in mitochondria, that brings about the catabolism of acetyl residues, liberating hydrogen equivalents which upon oxidation, leads to the release of energy. 20
  • 21. 21
  • 22. Functions of the Citric Acid Cycle 1. It is the final common oxidation pathway that oxidises acetyl CoA to CO2. 2. Energy production, every one mole of acetyl- CoA produces 12 moles of ATP. 3. It is the source of reduced coenzymes that provide the substrate for the respiratory chain. 4. It acts as a link between catabolic and anabolic pathway (amphibolic role). 5. It provides precursors for synthesis of amino acids and nucleotides. 6. Components of the cycle have direct or indirect controlling effects on key enzymes of other pathways. 22
  • 23. Total ATP produced from complete oxidation of one molecule of glucose during glycolysis, oxidative decarboxylation and CAC : Glycolysis G → 2PA 8 ATP Oxidative decarboxylation 2PA → 2 acetyl CoA 6 ATP (2 NADH + H+ ×3) Oxidation of 2 acetyl CoA in CAC → (12 ATP ×2) 24 ATP ------------------- 38 ATP 23
  • 24. Inhibitors of CAC 1- Fluorocitrate inhibits aconitase. 2- Mercury and arsenite inhibit pyruvate and α– ketoglutarate dehydrogenase complex. 3- Malonic acid inhibits succinic acid dehydrogenase. 24
  • 25. Gluconeogenesis • i. It is the process by which new glucose is synthesized from noncarbohydrate precursors like lactate, glycerol and glucogenic amino acids. • ii. It occurs mainly in the liver. • iii. Gluconeogenesis involves several enzymes of glycolysis, but it is not a reversal of glycolysis. 25
  • 26. 26