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Carbohydrates Metabolism

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Title: Carbohydrates Metabolism


1
  • Chapter 4
  • Carbohydrates Metabolism

The biochemistry and molecular biology department
of CMU
2
1 Overview
  • Carbohydrates in general are polyhydroxy
    aldehydes or ketones or compounds which yield
    these on hydrolysis.

3
Biosignificance of Carbohydrates
  • The major source of carbon atoms and energy for
    living organisms.
  • Supplying a huge array of metabolic intermediates
    for biosynthetic reactions.
  • The structural elements in cell coat or
    connective tissues.

4
Glucose transporters (GLUT)
  • GLUT15
  • GLUT1 RBC
  • GLUT4 adipose tissue, muscle

5
The metabolism of glucose
  • glycolysis
  • aerobic oxidation
  • pentose phosphate pathway
  • glycogen synthesis and catabolism
  • gluconeogenesis

6
glycogen
Glycogenolysis
Glycogenesis
starch
lactate
Glycolysis
Digestion absorption
glucose
aerobic oxidation
Lactate, amino acids, glycerol
H2OCO2
Gluconeo-genesis
Pentose phosphate pathway
Ribose, NADPH
7
2 Glycolysis
8
  • Glycolysis
  • The anaerobic catabolic pathway by which a
    molecule of glucose is broken down into two
    molecules of lactate.
  • glucose ?2lactic acid (lack of O2)
  • All of the enzymes of glycolysis locate in
    cytosol.

9
  • 1. The procedure of glycolysis

G
glycolytic pathway
pyruvate
lactic acid
10
  • 1) Glycolytic pathway
  • G ? pyruvate
  • including 10 reactions.

11
(1) G phosphorylated into glucose 6-phosphate
  • Phosphorylated G cannot get out of cell
  • Hexokinase , HK (4 isoenzymes) ,
  • glucokinase, GK in liver
  • Irreversible .

12
  • hexokinase
    glucokinase
  • occurrence in all tissues only in liver
  • Km value 0.1mmol/L 10mmol/L
  • Substrate G, fructose, glucose
  • mannose
  • Regulation G-6-P Insulin

Comparison of hexokinase and glucokinase
13
(2) G-6-P ? fructose 6-phosphate
14
(3) F-6-P ? fructose 1,6-bisphosphate
  • The second phosphorylation
  • phosphofructokinase-1, PFK-1

15
(4) F-1,6-BP ? 2 Triose phosphates
  • Reversible

16
(5) Triose phosphate isomerization
  • G?2 molecule glyceraldehyde-3-phosphate, consume
    2 ATP .

17
(6) Glyceraldehyde 3-phosphate ? glycerate
1,3-bisphosphate
18
(7) 1,3-BPG ? glycerate 3-phosphate
  • Substrate level phosphorylation

19
(8) Glycerate 3-phosphate ? glycerate 2-phosphate
20
(9) Glycerate 2-phosphate ? phosphoenol pyruvate
21
(10) PEP ?pyruvate
  • Second substrate level phosphorylation
  • irreversible

22
  • 2) Pyruvate ? lactate

23
Summary of Glycolysis
24
  • Total reaction
  • C6H12O6 2ADP 2Pi 2CH3CHOHCOOH
    2ATP 2H2O
  • Formation of ATP
  • The net yield is 2 P or 2 molecules of ATP per
    glucose.

25
2. Regulation of Glycolysis
  • Three key enzymes catalyze irreversible
    reactions Hexokinase, Phosphofructokinase
    Pyruvate Kinase.

26
1) PFK-1 The reaction catalyzed by PFK-1 is
usually the rate-limiting step of the Glycolysis
pathway. This enzyme is regulated by covalent
modification, allosteric regulation.
27

bifunctional enzyme
28
2) Pyruvate kinase
  • Allosteric regulation
  • F-1,6-BP acts as allosteric activator
  • ATP and Ala in liver act as allosteric
    inhibitors

29
  • Covalent modification
  • phosphorylated by Glucagon through cAMP and
    PKA and inhibited.

30
3) Hexokinase and glucokinase
  • This enzyme is regulated by covalent
    modification, allosteric regulation and isoenzyme
    regulation.
  • Inhibited by its product G-6-P.
  • Insulin induces synthesis of glucokinase.

31
  • 3. Significance of glycolysis
  • 1) Glycolysis is the emergency energy-yielding
    pathway.
  • 2) Glycolysis is the main way to produce ATP
    in some tissues, even though the oxygen supply is
    sufficient, such as red blood cells, retina,
    testis, skin, medulla of kidney.
  • In glycolysis, 1mol G produces 2mol lactic acid
    and 2mol ATP.

32
3 Aerobic Oxidation of Glucose
33
  • The process of complete oxidation of glucose to
    CO2 and water with liberation of energy as the
    form of ATP is named aerobic oxidation.
  • The main pathway of G oxidation.

34
1. Process of aerobic oxidation
35
1) Oxidative decarboxylation of Pyruvate to
Acetyl CoA
  • irreversible
  • in mitochodria.

36
  • Pyruvate dehydrogenase complex
  • E1 pyruvate dehydrogenase
  • Es E2 dihydrolipoyl transacetylase
  • E3 dihydrolipoyl dehydrogenase
  • thiamine pyrophosphate, TPP
    (VB1)
  • HSCoA (pantothenic acid)
  • cofactors lipoic Acid
  • NAD (Vpp)
  • FAD (VB2)

37
Pyruvate dehydrogenase complex
HSCoA
NAD
38
The structure of pyruvate dehydrogenase complex
39
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40
HSCoA
41
CO2
NADH H
NAD
CoASH
42
  • 2) Tricarboxylic acid cycle, TCAC
  • The cycle comprises the combination of a molecule
    of acetyl-CoA with oxaloacetate, resulting in the
    formation of a six-carbon tricarboxylic acid,
    citrate. There follows a series of reactions in
    the course of which two molecules of CO2 are
    released and oxaloacetate is regenerated.
  • Also called citrate cycle or Krebs cycle.

43
(1) Process of reactions
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Citrate cycle
48
Summary of Krebs Cycle ?
Reducing equivalents
49
? The net reaction of the TCAC acetylCoA3NADFA
DGDPPi2H2O ? 2CO23NADH3HFADH2GTP
HSCoA ? Irreversible and aerobic reaction ? The
enzymes are located in the mitochondrial matrix.
50
? Anaplerotic reaction of oxaloacetate
51
(2) Bio-significance of TCAC
  • ? Acts as the final common pathway for the
    oxidation of carbohydrates, lipids, and proteins.
  • ? Serves as the crossroad for the
    interconversion among carbohydrates, lipids, and
    non-essential amino acids, and as a source of
    biosynthetic intermediates.

52
Krebs Cycle is at the hinge of metabolism.
53
  • 2. ATP produced in the aerobic oxidation
  • acetyl CoA ? TCAC 3 (NADHH) FADH2 1GTP ?
    12 ATP.
  • pyruvate ?acetyl CoA NADHH ? 3 ATP
  • 1 G ? 2 pyruvate 2(NADHH) ? 6 or 8ATP
  • 1mol G 36 or 38mol ATP
  • (123 )2 6( 8 )36( 38 )

54
3. The regulation of aerobic oxidation
  • The Key Enzymes of aerobic oxidation
  • The Key Enzymes of glycolysis
  • Pyruvate Dehydrogenase Complex
  • Citrate synthase
  • Isocitrate dehydrogenase (rate-limiting )
  • ?-Ketoglutarate dehydrogenase

55
(1) Pyruvate dehydrogenase complex
56
  • (2) Citrate synthase
  • Allosteric activator ADP
  • Allosteric inhibitor NADH, succinyl CoA,
    citrate, ATP
  • (3) Isocitrate dehydrogenase
  • Allosteric activator ADP, Ca2
  • Allosteric inhibitor ATP
  • (4) ?-Ketoglutarate dehydrogenase
  • Similar with Pyruvate dehydrogenase complex

57
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58
  • Oxidative phosphorylation?TCAC?
  • ATP/ADP? inhibit TCAC,
  • Oxidative phosphorylation ?
  • ATP/ADP?,promote TCAC,
  • Oxidative phosphorylation ?

59
4. Pasteur Effect
  • Under aerobic conditions, glycolysis is inhibited
    and this inhibitory effect of oxygen on
    glycolysis is known as Pasteur effect.
  • The key point is NADH
  • NADH mitochondria
  • Pyr TCAC CO2H2O
  • Pyr cant produce to lactate.

60
4 Pentose Phosphate Pathway
61
  • 1. The procedure of pentose phosphate
    pathway/shunt
  • In cytosol

62
1) Oxidative Phase
63
2) Non-Oxidative Phase
Fructose 6-p
Glycolysis
Ribose 5-p
Fructose 6-p
Xylulose 5-p
Xylulose 5-p
Glyceraldehyde 3-p
  • Transketolase requires TPP
  • Transaldolase

64
  • The net reation
  • 3G-6-P 6NADP ?
  • 2F-6-P GAP 6NADPH H 3CO2
  • 2. Regulation of pentose phosphate pathway
  • Glucose-6-phosphate Dehydrogenase is the
    rate-limiting enzyme.
  • NADPH/NADP?, inhibit
  • NADPH/NADP?, activate.

65
3. Significance of pentose Phosphate pathway
  • 1) To supply ribose 5-phosphate for bio-synthesis
    of nucleic acid
  • 2) To supply NADPH as H-donor in metabolism
  • NADPH is very important reducing power for the
    synthesis of fatty acids and cholesterol, and
    amino acids, etc.

66
  • NADPH is the coenzyme of glutathione reductase
    to keep the normal level of reduced glutathione

So, NADPH, glutathione and glutathione
reductase together will preserved the integrity
of RBC membrane.
67
  • Deficiency of glucose 6-phosphate dehydrogenase
    results in hemolytic anemia.
  • favism
  • NADPH serves as the coenzyme of mixed function
    oxidases (mono-oxygenases). In liver this enzyme
    participates in biotransformation.

68
5 Glycogen synthesis and catabolism

69
  • Glycogen is a polymer of glucose residues linked
    by
  • ? (1?4) glycosidic bonds, mainly
  • ? (1?6) glycosidic bonds, at branch points.

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1. Glycogen synthesis (Glycogenesis)
  • The process of glycogenesis occurs in cytosol of
    liver and skeletal muscle mainly.

72
  • UDPG G active pattern, G active donor.
  • In glycogen anabolism, 1 G consumes 2P.
  • Glycogen synthase key E.

73
UDPG
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Branching enzyme
76
2. Glycogen catabolism (glycogenolysis)
Phosphorylase key E The end products 85 of
G-1-P and 15 of free G There is no the activity
of glucose 6-phosphatase (G-6-Pase) in skeletal
muscle.
77
Debranching enzyme glucan transferase
?-1,6-glucosidase
78
(?1?6) linkage
Nonreducing ends
Glycogen phosphorylase
Transferase activity of debranching enzyme
(?1?6) glucosidase activity of debranching enzyme
Glucose
79
  • 3. Regulation of glycogenesis and glycogenolysis
  • 1) Allosteric regulation
  • In liver
  • G phosphorylase glycogenolysis
  • In muscle

80
  • 2) Covalent modification

Adenylyl cyclase
Glucagon epinephrine
receptor
G protein
Phosphorylase
cAMP
PKA
Glycogen synthase
glycogenolysis
Blood sugar
glycogenesis
81
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6 Gluconeogenesis

83
  • Concept
  • The process of transformation of
    non-carbohydrates to glucose or glycogen is
    termed as gluconeogenesis.
  • Materials lactate, glycerol, pyruvate and
    glucogenic amino acid.
  • Site mainly liver, kidney.

84
1. Gluconeogenic pathway
  • The main pathway for gluconeogenesis is
    essentially a reversal of glycolysis, but there
    are three energy barriers obstructing a simple
    reversal of glycolysis.

85
1) The shunt of carboxylation of Pyr
86
2) F-1, 6-BP ?F-6-P
87
3) G-6-P ?G
  • 2 lactic acid G consume ATP?

88
gluconeogenesis
89
2. Regulation of gluconeogenesis
  • Substrate cycle
  • The interconversion of two substrates
    catalyzed by different enzymes for singly
    direction reactions is called substrate cycle.
  • The substrate cycle produces net hydrolysis of
    ATP or GTP.------futile cycle

90
  • Key enzymes of gluconeogenesis
  • PEP carboxykinase
  • Pyr carboxylase
  • Fructose-bisphosphatase
  • Glucose-6-phosphatase

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  • 3. Significance of gluconeogenesis
  • Replenishment of Glucose by Gluconeogenesis and
    Maintaining Normal Blood Sugar Level.
  • Replenishment of Liver Glycogen.
  • Regulation of Acid-base Balance.

94
First stages (cytosol)
Second stages (Mt.)
Third stages (Mt.)
95
Lactic acid (Cori) cycle
  • Lactate, formed by the oxidation of glucose in
    skeletal muscle and by blood, is transported to
    the liver where it re-forms glucose, which again
    becomes available via the circulation for
    oxidation in the tissues. This process is known
    as the lactic acid cycle or Cori cycle.
  • prevent acidosisreused lactate

96
Lactic acid cycle
97
  • 6 Blood Sugar and Its Regulation

98
1. The source and fate of blood sugar
99
Blood sugar level must be maintained within a
limited range to ensure the supply of glucose to
brain. The blood glucose concentration is
3.896.11mmol/L normally.
100
2. Regulation of blood sugar level
  • 1)insulin for decreasing blood sugar levels.
  • 2)glucagonfor increasing blood sugar levels.
  • 3)glucocorticoid for increasing blood sugar
    levels.
  • 4)adrenalinefor increasing blood sugar levels.

101
3. Abnormal Blood Sugar Level
  • Hyperglycemia gt 7.227.78 mmol/L
  • The renal threshold for glucose
    8.8910.00mmol/L
  • Hypoglycemia lt 3.333.89mmol/L

102
Pyruvate as a junction point
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