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Chapter 6 Carbohydrate Metabolism

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Chapter 6 Carbohydrate Metabolism Jia-Qing Zhang Biochemistry department Medical college Jinan university Mar. 2007 What s metabolism? Glucose transport ... – PowerPoint PPT presentation

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Title: Chapter 6 Carbohydrate Metabolism


1
Chapter 6 Carbohydrate Metabolism
Jia-Qing Zhang ??? Biochemistry
department Medical college Jinan university Mar.
2007
2
Whats metabolism?
3
Metabolism..
What is Life?
What are the properties of life?
Movement
Reproduction of ones kid
Metabolism
4
Carbohydrate metabolism
Protein metabolism
Lipid metabolism
5
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6
metabolism
Carbohydrate metabolism
Metabolism of lipid
Catabolism of protein
7
  • Carbohydrate Metabolism

8
Section 1 Introduction Carbohydrates are the
major source of carbon atoms and energy for
living organisms.
9
Carbohydratesf of the diet
Starch
Sugar
cellulose
Lactose
10
Starch Sugar Cellulose
11
Glucose, the hydrolyzed product of most starch,
will be focused in this chapter.
12
Glucose transport

13
The fate of absorbed glucose
14
Section 2 Anaerobic degradation of glucose
Glycolysis
Pyruvate or lactate
Glucose
ATP
cytosol
15
2.1 Basic process of glycolysis
Glucose
Phase 1
Pyruvate
Phase 2
Lactate
16
Phase1 Pyruvate formation from glucose
Reaction1
Glucose
Glucose-6- Phosphate
                                   
Hexokinase
17
Hexokinase
18
Hexokinases
Hexokinases is a key enzyme in glycolysis and
have 4 isoenzymes , isoenzyme 4 present in liver,
and named glucokinase.
1 2
3 4
Glucokinase present in liver
Hexokinases in all extrahepatic cells
19
Hexokinase has a low Km 0.1mol/L,
high affinity for
glucose. Hepatic glucokinase has high Km gt
10mol/L,
a low affinity for glucose
20
Glucose-6-Phosphate
Reaction 2
                                   
Fructose-6-Phosphate
Glucose-6-Phosphate
Phosphohexose isomerase
21
Phosphohexose isomerase
22
Reaction 3

23
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24
Reaction 4
helpful
Fructose-1,6-Phosphate

Glyceraldehyde 3-Phosphate Dihydroxyacetone
Phosphate(DHAP)
                                   
      Aldolase
25
Aldolase
26
Reaction 5
Glyceraldehyde 3-Phosphate Dihydroxyacetone
Phosphate
2 Glyceraldehyde 3-Phosphate
Triose Phosphate Isomerase
27
Triose Phosphate Isomerase
28
Reaction 6
Glyceraldehyde 3-Phosphate
1,3-Bisphosphoglycerate
Glyceraldehyde 3-Phosphate Dehydrogenase
High energy
29
Glyceraldehyde 3-Phosphate Dehydrogenase
30
Reaction 7
Substrate level phosphorylation

1,3-Bisphosphoglycerate
3-Phosphoglycerate
      Phosphoglycerate Kinase
31
Phosphoglycerate Kinase
32
Reaction 8
3-Phosphoglycerate
2-Phosphoglycerate
Phosphoglycerate Mutase
33
Mutase
34
Reaction 9

2-Phosphoglycerate
Phosphoenolpyruvate
      Enolase
PEP
High energy
35
Enolase
36
Reaction 10

Phosphoenolpyruvate
Pyruvate
      Pyruvate Kinase
PEP
37
Pyruvate Kinase
38
CO2 H2O
O2
Glucose
pyruvate
lactate
no O2
39
Conversion of pyruvate to lactate
40
Conversion of pyruvate to lactate
NAD
NADH H
Lactate
Pyruvate
Lactate dehydrogenase(LDH)
L-lactate
Pyruvate
41
  • How many ATP are produced in above process?
  • 2? 4?

Net ATP in glycolysis is 2
42
The features of the glycolysis pathway
  • Major anaerobic pathway in all cells
  • NAD is the major oxidant
  • Requires PO4
  • Generates 2 ATPs per glucose oxidized
  • End product is lactate (mammals)
  • Connects with Krebs cycle via pyruvate

43
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44
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45
2.2 Regulation of Glycolysis
46






47
6-phosphofructokinase-1
48
6-phosphofructokinase-1(PFK-1)
  • Allosteric enzyme
  • negative allosteric effectors
  • Citrate , ATP
  • Positive allosteric effectors
  • AMP, fructose1,6-bisphosphate,
    fructose2,6-bisphosphate
  • Response to changes in energy state of the cell
    (ATP and AMP)

49
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50
,
, is a potentially positive effector of PFK-1.

formed by phosphorylation of Fructose--6-PO4
catalyzed by PFK-II.
Fructose-2,6-bisphosphate
Fructose-2,6-bisphosphate
51
Regulation of Pyruvate Kinase
52
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53
  • Allosteric enzyme
  • Inhibited by ATP. alanine
  • Activated by fructose 1,6 bisphosphate
  • Regulated by phosphorylation and dephosphorylation

Active
Inactive
enzyme
PO4
54
Regulation of Hexokinase
Allosteric enzyme Inhibitor
Glucose-6-phosphate except for glucokinase
55
The Energy Story of Glycolysis
2 Pyruvate 2ATP 2NADH 2H 2H2O
Overall ANAEROBIC (no O2)
2Pyruvate 2NADH Lactate
2NAD
Overall AEROBIC(O2)
2NADH
5 ATPs
Oxidative phosphorylation
56
The Significance of Glycolysis
  • Glycolysis is the emergency energy-yielding
    pathway----ineffient
  • Main way to produce ATP in some tissues
  • red blood cells, retina, testis, skin,
    medulla of kidney
  • In clinical practice
  • acidosis

57
Section 3 Aerobic Oxidation of Glucose
  1. Oxidation of glucose to pyruvate in cytosol
  2. Oxidation of pyruvate to acetylCoA in
    mitochondria
  3. Tricarboxylic acid cycle and oxidative
    phosphorylation

58
Oxidation of pyruvate to acetylCoA
Acetyl CoA CO2
Pyruvate CoA
      Pyruvate dehydrogenase complex
mitochondria
This reaction is irreversible.
59
Pyruvate dehydrogenase complex
  • Comprises of 3 kinds of enzyme and 5 cofactors
  • E1 pyruvate dehydrogenase
  • E2dihydrolipoyl transacetylase
  • E3dihydrolipoyl dehydrogenase
  • Cofactors
  • Thiamine pyrophosphate(TPP), FAD,
    NAD, CoA and lipoic acid.

60


61
Pyruvate Dehydrogenase Complex
Acetyl-CoA
HS-CoA
..
..
H2
acetyl
..
..
hydroxyethyl
Pyruvate Dehydrogenase
Dihydrolipoyl dehydrogenase
Dihydrolipoyl Transacetylase
62
Tricarboxylic Acid Cycle

63
Krebs Cycle
Tricarboxylic Acid Cycle
Citric Acid Cycle
All Mean the Same
64
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65
CARBON BALANCE
4
Oxaloacetate
6
Citrate
2 carbons in 2 carbons out
4
Malate
Isocitrate
6
TCA cycle
4
Fumarate
5
a-ketoglutarate
4
4
Succinyl-CoA
Succinate
8 reactions
66
Reaction 1.
Oxaloacetate Acetyl CoA
Citrate Coenzyme A
Citrate Synthase
67
Citrate Synthase
Oxaloacetate
(OAA)
Citric Acid or Citrate
68
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69
Reaction 2


   
Isocitrate
Citrate
Aconitase
70
Isocitrate Formation
-H2O
H2O
cis-Aconitate
Isocitrate
Citrate
Aconitase
71
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72
Reaction 3
?-Ketoglutarate Carbon Dioxide
Isocitrate
Isocitrate Dehydrogenase
73
Isocitrate
?-Ketoglutarate
Isocitrate Dehydrogenase
74
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75
Reaction 4
?-Ketoglutarate CoA
Succinyl CoA Carbon Dioxide
?-Ketoglutarate Dehydrogenase
76
NAD
FAD
Lipoic acid
HS-CoA
TPP
Succinyl-CoA
?-Ketoglutarate dehydrogenase Complex
77
ketoglutarate
78
Reation 5
Succinate CoA
Succinyl CoA
Succinyl CoA Synthetase
79
Succinate
Succinyl-CoA
Succinyl-CoA Synthetase
80
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81
Reaction 6
Succinate
Fumarate
Succinate Dehydrogenase
82
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83
Reaction 7
Malate
Fumarate
Fumarase
84
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85
Reaction 8
Oxaloacetate
Malate
Malate Dehydrogenase
86
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87
H2O
Succinate
Fumarate
Malate
Oxaloacetate
88
CARBON BALANCE
4
Oxaloacetate
6
Citrate
2 carbons in 2 carbons out
4
Malate
Isocitrate
6
3 NADH 1 FADH2
4
Fumarate
5
a-ketoglutarate
4
4
Succinyl-CoA
Succinate
GTP
89
ATP Generated in the Aerobic Oxidation of Glucose
  • There are two ways for producing ATP
  • Substrate level phosphorylation
  • Succinyl CoA to succinate
  • Oxidative phosphorylation

90
3.2 ATP Generated in the Aerobic Oxidation of
Glucose
  • In aerobic oxidation of glucose
  • Gycolysis 2 NADH and 2ATP produced by
    substrate level phosphorylation
  • Production of acetylCoA 2 NADH
  • TCA cycle 2 3NADH ,2 1 FAD and 2GTP
  • Stoichiometry 2.5 ATP per NADH
  • 1.5 ATP per FADH

Table 6-1
32 ATP are produced for one glucose
91
Features
Acetyl-CoA enters forming citrate
3 NADH, 1 FADH2, and 1 GTP are formed
Oxaloacetate returns to form citrate
92
3.3 the regulation of aerobic oxidation of
glucose
The regulation of pyruvate dehydrogenase complex
The regulation of tricarboxylic acid cycle
93
Regulation of Pyruvate Dehydrogenase complex
Pyruvate HS-CoA NAD ? Acetyl-CoA
NADH H
Activators
Inhibitors
High NADH means that the cell is experiencing a
surplus of oxidative substrates and should not
produce more. Carbon flow should be redirected
towards synthesis.
High Acetyl-CoA means that carbon flow into the
Krebs cycle is abundant and should be shut down
and rechanneled towards biosynthesis
94
Mechanism
1. allosteric regulation
NADH and acetyl-CoA
2. Covalent Modification
E-1 subunits of PDH complex is subject to
phosphorylation
Epinephrine Glucagon
95
Regulation of the Citric Acid Cycle
Key enzymes
1. Citrate synthase
2. Isocitrate dehydrogenase
3. a-ketoglutarate dehydrogenase complex
Modulators The ratios of NADH/NAD and
ATP/ADP, high ratios inhibit Additonally,
Ca2 is an activitor
Succinyl CoA is a inhibitor
summary of TCA
96
Pentose Phosphate Pathway
97
PENTOSE PHOSPHATE Pathway
Take Home The PENTOSE PHOSPHATE pathway is
basically used for the synthesis of NADPH and
D-ribose. It plays only a minor role (compared
to GLYCOLYSIS) in degradation for
ATP energy.
98
The primary functions of this pathway are
  1. To generate NADPH,
  2. To provide the cell with ribose-5-phosphate.

99
NADPH differs from NADH physiologically 1)its
primary use is in the synthesis of metabolic
intermediates (NADPH as reductant provides the
electrons to reduce them), 2) NADH is used to
generate ATP
100
Basic Process
  • Found in cytosol
  • Two phases
  • Oxidative phase nonreversible
  • Nonoxidative phase reversible

101
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102
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103
  • The significance of PPP
  • Ribose 5- phosphate
  • Ribose 5- phosphate is the starting
    pointing for the synthesis of the nucleotides and
    nucleic acids.

104
2) NADPH a. NADPH is very important reducing
powerfor synthesis of fatty acids and
cholesterol, and the synthesis of amino acids via
glutamate dehydrogenase. b. In erythrocytes,
NADPH is the coenzyme of glutathione reductase to
keep the normal level of reduced
glutathione Additonally, NADPH serves as the
coenzyme of mixed funtion oxidases.
105
Glycogen Formation and Degradation
106
Location of glycogen
Glycogen is the storage form of glucose in
animals and humans Glycogen is synthesized and
stored mainly in the liver and the muscles
107
Features
  • The structure of glycogen consists of long
    polymer chains of glucose units connected by an
    alpha glucosidic bonds.
  • All of the monomer units are alpha-D-glucose,
  • 93 of glucose units are joined by
    a-1,4-glucosidic bond
  • 7 of glucosyl residues are joined by
    a-1,6-glucosidic bonds
  • Fig.6-11

108
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109
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110
Main chains branch point every 3 units on
average. Branch 5-12 glucosyl residues. Two
properties of this structure 1) High
solubility. many terminals 4
hydroxyl groups 2) More reactive points for
synthesis and degradation of glycogen.
111
Glycogen Formation (glycogenesis)
Occurs in cytosol of liver and skeletal muscle
Dived into 3 phases
  • ACTIVATION OF D-GLUCOSE
  • GLYCOSYL TRANSFER
  • BRANCHING

112
Glucose-6- Phosphate
Glucose
1.
                                   
Glucokinase(liver Hexokinase(muscle)
phosphoglucomutase
Glucose-1-phosphate
113
ACTIVATION
UDP-GLUCOSE
G-1-P UTP
UDP-GLUCOSE PPi
UDP-Glucose pyrophosphorylase
2 Pi
114
GLYCOSYL TRANSFER
UDPG
NON-REDUCING END
NEW
115
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116
BRANCHING
  • a1.,4-gt1,6-glucantransferase

Branching Enzyme
117
GLYCOGEN SYNTHESIS ENZYMES
  • UDP-glucose pyrophosphorylase
  • forms UDP-glucose
  • Glycogen Synthase
  • major polymerizing enzyme
  • a1.,4-gt1,6-glucantransferase

118
Glycogen Degradation (Glycogenolysis)
  • Glycogenolysis is not the reverse of glycogenesis

119
Glycogen Synthesis
Glycogen
Synthesis
Degradation
Glucose-1-PO4
UDP-Glucose
Glucose-6-PO4
glucose
120
Phosphorylase and Debranching Enzyme
Highly branched core
Phosphorylase
Phosphorylase
Phosphorylase
G-1-p
Glycogen
Debranching enzyme1
Limit Branch
Debranching enzyme2

D-glucose
121
Debranching enzyme a tandem enzyme
glucosidase
Oligo a1,4 a 1,4 glucantransferase
Hydorlyze a 1,6 branch point
Transfer a trisaccharide unit
122
Glycogen Breakdown
Phosphorylase and Debranching Enzyme
Phosphoglucomutase
Glucose
Glycolysis
Take home Glycogen contributes glucose to
glycolysis and to blood glucose (Liver)
123
The regulation of glycogensis and glycogenolysis
124
  • Regulatory site of glycogenesis and
    glycogenolysis
  • Phosphorylase
  • Glycogen synthase

125
Phosphorylase
Phosphorylase
G-1-p
126
Adenylate cyclase
Glucagon,epinephrine
Inactive
PKA protein kinase A
cAMP
b
Phosphorylase b kinase
Phosphorylase b kinase
inactive
a
Active
Phosphorylase
127


128
Glycogen synthase
129
Glycogen

Glycogen synthase

130
Adenylate cyclase
Glucagon,epinephrine
active
a
cAMP
PKA protein kinase A
b
inactive
Glycogen synthase
131
Adenylyl cyclase
Glucagon,epinephrine
cAMP
PKA protein kinase A
synthase
phosphorylase
b
b
Phosphorylating inhibitor-1
hydrolyze
inactive
hydrolyze
Active
Protein phosphatase-1
132
Active
inactive
133
Allosteric regulation
Phosphorylase Activitor AMP Inhibitor ATP,
glucose-6-phosphate Glycogen synthase Activitor
ATP, Glucose-6-phosphate
134
TAKE HOME
DEGRADATION
What activates glycogen degradation inactivates
glycogen synthesis.
SYNTHESIS
What activates glycogen synthesis inactivates
glycogen degradation
135
The Significance of Glycogenesis and
Glycogenolysis
  • Liver
  • maintain blood glucose concentration
  • Skeletal muscle
  • fuel reserve for synthesis of ATP

136
Glycogen Storage Diseases
  • Deficiency of
  • glucose 6-phosphatase
  • liver phosphorylase
  • liver phosphorylase kinase
  • branching enzyme
  • debranching enzyme
  • muscle phosphorylase
  • Table 6-2

137
Gluconeogenesis
GluconeogenesisThe process of transformation of
non-carbohydrates to glucose or glycogen
  • glucogenic amino acids
  • lactate
  • glycerol
  • organic acids

Glucose Glycogen
  • liver, kidney

138
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139
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140
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141
Ribose 5-PO4
Phosphatase
Blood Glucose
Glycogen
G6P
Glucose
Kinase
F6P
Kinase
Phosphatase
F1,6bisP
Gly-3-P
DHAP
1,3 bisPGA
Kinase
3PGA
2PGA
PEP
Kinase
Pyruvate
OAA
L-lactate
142
3 irreversible reactions
?Go -61.9 kJ per mol
?Go -17.2 kJ per mol
F-6-PO4 F1,6-bisPO4
Glucose Glucose-6-PO4
?Go -20.9 kJ per mol
Take home Gluconeogenesis feature enzymes
that bypass 3 irreversible KINASE steps
143

Reaction1
Glucose
Glucose-6- Phosphate
                                   
Hexokinase
144
Reaction 3
145
Reaction 10
Phosphoenolpyruvate
Pyruvate
146
3 reactions need to bypass
Pruvate phosphoenolpyruvate
Fructose 1,6-bisphosphate
fructose 6-phosphate
Glucose 6-phosphate glucose
147
The conversion of pyruvate to phosphoenolpyruvate
(PEP)
mitochondria
CO2
oxaloacetate
Pyruvate
Pyruvate carboxylase
148
oxaloacetate
malate
aspartate
cytosol
PEP
malate
oxaloacetate
mitochondria
aspartate
149
Mitochondria or cytosol
GTP GDP
oxaloacetate
PEP
CO2
Phosphoenolpyruvate carboxykinase
150
The conversion of Fructose 1,6-bisphosphate to
Fructose 6-phosphate
Fructose 1,6-bisphosphate
Fructose 6-phosphate
Fructose 1,6-bisphosphatase
151
The conversion of glucose 6-phosphate to Glucose
glucose 6-phosphate Glucose
Glucose 6-phosphatase
152
Substrate cycle
The interconversion of two substrates catalyzed
by different enzymes for singly direction
reactions is called substrate cycle.
Glucose
glucose-6-phosphote
153
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154
Significance
Primarily in the liver (80) kidney (20)
Maintains blood glucose levels
The anabolic arm of the Cori cycle
155
Cori Cycle

156
Cori cycle is a pathway in carbohydrate
metabolism that links the anaerobic glycolysis in
muscle tissue to gluconeogenesis in liver.
157
Liver is a major anabolic organ
L-lactate
D-glucose
Blood Glucose
Blood Lactate
THE CORI CYCLE
D-glucose
L-lactate
Muscle is a major catabolic tissue
158
  • Significance of cori cycle
  • avoid the loss of lactate and accumulation of
    lactate in blood to low blood pH and acidosis.
  • 6 ATP are sonsumed per 2 lactate to glucose

159
Regulation of gluconeogenesis
There are 2 important regulatory points
Fructose 1,6-bisphosphatase
160
Fructose 1,6-bisphosphatase
Inhibitor Fructose 2,6-bisphosphate and
AMP Activitor Citrate
161
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162
To summarize, when the concentration of
glucose in the cell is high, the concentration of
fructose 2,6-bisphosphate is elevated. This leads
to a stimulation of glycolysis .
Conversely, when the concentration of glucose is
low, the concentration of fructose
2,6-bisphosphate is decreased. This leads to a
stimulation of gluconeogenesis. Gluconeogenesis
predominates under starvation conditions.

163
. pyruvate carboxylase
Pyruvate carboxylase is allosterically activated
by acetyl CoA
164
The Significance of Gluconeogenesis
  • Replenishment of glucose and maintaining normal
    blood sugar level
  • Replenishment of liver glycogen
  • three carbon compounds
  • Regulation of Acid-Base Balance
  • Clearing the products
  • lactate, glycerol
  • Glucogenic amino acids to glucose

165
Blood Sugar and Its Regulation
  • Blood sugar level
  • 3.89-6.11mmol/l
  • Sources of blood sugar---income
  • digestion and absorption of glucose from
    dietary
  • gluconeogenesis
  • glycogen
  • other saccharides

Outcome aerobic oxidation Glycogen PPP Lipids
and amino acids
166
Regulation of Blood Glucose Concentration
  • Insulin
  • decreasing blood sugar levels
  • Glucagon, epinephrine glucocorticoid
  • increasing blood sugar levels

167
Insulin
The unique hormone responsible for decreasing
blood sugar level and promoting glycogen
formation, fat, and proteins simultaneously.
168
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169
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170
The effects of insulin Effects on membrane
actively transport. Effects on glucose
utilization Effects on gluconeogenesis.
171
Glucagon
172
Epinephrine
Stimulates glucogen degradation and
gluconeogenesis
173
Glucocorticoids
Inhibit the utilization of glucose Stimulate
gluconeogenesis by stimulating protein
degradation to liberate amino acids
174

Review questions
175
Glucagon
176
  • Epinephrine
  • glucocorticoids
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