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Chapter 8~9 Carbohydrate Metabolism

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Title: Chapter 8~9 Carbohydrate Metabolism


1
Chapter 89 Carbohydrate Metabolism
  • ???

2
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6.???(??) 7.???????????Cori cycle
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4
outline
  • Background
  • Glycolysis (Anaerobic Degradation)
  • Aerobic oxidation of glucose
  • The Pentose Phosphate Pathway
  • Glycogen Formation and Degradation
  • Gluconeogenesis

5
Background
  • Metabolism (Greek for change)
  • all the chemical and physical
    processes that take place in the body
  • Synthesis (anabolism)
  • A Glucose Glycogen
  • A FA Glycerol TG
  • A Amino Acids Protein

Macromolecules
A Requires Energy
A Energy is released
Breakdown (catabolism) A
Glycogen Glucose A TG Fatty
Acids Glycerol A Protein
Amino Acids
Small molecules
6
What are Carbohydrates?
  • Carbohydrates are aldehyde or ketone compounds
    with multiple hydroxyl groups
  • Empirical formula (CH2O)n, literally a carbon
    hydrate
  • CH2O make up 3 of the bodys organic matter

7
Functions of CH2O
  • Energy Source(66.8 kJ/1g carbohydrate)
  • Structural elements
  • Component of nucleic acids
  • Conversion to lipids and non-essential amino
    acids
  • .

8
Categories of Carbohydrates
  • Monosaccharides (Single sugar units) the
    smallest carbohydrates ,serve as fuel and carbon
    sources
  • Disaccharides (formed from 2 monosaccharides
    joined by a glycoside linkage)
  • Polysaccharides many monosaccharide units
    (starch, cellulose)

9
Monosaccharides
  • Glucose (C6H12O6) ???
  • -found in fruits, vegetables, honey
  • -blood sugar
  • -used for energy
  • Fructose ??
  • - Found in fruits, honey, corn syrup
  • -fruit sugar
  • Galactose ???
  • - Found as part of lactose in milk

Glucose (C6H12O6)
??
??
10
Disaccharides
  • Sucrose glucose fructose (brown sugar25 of
    sugar intake) ??
  • Maltose glucose glucose (honey) ???
    Natural Sweetness
  • Lactose glucose galactose (milk sugar least
    sweet) ??

??gt??gt???gt???gt???
Sucrose
Maltose
11
Polysaccharides
?? a-1,6-??? ?? a-1,4-???
starch

12
Section 1 Digestion of carbohydrates
Starch
Pancreatic amylase
13
BLOOD
Brush Border of the Mucosal Epithelium
stomach
Mouth
Starch
maltose
1
a-mylase
glucose
Glycogen
sucrose
2
fructose
lactose
3
galactose
galactose
glucose
Monosaccharides
fructose
no significant digestive enzymes present
Responsible for most of carbohydrate digestion
limited breakdown of starch and glycogen occurs
???? ??
14
Na dependent glucose Absorption and
transporter, GLT
facilitated diffusion
GLT
GLT
Nadependent co-transport
Intestinal Epithelial cell
15
Family of glucose transporters
Name Tissue location Km
Comments
GLUT1 All mammalian tissues 1mmol/L
Basal glucose uptake GLUT2 Liver
and pancreatic 1520mmol/L In the
pancreas,plays a role ?
cells
in regulation of insulin

In the liver, removes
excess

glucose from the blood GLUT3 All mammalian
tissues 1mmol/L Basal glucose
uptake GLUT4 Muscle and fat cells
5mmol/L Amount in muscle plasma

membrane
increases with

endurance training GLUT5 Small
intestine -
Primarily a fructose transporter
16
Not digested Dietary Fiber
  • Water insoluble fibers
  • - Cellulose, hemicellulose , pectins ??
  • Water soluble fiber
  • - beans, rice, carrots, fruits
  • - Obesity, diabetes, cancer
  • Recommended intake of fiber
  • 20-35 g/day insolublesoluble 31

17
Overview of carbohydrate metabolism
Glycogen
Glycogenesis
Glycogenolysis
UDPG
4
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5
G1P
glucose
G6P
6
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Anaerobic degradation (glycolysis)
Pyruvate
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1
Aerobic oxidation
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18
Section 2 Glycolysis (Anaerobic Degradation)
  • Glycolysis is derived from Greek words glycos
    (sugar, sweet) and lysis (dissolution)
  • The glycolytic pathway (Glucose to pyruvate) was
    elucidated by 1940, largely through the
    pioneering contributions of Gustav Embden. so
    glycolysis is also known as the Embden-Meyerhof
    pathway

19
Glycolysis ???
  • For glycolysis, the overall goal is to break the
    glucose molecule into smaller, more oxidized
    pieces
  • 11 steps metabolic pathway to convert 6 carbon
    glucose into 2 molecules of 3 carbon lactate
    ??and two molecules ATP (and NADH )
  • Occurs in cytoplasm
  • glycolysis has two stages
  • 1. glycolytic pathway (Glucose to pyruvate)
    ,including two phases
  • 2.Fermentation phase ?? (pyruvate to lactate)
  • Anaerobic
  • Does not REQUIRE oxygen
  • Occurs whether oxygen is available or not

20
glycolytic pathway breakdown of glucose to
yield energy and pyruvate
break C3-C4 bond
breakage of C3-C4 bond
21
glycolytic pathway has two phases
A. Energy investment phase (Reactions, 1-5)
Glucose(6C) is first phophorylated (thus
activated) and then cleaved to produce two
glyceraldehyde-3-phosphate(3C) intermediates. 2
ATPs are invested (the preparatory phase) B.
Energy payoff phase (Reactions 6-10) two
glyceraldehyde 3-phosphate intermediates are
oxidized, generating to two pyruvate plus four
ATP molecules
22
Energy investment phase
isomerase
Step 1. Hexokinase (1 ATP utilization)
Step 2. Phosphoglucose Isomerase (PGI)
Step 3. Phosphofructokinase -1 (PFK-1) (2 ATP
utilization)
23
energy investment phase
dihydroxyacetone phosphate
4. Aldolase
24
energy investment phase
dihydroxyacetone phosphate
Glyceraldehyde 3-PO4
TPI
isomerase
The isomerization of an aldose to a ketose
5. Triose Phosphate Isomerase (TIM or TPI )
25
energy investment phase
ATP
Hexokinase
ADP
Glucose 6-phosphate
Phosphogluco- isomerase
Uses 2 ATP
Fructose 6-phosphate
ATP
Phosphofructokinase
ADP
Fructose 1.6-bisphosphate
Aldolase
Glyceraldehyde 3-phosphate
Dihydroxyacetone phosphate
Triose phosphate isomerase
26
Energy payoff phase
(Reactions, 6-10)
Glyceraldehyde-3-PO4 dehydrogenase
Phosphoglycerate kinase
Where ?
27
Energy payoff phase
High energy
Low energy
28
Glyceraldehyde 3-phosphate
Glyceraldehyde
3-phosphate
dehydrogenase
1,3-Bisphosphoglycerate
ADP
Phosphoglycerate kinase
ATP
3-Phosphoglycerate
Phosphoglyceromutase
2-Phosphoglycerate
Enolase
H2O
Phosphoenolpyruvate
ADP
Pyruvate kinase
ATP
energy payoff phase
29
Energy payoff phase
Energy investment phase
30
Summary of Energy Relationships for glycolytic
pathway
  • Input 2 ATP
  • 1. glucose ATP ? glucose-6-P
  • 2. fructose-6-P ATP ? fructose 1,6
    bisphosphate
  • Output 4 ATP 2 NADH
  • 1. 2 glyceraldehyde-3-P 2 Pi 2 NAD?
  • 2 (1,3
    bisphosphoglycerate) 2 NADH
  • 2. 2 (1,3 bisphosphoglycerate) 2 ADP?

  • 2 (3-P-glycerate) 2 ATP
  • 3. 2 PEP 2 ADP ? 2 pyruvate 2 ATP
  • Net 2 ATP and 2 NADH

31
Fate of Pyruvate
  • Two anerobic pathways (Low O2 )
  •  - to lactate via lactate dehydrogenase in
    muscle
  • - to ethanol (fermentation) via ethanol
    dehydrogenase
  • Aerobic pathway through citric acid cycle and
    respiration Enough O2,this pathway yields far
    more energy
  • NADH O2 ? NAD energy
  • Pyruvate O2 ? 3CO2 energy

Oxygen availability determines fate of Pyruvate
32
The anaerobic fate of Pyruvate ( Reaction 11 of
glycolysis )
From?
  • Hydrogen at C4 of NADH is transferred to the
    pyruvate

uses up all the NADH (reducing equivalents)
produced in glycolysis
33
Energy Yield From Glycolysis
Overall process of anaerobic glycolysis in muscle
can be represented
The lactate, the end product, is exported from
the muscle cell and carried by the blood to the
liver, where it is reconverted to glucose
  • Glucose ---------6 CO2 -2840 kJ/mol
  • 2 ATPs produced 61 kJ/mol glucose
  • Energy yield 61/2840 2
  • in all high investment, low output

34
Summary of Glycolysis
6c?? 6c?3c ??? 3c-3c ??? 3c-3c
  • 11 steps Location cytosol
  • Original material glucose (C6H12O6)
  • End product lactate
  • - Twice substrate level phosphorylations
  • - Net of 2 ATP
  • d. Key enzymes Hexokinase (HK) energy
    investment phase
  • Phosphofructokinase 1 (PFK-1)
    energy investment phase
  • Pyruvate kinase (PK) energy payoff
    phase
  • e. Once dehydrogenation oxidation
  • Once hydrogenation reduction
  • No oxygen is required

35
The regulation of glycolysis
Hormone regulation Covalent regulation Allosteric
regulation
ATP
Glucagon
AMP
Adenylate cyclase
Citrate
cAMP
ADP
Glucose
ATP
Glucose 6-phosphate
ATP
F-6-P
F-2,6-BP
Phosphoprotein Phosphatase
PKA
ADP
Pi
glycolysis
ATP
PFK-1
Pi
ADP
F-1,6-BP
Lactate
AMP
Citrate
36
3. The significance of glycolysis
  • Glycolysis is the emergency energy-yielding
    pathway, such as play ball, climb mountain...
  • Glycolysis is the major way to produce ATP in
    some tissues, even though the oxygen supply is
    sufficient, such as RBC, retina, testis, skin

37
Section 3 Aerobic oxidation of glucose
  • The process of oxidation completely from glucose
    to CO2 and H2O is named aerobic oxidation
  • This process is the major process to provide
    energy for most tissues

38
3 phases of Glucose Aerobic oxidation
1. Oxidation from glucose to pyruvate in cytosol
(6C to 3C)
  • 2. Oxidation from pyruvate to acetyl CoA in
    mitochondria (3C to 2C)
  • 3. Tricarboxylic acid cycle and oxidative
    phosphorylation (2C to 1C)

O2
O2
H2O
O2
Acetyl CoA
H e
Glucose
G-6-P
CO2
Pyruvate
Pyruvate
cytosol
mitochondria
39
2. Oxidation from pyruvate to acetyl CoA (3C to
2C)
NADH
Pyruvate DH complex

CoASH
NAD
Acetyl-CoA a common two-carbon unit
PyruvateNADHSCoA
Acetyl CoANADHHCO2
40
Pyruvate dehydrogenase complex
E1. pyruvate dehydrogenase (??????) E2.
dihydrolipoyl transacetylase (??????????) E3.
dihydrolipoyl dehydrogenase (?????????)
41
Pyruvate dehydrogenase complex
42
3. Two stages of the 3rd phase of Glucose
Aerobic oxidation
  • Stage I The acetyl-CoA is completely oxidized
    into CO2, with electrons collected by NAD and FAD
    via a cyclic pathway (tricarboxylic acid cycle)
  • Stage II Electrons of NADH and FADH2 are
    transferred to O2 via a series carriers,
    producing H2O and a H gradient, which will
    promote ATP formation (oxidative phosphorylation)
  • (NEXT CHAPTER)

43
Tricarboxylic acid cycle (2C to 1C)
  • Citric Acid Cycle or Krebs cycle
  • Occurs in mitochondrial matrix
  • Is the biochemical hub of the cell, oxidizing
    carbon fuels, usually in the form of acetyl CoA,
    interconversion of carbohydrates, lipids, and
    some amino acids, as well as serving as a source
    of precursors for biosynthesis
  • For the citric acid cycle, the goal is to use the
    oxidative power of O2 to derive as much energy as
    possible from the products of glycolysis

44
Substrates required Oxaloacetic Acid
GDP 3NAD FAD two-carbon
units (Acetyl-CoA) Intermediate Reactants
Citric Acid
Each Acetyl-CoA yields 2 CO2, 3 NADH H, 1
FADH2, 1 GTP
Output Oxaloacetic Acid GTP 3 NADH
FADH2 2CO2 (4 high-energy electrons)
C6
C4
Tricarboxylic acid cycle
C5
C4
45
Stage I Tricarboxylic acid cycle
CoASH
2C
Citrate synthase

6 C
4C
Citrate
Oxaloacetic Acid
46
Aconitase
cis-aconitate intermediate
6 C
6 C
47
Isocitrate DH

NAD
NADH
5 C
a-ketoglutarate
6 C
Isocitrate
48
a-ketoglutarate DH

NAD, CoASH
NADH
5 C
4 C
Succinyl CoA
a-ketoglutarate
49
CoASH
SuccinylCoA synthetase

GTP
GDP, Pi
4C
4C
Succinyl CoA
50
(FADH2)

(FAD)
4C
fumarate
4C
51
H2O
4C
4C
fumarate
malate
52
malate DH

NAD
NADH
Oxaloacetic Acid
malate
4C
4C
53
citrate synthase
Tricarboxylic acid cycle
isocitrate dehydrogenase
?- ketoglutarate dehydrogenase
54
Aerobic oxidation of glucose
55
Generation of ATP in aerobic oxidation of
glucose
Reactions Catalyzed by
Methods of ATP production
formed moles of ATP
Glyceraldehyde 3-phosphate
dehydrogenase
6 or 4 /5 or 3
Respiratory chain Oxidation of 2 NADH
Glycolytic pathway
Phosphoglycerate kinase
Phosphorylation at substrate level
2
Pyruvate kinase
Phosphorylation at substrate level
2
consumption of ATP by reactions catalyzed by
hexokinase and phosphofructokinase
- 2
Production of acetyl CoA
Pyruvate dehydrogenase complex
Respiratory chain Oxidation of 2 NADH
6 or 5
Isocitrate dehydrogenase
Respiratory chain Oxidation of 2 NADH
6 or 5
Alpha-ketoglutarate Dehydrogenase complex
Respiratory chain Oxidation of 2 NADH
6 or 5
TCA cycle
Phosphorylation at substrate level
2
Succinyl CoA synthetase
Succinate dehydrogenase
Respiratory chain Oxidation of 2 FADH2
4 or 3
Malate dehydrogenase
Respiratory chain Oxidation of 2 NADH
6 or 5
Total per mole of glucose under aerobic
conditions 32 or 30(38 or 36) ATPs
56
Regulation of aerobic oxidation
pyruvate
Regulation of pyruvate dehydrogenase
C2
3 control points of citric acid
cycle citrate synthase isocitrate
dehydrogenase ?-ketoglutarate dehydrogenase
C6
C4
Iso C6
Krebs Cycle
C5
C4
57
Regulation of pyruvate dehydrogenase
Inhibited by products, NADH Acetyl CoA
Also regulated by covalent modification, the
kinase phosphatase also regulated
58
The Alosteric regulation of citric acid cycle
citrate synthase isocitrate dehydrogenase ?-
ketoglutarate dehydrogenase

Acetyl CoA
Oxaloacetate

ADP allosteric activator
NADH allosteric inhibitor
Allosteric inhibitor
4

GTP allosteric inhibitor

Succinate

GDP
GTP

59
Pastuer effect
  • The total amount of glucose consumed by yeast are
    about 7 times greater under anaerobic conditions
    than under aerobic conditions
  • This effect is also seen in muscle under
    anaerobic conditions
  • The yield of ATP under anaerobic conditions is 2
    per molecule but under aerobic conditions the
    yield is 38 ATP per glucose
  • Therefore, glucose flux through the pathway is
    regulated to achieve constant ATP levels or
    decided by the fate of NADHH
  • Crabtree effect

60
Section 4 The Pentose Phosphate Pathway (PPP)
  • The PENTOSE PHOSPHATE pathway ,by carring out
    oxidation and decarboxylation of the 6-C sugar
    glucose-6-P, is basically used for the synthesis
    of NADPH and 5-C sugar ribulose-5-P
  • It plays only a minor role (compared to
    GLYCOLYSIS) in degradation for ATP energy
  • Other names
  • Pentose phosphate Shunt
  • Hexose Monophosphate Shunt

61
Pentose phosphate pathway
  • Two stages
  • Oxidative portion (NADPH producing)
  • Non-oxidative (carbon recycling/unit
    transferring)
  • Location cytosol
  • Original material glucose 6-phosphate
  • End product NADPH , pentose phosphate
  • Important in adipose tissue, adrenal cortex,
    liver (biosynthesis), Important in red blood
    cells (antioxidant reasons)

62
STAGE I
(OxidationNADPH producing and formation of
pentose phosphate)
NADP
H2O
NADPH H
Lactonase
G-6-P dehydrogenase
6-Phosphoglucono-?- lactone
6-Phospho- gluconate
Glucose-6-PO4
G-6-P dehydrogenase Rate limiting step,
controlled by NADP levels Glucose-6-phosphate
Dehydrogenase catalyzes oxidation of the aldehyde
(hemiacetal), at C1 of glucose-6-phosphate, to a
carboxylic acid, in ester linkage (lactone).
NADP serves as electron acceptor
63
STAGE I
Ribose-5-PO4
Ribulose-5-PO4 (Ru5P)
5C
Ru5P isomerase
NADP
5C
NADPH H
Ru5P epimerase
6-phosphogluconate Dehydrogenase
6C
6-Phosphogluconate
5C
5-p-??? Xylulose-5-PO4
64
STAGE II ( Non-oxidativecarbon recycling)
5C
????? 2C Transketolase

5C
Xyulose-5-PO4
Ribose-5-PO4
7-p-??? Sedoheptulose-7-PO4
7C
3C
Glyceraldehyde-3-PO4
65
STAGE II ( Non-oxidativecarbon recycling)

3C
Glyceraldehyde-3-PO4
6C
Sedoheptulose-7-PO4
Fructose-6-PO4
7C
Transaldolase ????? 3C
4-p-??? Erythrose-4-PO4
4C
66
STAGE II ( Non-oxidativecarbon recycling)


Glyceraldehyde-3-PO4
3C
Erythrose-4-PO4
Xylulose-5-PO4
Fructose-6-PO4
4C
5C
6C
Transketolase
glycolysis
67
Pentose phosphate pathway
Glucose 6-P
6-Phosphogluconate
Ribulose 5-P (5C)
Xylulose 5-P ( 5C)
Ribose 5-P (5 C)
Glyceraldehyde 3-P
Sedoheptulose 7-P (7 C)
Glyceraldehyde 3-P (3C)
Fructose 6-P
Erythrose 4-P (4C)
Fructose 6-P (6C)
68
SUMMARY
C5 C5 ? C3 C7 (Transketolase) C3 C7 ?
C6 C4 (Transaldolase) C5 C4 ? C6 C3
(Transketolase) 3 C5 ? 2 C6 C3
(Overall)
  • Per glucose oxidized, 2 NADPHs are formed
  • C7?C4 are strictly intermediates
  • Glyceraldehyde-3-PO4 is both an intermediate and
    final product
  • Fructose-6-PO4 is never used as an intermediate,
    return to the glycolytic pathway

69
The significance of PPP
  • Produce ribose 5-phosphate
  • needed for DNA and RNA synthesis
  • 2. Generate reducing equivalents NADPH
  • 1) Reducing power for biosynthesis of fatty
    acids, cholesterol, folate, and so on
  • 2) Coenzyme of glutathione reductase to keep
    the normal level of reduced glutathione
  • 3) NADPH serves as the coenzyme of mixed
    function oxidases (mono-oxygenases)

70
Section 5Glycogen Biosynthesis and Degradation
  • Introduction
  • A constant source of blood glucose is an absolute
    requirement for life
  • - glucose is the preferred energy source
    for the brain and for cells with few or no
    mitochondria, such as mature erythrocytes
  • - glucose is an essential energy source in
    exercising muscle

71
What is Glycogen?
a-1,6-glycosidic linkage))
Reducing end
1. Glycogen is a highly branched homopolymer of
a-glucose (polysaccharide) 2. Approx. every 10
residues there is a branch, linked by an
a-1,6-glycosidic linkage
72
Glycogen Biosynthesis(Glycogenesis)
  • Glycogenesis the process of storing excess
    glucose as glycogen (In times of plenty the
    body needs to store fuel)
  • occurs in the cell cytoplasm of liver, muscle
    kidney, when blood glucose levels are high
  • Excess glucose is stored (limited capacity)
  • liver and muscle are major glycogen storage sites
  • liver glycogen used to regulate blood glucose
    levels
  • brain cells cannot live for gt 5 minutes without
    glucose
  • muscle glycogen used to fuel an active muscle
  • Glycogenesis involves addition of a-D-glucose
    residues to the C4 (non-reducing end) of an
    pre-existing chain

73
Requirement of formation glycogen
  • Glycogenin
  • glycogen synthase
  • glycogen-branching enzyme
  • UDP-glucose pyrophosphorylase

74
Requirement of Formation glycogen
  • Primer
  • glycogenin acts as the primer to which the first
    glucose residue is attached
  • glycogenin also catalyzes attachment of
    additional glucose units to form chains of up to
    eight units
  • Glycogen-branching enzyme
  • takes over at this point
  • chain cannot extend indefinitely

75
Requirement of Formation glycogen
  • Glycogen Synthase
  • exists in an active (dephosphorylated) and
    inactive (phosphorylated) form
  • relative amount of each form is regulated by
    cellular level of cAMP
  • cAMP is regulated by insulinglucagon ratio
  • High insulin keeps GS in dephosphorylated, active
    form
  • High insulin can also stimulate dephosphorylation
    of GS
  • High glucagon activates cAMP which activates PK
    which phosphorylates and inactivates GS
  • Glycogen Synthase reaction is primary target of
    insulins stimulatory effect on glycogenesis

76
Glycogenesis
glycogen primer
PPi
UTP
77
Glycogenesis
glycogen synthase
oligo ? 1,6-glucantransferase Debranching
glycogen synthase
oligo ? 1,6-glucantransferase Debranching
78
Glycogenolysis
  • Glycogenolysis glycogen ? glucose
  • In times of need the body needs to mobilize its
    fuel stores
  • Hepatic glycogen not sufficient during 12 hr fast
  • Glycogen degradation
  • Occurs in cytosol
  • Signal that glucose is needed is given by
    hormones
  • epinephrine stimulates glycogen breakdown in
    muscle
  • glucagon which stimulates glycogen breakdown in
    liver in response to low BG
  • used to sustain blood glucose level between meals
    and to provide energy during an emergency/exercise

79
phosphorylase a
Glycogenolysis
1,4 glucose 1-phosphate
phosphorylase a
glucan transferase
glucosidase
Debranching has two enzyme activities in one
peptide oligo -1,4 1,4-glucantransferase
and 1,6-glucosidase
1 glucose
?
?
?
phosphorylase a
12 glucose 1-phosphate
80
Glycogen Phosphorylase Regulation
  • Glycogen phosphorylase
  • exists in a b inactive form (dephosphorylated)
    and an a active form (phosphorylated)
  • phosphorylase kinase converts glycogen
    phosphorylase to active form a via addition of
    inorganic phosphate
  • phosphorylase kinase also exists in an active a
    and an inactive b form
  • activated by cAMP-dependent protein kinase it is
    also activated by calcium ions
  • PK is activated by glucagon and epinephrine
  • via 2nd messenger cAMP

81
Glycogen Phosphorylase Regulation
  • Glycogen phosphorylase a (active) is converted
    to b form by phosphoprotein phosphatase
  • Stimulated by insulin
  • Glycogen phosphorylase can also be regulated by
    allosterically
  • GP b inactive form can be converted to GP b
    active form by high AMP
  • GP b active form can be converted back to GP
    b inactive form by high ATP

82
Regulation of Glycogenesis and Glycogenolysis
83
The significance of glycogenesis and
glycogenolysis
- Liver glycogen (as much as 10 of liver wet
weight) functions as a glucose reserve for
maintaining blood glucose concentration - Muscle
glycogen (total 400 gram) serves as a fuel
reserve for synthesis of ATP within that tissue
84
Section 6 Gluconeogenesis
  • Synthesis of glucose from non-CHO precursors
  • Lactate, most amino acids and glycerol
  • Lactate and amino acids (except leucine and
    lysine) are converted to either pyruvate or OAA
    (oxalloacetate)
  • Glycerol is converted (phosphorylated) to G3P and
    then to dihydroxyacetone phosphate
  • Occurs primarily in liver, sometimes kidney

85
Ribose 5-PO4
Phosphatase
Blood Glucose
Glycogen
G6P
Glucose
Kinase
F6P
Kinase
Phosphatase
F1,6bisP
Gly-3-P
DHAP
1,3bisPGA
Gluconeogenesis
Kinase
3PGA
2PGA
PEP
Kinase
Pyruvate
OAA
L-lactate
86
Gluconeogenesis
  • Reversal of glycolysis except at 3 steps
  • HK(GK), PFK and PK
  • 3 Steps need to be bypassed
  • Hexokinase and Phosphofructokinase are bypassed
    by glucose 6 phosphatase and fructose
    1,6-bisphosphatase
  • Pyruvate Kinase bypass involves formation of OAA
    as an intermediate
  • OAA in mitochondrial matrix cannot directly cross
    membrane so is converted to malate

87
Gluconeogenesis
  • Bypass of PK reaction continued
  • Malate and aspartate can transverse mitochondrial
    matrix
  • converted back to OAA in cytoplasm
  • OAA is decarboxylated and phosphorylated to PEP
    by PEP carboxykinase
  • Carbon skeletons of many amino acids that enter
    TCA cycle can thus be used for glucose synthesis
    (glucogenic amino acids)

88
  • Bypasses in Gluconeogenesis-1 (2 reactions)
  • Pyruvate Carboxylase (Gluconeogenesis) catalyzes
  • pyruvate HCO3- ATP ? oxaloacetate ADP
    Pi
  • PEP Carboxykinase (Gluconeogenesis) catalyzes
  • oxaloacetate GTP ? PEP GDP CO2


Pyruvate Carboxylase PEP Carboxykinase
-
O
O
C
-
-
O
O
O
O
A
T
P


A
D
P


P
C
O
G
T
P


G
D
P
C
C


i
-
2
C
H
C
O
P
O
C
O
2
3
-
H
C
O
C
O
3
C
2
C
H
C
H
2
3
-
O
O
pyruvate oxaloacetate
PEP

89
Bypasses in Gluconeogenesis-2
glycolysis
Fructose 1,6 bi-sphosphatase
90
Bypasses in Gluconeogenesis-3
  • Glucose-6-Phosphatase (Gluconeogenesis)
    catalyzes
  • glucose-6-phosphate H2O ? glucose Pi

Glucose 6 phosphatase
91
Substrate cycle is a pair of opposed
irreversible reactions
Substrate cycle or futile cycle nothing is
accomplished but the waste of ATP. In substrate
cycle, ATP is formed in one direction and then is
hydrolyzed in the opposite direction. Substrate
cycle produces net hydrolysis of ATP We
must remember that the direction of the substrate
cycle is strictly controlled by allosteric
effectors to meet the needs of the body for
energy
92
Glucose Paradox
  • Evidence that glucose ingested during a meal is
    not used to form glycogen directly
  • Glucose is first taken up by RBCs in bloodstream
    and converted to lactate by glycolysis
  • Lactate is taken up by liver and converted to G6P
    by gluconeogenesis
  • G6P converted to glycogen

93
The significance of gluconeogenesis
  • To keep blood sugar level stable
  • To replenish liver glycogen
  • 3. To clear the products of other tissues
    metabolites from the blood
  • 4. To convert glucogenic amino acids to glucose
  • 5. To regulate acid-base balance

94
Cori Cycle(Muscles lack G6-phosphatase ) -
used to prevent high blood lactate levels and to
fuel muscle activity - l-actate leaves muscle
cells - transported via blood to liver -
liver converts to glucose - glucose released
back into circulation - returned to muscles
95
Regulation of gluconeogenesis and glycolysis
F-6-P
ATP citrate ADP AMP F-2,6-BP F-1,6-BP
phosphofructokinase-1
F-1,6-biphosphatase
F-1,6-BP
insulin
gluconeogenesis
glycolysis
pyruvate carboxylase
glucokinase
phosphoenolpyruvate carboxykinase
phosphofructokinase-1
fructose 1,6-biphosphatase
pyruvate kinase
glucose 6-phosphatase
glucagon
Glucocorticoids epinephrine
96
Section VII Blood Sugar and Its
Regulation
Fate (outcome)
Origin (income)
Dietary supply
Blood sugar 3.896.11mmol/L
Liver glycogen
Gluconeoesis (non-carbohydrate)
Other saccharides
97
Regulation of high Blood Sugar
4
1
2
3
5
5
glycogenolysis
6
2
98
Regulation of Low Blood Sugar
cAMP
Modulating system
1
1
2
3
3
4
99
????? ???
100
1. ???????????( )
A ???? B ????? C ????? D ???? E ????
101
2. ???????????,????( )
A ?????????? B ?????????? C ??????????? D
??????????????? E ?????????-1,6-???
102
3. ????????????????( )
A ??????-1 B ??????-1 C ??????? D ?????? E
??????-2
103
4. 1???????????????????????ATP??????( )
A 2 B 4 C 6 D 19 E 36
104
5. 1????CoA?????????????( )
A ??? B ???? C 2CO2 4?????? D CO2H2O E
????CO2
105
6. ??????????????????
A ?? B ??? C ??? D ??? E ????
106
7. ???????????????????
A ??? B ??? C ??? D ???? E ???
107
8. ?????????????( )
A ???????????? B ???????NADPHH C ??6-????? D
??3-????? E ??6-??????
108
9. ?????????????( )
A ?????????UDPG B ?1-????????????????? C
?????????????????? D ??????????-1,4?????????? E
??????????????C4?
109
10. ???????????????
A ?????? B ??????????? C ??????? D ?????? E
???6-???
110
11. Which one is the main organ that regulate
blood sugar metabolism?
A brain B kidney C liver D pancreas E
adrenal gland
111
12. The end product of glycolytic pathway in
human body is ( )
A CO2 and H2O B pyruvic acid C acetone D
lactic acid E oxalacetic acid
112
13. Which one can promote synthesis of glucogen,
fat and protein simultaneously?
A glycagon B insulin C adrenaline D adrenal
cortex hormone E glucocorticoid
113
14. Which one is the allosteric inhibitor of
6-phosphofructokinase-1?
A 1,6-diphosphofructose B 2,6
-diphosphofructose C AMP D ADP E citric acid
114
15. ????????,?????????
A ?????????? B ???1????????????2??ATP C
?????????? D ??????? E ?1???????2????
115
16. ??????,???????( )

A ??? ? ???? B ???? ? ?-???? C ?-???? ?
???CoA D ??? ? ???? E ??? ? ????
116
17. ?????????,???????( )
A ???? B ?????? C ????? D ?????? E ?????????

117
18. ??????????( )

A ?????????????? B ????????????? C ???????? D
?????? E ??????????
118
19. The cofactors of pyruvic dehydrogenase
complex is ( )

A thioctic acid B TPP C CoA D FAD E NAD
119
20. The high-energy compounds produced by
substrate level phosphorylation in glyco-aerobic
oxidation are ( )

A ATP B GTP C UTP D CTP E TTP
120
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