Chapter 4 Carbohydrate Metabolism

1
Chapter 4 Carbohydrate Metabolism

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2
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3
???????

• ?????glycolysis ???????????Pastuer effect???????
  ???????????gluconeogenesis?????Cori cycle ???
• ??????????(TCA cycle)????????????????glycogenesis?
  ??glycogenolysis??????????????????
• ??????????????

4
outline

• Introduction
• Glycolysis (Anaerobic Degradation)
• Aerobic oxidation of glucose
• The Pentose Phosphate Pathway
• Glycogen Formation and Degradation
• Gluconeogenesis

5
Definition of Metabolism

• 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
• A Requires Energy

Macromolecules
Breakdown (catabolism) A
Glycogen Glucose A TG Fatty
Acids Glycerol A Protein
Amino Acids A Energy is
released
Small molecules
6
1. What are Carbohydrates?

• Carbohydrates are aldehyde or ketone compounds
  with multiple hydroxyl groups
• Empirical formula (CH2O)n, literally a carbon
  hydrate
• CHO make up 3 of the bodys organic matter

7
Functions of CHO

• 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)
• Lactose glucose galactose (milk sugar least
  sweet)
• Maltose glucose glucose (honey)
• Natural Sweetness

Sucrose
Maltose
11
Polysaccharides
starch
CH2OH

12
Section 1Digestion of carbohydrates
Brush Border of the Mucosal Epithelium
BLOOD
Mouth
stomach
1
maltose
Starch
a -amylase
glucose
Salivary amylase Pancreatic amylase
Glycogen
2
sucrose
fructose
lactose
3
galactose
galactose
glucose
Monosaccharides
fructose
no significant digestive enzymes present
limited breakdown of starch and glycogen occurs
Responsible for most of carbohydrate digestion
13


Na


Glucose
Galactose
Fructose

also glucose,

Na
SGLT-1
GLUT-5

Lumen of intestine
Intestinal Epithelial cell


Brush border
Na




Na
Fructose
2K
ATP


3Na
2K


ADP Pi
2K
3Na


2K
3Na
to capillaries


facilitated diffusion
Na,K-ATPase


Na
-
dependent co-transport
Na dependent glucose Absorption and
transporter,SGLT
14
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
15
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

16
3. Overview of carbohydrate metabolism
Glycogen
G
l
y
c
o
g
e
n
e
s
i
s
G
o
l
y
s
i
s
U
D
P
G
G
-
1
-
P
glucose
Anaerobic degradation (glycolysis)
Aerobic oxidation
2

2
17
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

18
Glycolysis

• Where in cell ?
• What are the inputs ?
• What are the outcomes ?
• Oxygen required ?

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 each of and ATP
• Occurs in cytoplasm
• glycolysis has two stages glycolytic pathway
  (Glucose to pyruvate) 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
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
Fructose 6-phosphate
ATP
Phosphofructokinase
ADP
Fructose 1.6-bisphosphate
Uses 2 ATP
Aldolase
Glyceraldehyde 3-phosphate
Dihydroxyacetone phosphate
Triose phosphate isomerase
26
Energy payoff phase
(Reactions, 6-10)
Glyceraldehyde-3-PO4 dehydrogenase
Phosphoglycerate kinase
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
Overview of glycolytic pathway
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 )

• 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

• 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
4C
fumarate
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 38 or 36 (32 or 30) 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

60
Section 4 The Pentose Phosphate Pathway (PPP)
61
Pentose phosphate pathway

• 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

62
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)

63
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
64
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
65
STAGE II ( Non-oxidativecarbon recycling)
5C
????? Transketolase

5C
Xyulose-5-PO4
Ribose-5-PO4
7-p-??? Sedoheptulose-7-PO4
7C
3C
Glyceraldehyde-3-PO4
66
STAGE II ( Non-oxidativecarbon recycling)

3C
Glyceraldehyde-3-PO4
6C
Sedoheptulose-7-PO4
Fructose-6-PO4
7C
Transaldolase ?????
4-p-??? Erythrose-4-PO4
4C
67
STAGE II ( Non-oxidativecarbon recycling)


Glyceraldehyde-3-PO4
3C
Erythrose-4-PO4
Xylulose-5-PO4
Fructose-6-PO4
4C
5C
6C
Transketolase
glycolysis
68
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)
69
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
  finalproduct
• Fructose-6-PO4 is never used as an intermediate,
  return to the glycolytic pathway

70
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)

71
Section 5

• Glycogen Biosynthesis and Degradation

72
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

73
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
74
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

75
Requirement of formation glycogen

• Glycogenin
• glycogen synthase
• glycogen-branching enzyme
• UDP-glucose pyrophosphorylase

76
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

77
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

78
Glycogenesis
glycogen primer
PPi
UTP
79
Glycogenesis
glycogen synthase
oligo ? 1,6-glucantransferase Debranching
glycogen synthase
oligo ? 1,6-glucantransferase Debranching
80
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

81
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
82
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

83
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

84
Regulation of Glycogenesis and Glycogenolysis
85
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
86
Section 6

• Gluconeogenesis

87
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

88
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
89
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

90
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)

91

• 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

92
Bypasses in Gluconeogenesis-2
glycolysis
Fructose 1,6 bi-sphosphatase
93
Bypasses in Gluconeogenesis-3

• Glucose-6-Phosphatase (Gluconeogenesis)
  catalyzes
• glucose-6-phosphate H2O ? glucose Pi

Glucose 6 phosphatase
94
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
95
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

96
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

97
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
98
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
99
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
100
Regulation of high Blood Sugar
4
1
2
3
5
5
glycogenolysis
6
2
101
Regulation of Low Blood Sugar
cAMP
Modulating system
1
1
2
3
3
4
102
????? ???
103
1. ???????????( )
A ???? B ????? C ????? D ???? E ????
104
2. ???????????,????( )
A ?????????? B ?????????? C ??????????? D
??????????????? E ?????????-1,6-???
105
3. ????????????????( )
A ??????-1 B ??????-1 C ??????? D ?????? E
??????-2
106
4. 1???????????????????????ATP??????( )
A 2 B 4 C 6 D 19 E 36
107
5. 1????CoA?????????????( )
A ??? B ???? C 2CO2 4?????? D CO2H2O E
????CO2
108
6. ??????????????????
A ?? B ??? C ??? D ??? E ????
109
7. ???????????????????
A ??? B ??? C ??? D ???? E ???
110
8. ?????????????( )
A ???????????? B ???????NADPHH C ??6-????? D
??3-????? E ??6-??????
111
9. ?????????????( )
A ?????????UDPG B ?1-????????????????? C
?????????????????? D ??????????-1,4?????????? E
??????????????C4?
112
10. ???????????????
A ?????? B ??????????? C ??????? D ?????? E
???6-???
113
11. Which one is the main organ that regulate
blood sugar metabolism?
A brain B kidney C liver D pancreas E
adrenal gland
114
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
115
13. Which one can promote synthesis of glucogen,
fat and protein simultaneously?
A glycagon B insulin C adrenaline D adrenal
cortex hormone E glucocorticoid
116
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
117
15. ????????,?????????
A ?????????? B ???1????????????2??ATP C
?????????? D ??????? E ?1???????2????
118
16. ??????,???????( )

A ??? ? ???? B ???? ? ?-???? C ?-???? ?
???CoA D ??? ? ???? E ??? ? ????
119
17. ?????????,???????( )
A ???? B ?????? C ????? D ?????? E ?????????

120
18. ??????????( )

A ?????????????? B ????????????? C ???????? D
?????? E ??????????
121
19. The cofactors of pyruvic dehydrogenase
complex is ( )

A thioctic acid B TPP C CoA D FAD E NAD
122
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