Chap 4

1

• Chap 4
• Metabolism of Carbohydrates

2
Substance metabolism
3
Relationship of each metabolism
External substance ? internal subtance
Assimilation
Micromolecule?Biomacromolecule
Anabolism
Endergonic reaction
Metabolism
Substance metabolism
Energy metabolism
Exergonic reaction
Dissimilation
Biomacromolecule?Micromolecule
Catabolism
Internal substance ? External substance
4

• Definition of carbohydrate (saccharide)

Carbohydrates Carbohydrates are polyhydroxy
aldehydes or ketones, or substances that yield
such compounds on hydrolysis.
5

• classes and structure of carbohydrates

Carbohydrates are classified into four types
according to their hydrolysates

• monosaccharide
• oligosaccharide
• polysaccharide
• glycoconjugate

6

• monosaccharide
• Its the simplest of the carbohydrates that could
  not be
• hydrolyzed any more.

glucose (aldohexose)
fructose (ketohexose)
7
galactose ( aldohexose )
ribose (aldopentose)
8

• oligosaccharide
• Consist of short chains of monosaccharide units,
  or residues, joined
• by characteristic linkages called glycosidic
  bonds. The most abundant
• Are the disaccharides, with two monosaccharide
  units.

The common disaccharides
maltoseglucose glucose
sucroseglucose fructose
lactoseglucose galactose
9

• polysacchride
• The polysaccharides are sugar polymers containing
• more than 20 or so monosaccharide units, and some
• have hundreds or thousands of units.

The common polysaccharides

• starch

• glycogen

• cellulose

10

• Starch The most important storage
  polysaccharides are starch in plant cells

Starch granules
11

• Glycogen glycogen are stored forms of fuel in
  animal cells

12

• cellulose the skeleton of plants

ß1-4 linkage
13

• glycoconjugate
• the informational carbohydrate is covalently
  joined to a
• protein or a lipid to form a glycoconjugate,
  which is
• the biologically active molecule.

The common glycoconjugates
glycolipida compound that consists of a lipid
and a
carbohydrate glycoproteinhave one or several
oligosaccharides of
varying complexity joined covalently
to a protein.
14
Part I
Introduction
15
1. The main physiological function of
carbohydrate Oxidation of fuel

• The main function of carbohydrates is to provide
  
• your body with energy and carbon.

• Source of material for anabolism

e.g. Carbohydrate provides material for synthesis
of amino acid, nucleotide, coenzyme, fatty acid,
or other metabolic intermediate.

• Structural elements of cells and tissues

e.g. Carbohydrates are components of
glycoprotein, proteoglycans and glycolipids.
16
2. Digestion and absorption of carbohydrates

• Digestion of carbohydrates

For most humans, starch is the major source of
carbohydrates in the diet which including plant
starch, Animal glycogen, maltose, sucrose,
lactose and glucose.

• Digestion sitemost in the small intestine,
• some in the mouse

17

• Process of digestion

Starch
Oral cavity
a-amylase in saliva
Enteric cavity
a-amylase in pancreatic
Maltose maltotriose (40) (25)
a-limit dextrin isomaltose (30)
(5)
brush border of Intestinal epithelial cells
a-limit dextrinase
a-glucosidase
Glucose
18
Despite the fact that humans cannot digest
cellulose (lacking an enzyme to hydrolyze the (ß
1,4) linkages), cellulose is nonetheless a very
important part of the healthy human diet. This is
because it forms a major part of the dietary
fiber that we know is important for proper
digestion. Since we cannot break cellulose down
and it passes through our systems basically
unchanged, it acts as what we call bulk or
roughage that helps the movements of our
intestines.
19

• absorption of carbohydrates

• absorption position The upper small intestine

• Absorption Type monosaccharide

20

• Absorption mechanism

Mucosal cells of Intestinal
Portal
Lumen
K
ATP
ADPPi
Na
G
cellular inner membrane
Brush border
Na-dependent glucose transporter, SGLT
21
3.Overview of carbohydrate metabolism

• Glucose are transported into cells

This process is dependent on glucose transporter
(GLUT).
22

• Extracellular

Extracellular Polysaccharide and oligosaccharide

• intracellular

glycogen
Activation hydrolysis
Branched-chain break
Activation hydrolysis
23
The sources and outlet of blood glucose
Blood glucose
24
Part II
Glycolysis
25

• Glycolysis A process in which glucose is
  partially broken down to two molecules of
  pyruvate (it is converted into lactate finally )
  by cells in enzyme reactions that do not need
  oxygen. Glycolysis is also called anaerobic
  oxidation.
• Position of glycolysiscytoplasm

26
1. Glycolysis Has Two Phases

• Phase I------ glycolytic pathway The six-carbon
  glucose break down into two molecules of the
  three-carbon pyruvate.
• Phase II Pyruvate is converted to lactate.

27
Phase I------ glycolytic pathway The six-carbon
glucose break down into two molecules of the
three-carbon pyruvate
1. Phosphorylation of Glucose
28

• Hexokinase, which catalyzes the entry of free
  glucose into the glycolytic pathway, is a
  regulatory enzyme. There are four isozymes
  (designated I to IV). The predominant hexokinase
  isozyme of liver is hexokinase IV (glucokinase).
• Characteristic?Low affinity to glucose
• ?Regulated by
  hormone
• Glucokinase play a critical role in the
  maintenance of blood glucose and metabolism of
  carbohydrates.

29
2. Conversion of Glucose 6-Phosphate to Fructose
6-Phosphate
30
3. Phosphorylation of Fructose 6- Phosphate to
Fructose 1,6-Bisphosphate

• 6-phosphfructokinase-1

31
4. Cleavage of Fructose 1,6-Bisphosphate

• Aldolase

32
5. Interconversion of the Triose Phosphates
33
6. Oxidation of Glyceraldehyde 3- Phosphate to
1,3-Bisphosphoglycerate
34
7. Phosphoryl Transfer from 1,3- Bisphosphoglycera
te to ADP

• The formation of ATP by phosphoryl
• group transfer from a substrate such as
  1,3-bisphosphoglycerate
• is referred to as a substrate-level
• phosphorylation

35
8. Conversion of 3-Phosphoglycerate to
2-Phosphoglycerate
36
9. Dehydration of 2-Phosphoglycerate to
Phosphoenolpyruvate
37
10. Transfer of the Phosphoryl Group from
Phosphoenolpyruvate to ADP
38
Phase II Pyruvate is converted to lactate.
NADHH needed in this reaction is provided by
Oxidation of Glyceraldehyde 3-Phosphate in step 6
of glycolytic pathway.
39
Glycolysis
40
Summary of glycolysis

• Position of glycolysiscytoplasm
• Glycolysis is an anaerobic process through which
  ATP is synthesized .
• There are three irreversible steps in the process.

41

• Method and Quantity of energy-producing
• Method substrate-level Phosphorylation
• Quantity of ATPFrom G 22-2 2ATP
• From Gn 22-1
  3ATP
• Fates of lactate
• Lactate is released into blood and metabolized in
  liver
• Decomposition
• Cori cycle(glyconeogenesis)

42
Many hexose besides glucose meet their catabolic
fate in glycolysis, after being transformed into
hexosephosphate
43
2. Regulation of Glycolysis 3 key enzymes
Key Enzymes
Method of regulation
44

• 1.Phosphofructokinase-1 (PFK-1) is the most
• important enzyme to regulate the yield of
  glycolysis

• Allosteric regulation

• allosteric activatorAMP ADP
• 
  F-1,6-2P F-2,6-2P
• allosteric inhibitorcitrate ATP(High level)

45
ATP regulate the acitivity of Phosphofructokinase
-1 (PFK-1)
ATP binding site Regulation
substrate-binding site in active center (low level) activation
allosteric regulation site beside active center(high level) inhibition
46

• Fructose 2,6-bisphosphate regulate the activity
  of Phosphofructokinase-1 (PFK-1)

• Fructose 2,6-bisphosphate is the strongest
  allosteric activator of Phosphofructokinase-1
• When fructose 2,6-bisphosphate binds to its
  allosteric site on PFK-1, it increases that
  enzymes affinity for its substrate, fructose
  6-phosphate, and reduces its affinity for the
  allosteric inhibitors ATP and citrate.

47
Phosphoprotein phosphatase
F-6-P
PKA
ATP
PFK-1
ADP
PKAprotein kinase A
F-1,6-2P
48
Glucogen Fat
Protein
?
Glucose Fatty acie Glycerine
Amino acid
?
Acetyl-CoA
Oxaloacetate
Citrate
Malate
a-Ketoglutarate
?
Succinate
CO2
Oxidative phosphorylation
Succinyl-CoA
2H
ADPPi
ATP
49
2. Pyruvate kinase is the second regulation
point of glycolysis

• Allosteric regulation

• allosteric activatorF-1,6-2P
• allosteric inhibitorAlanine ATP.

50

• Covalent modification regulation

Pi
phosphoprotein phosphatase
Pyruvate kinase
Pyruvate kinase
(inactive)
(active)
ATP
ADP
PKAprotein kinase A
CaM calmodulin
51
3. Hexokinase is regulated by feedback suppression

• Except for liver glucokinase, hexokinase is
  suppressed by feedback of glucose 6-phosphate.
• Long-chain fatty acyl CoA is a allosteric
  inhibitor of glucokinase.
• Insulin promote the synthesis of glucokinase
  throuth inducing its transcription.

52
3. The main physiological function of
glycolysis provide energy quickly under
anaerobic conditions

• Glycolysis is an effective way to get energy
  under anaerobic conditions.
• The glycolytic breakdown of glucose is the sole
  source of metabolic energy in some mammalian
  tissues and cell types.

? Cells without mitochondriaerythrocytes
? Metabolic active cellsleucocyte?myeloid cell
53
Part III
Aerobic Oxidation of Carbohydrate
54

• Definition

The aerobic oxidation of carbohydrates is
referred to glucose is oxidized to H2O and CO2
under aerobic conditions. Its the main energy
supply mode. Positioncytoplasm and
mitochondria
55
1. There are four phases in the process of
aerobic oxidation of carbohydrates
G(Gn)
Phase IGlytolytic pathway
cytoplasma
Pyrutate
Phase IIOxidative decarboxylation
of pyruvate
Acetyl-CoA
Phase IIITAC cycle
mitochondria
Citrate
Phase IV Oxidative phosphorylation
TAC
O
H2O
ATP
ADP
56

• 1. Glucose break down into two molecules of the
  three-carbon pyruvate in glycolytic pathway

2. Pyruvate is oxidized to Acetyl-CoA and CO2 in
mitochondria

• Overall reaction

57

• The composition of pyruvate dehydrogenase complex

enzymes
Coenzymes
E1pyruvate dehydrogenase E2dihydrolipoyl
transacetylase E3dihydrolipoyl dehydrogenase
TPP lipoate( ) HSCoA FAD, NAD
58

• Oxidative decarboxylation of pyruvate to
  acetyl-CoA by the PDH complex.

1. Pyruvate reacts with the bound thiamine
pyrophosphate (TPP) of pyruvate
dehydrogenase (E1), undergoing decarboxylation to
the Hydroxyethyl derivative. 2. Form the
acetyl thioester-E2 of the reduced lipoyl
group. 3. The -SH group of CoA replaces the -SH
group of E2 to yield acetyl CoA and the
fully reduced (dithiol) form of the lipoyl
group. 4. Dihydrolipoyl dehydrogenase (E3)
promotes transfer of two hydrogen atoms
from the reduced lipoyl groups of E2 to the FAD
prosthetic group of E3, restoring the
oxidized form of the lipoyllysyl group of
E2. 5. The reduced FADH2 of E3 transfers a
hydride ion to NAD forming NADH.
59
1.Generation of ?-hydroxyethyl-TPP
CO2
2.Generation of Acyl lipoyllysine
NADHH
5. Generation of NADHH
NAD
CoASH
3.Generatin of Acetyl-CoA
4. Generation of lipoyllysine
60
2. TCA is a circulation response system based on
the formation of citric acid as starting material

• overview

• Tricarboxylic Acid Cycle (TAC) is also named
  citric acid cycle,because the first intermediate
  product is citric acid containing three
  carboxylor, or the Krebs cycle (after its
  discoverer, Hans Krebs).

• Position of reaction mitochondria

61
1. The Citric Acid Cycle Has Eight Steps

• 1. The condensation of acetyl-CoA with
  oxaloacetate to
• form citrate.
• 2. Formation of Isocitrate via cis-Aconitate.
• 3. Oxidation of Isocitrate to a-Ketoglutarate and
  CO2.
• 4. Oxidation of a-Ketoglutarate to Succinyl-CoA
  and
• CO2.
• 5. Conversion of Succinyl-CoA to Succinate.
• 6. Oxidation of Succinate to Fumarate.
• 7. Hydration of Fumarate to Malate.
• 8. Oxidation of Malate to Oxaloacetate

62
?
?
NADHH
?
NAD
?citrate synthase
?
?aconitase
?isocitrate dehydrogenase
?a-ketoglutarate dehydrogenase complex
NAD
?succinyl-CoA synthetase
?succinate dehydrogenase
NADHH
?
?fumarase
?
?malate dehydrogenase
FADH2
NAD
?
FAD
GDPPi
?
NADHH
GTP
?
63

• ? Formation of Citrate

Inreversible reaction
64

• ? Formation of Isocitrate

65

• ? Oxidation of Isocitrate to a-Ketoglutarate
  

Mg2
Inreversible reaction
66

• ?Oxidation of a-Ketoglutarate to Succinyl-CoA
  

Inreversible reaction
67

• ?substrate-level phosphorylationConversion of
  Succinyl-CoA to Succinate

The only substrate-level phosphorylation reaction
which produced GTP in TAC
68

• ? Oxidation of Succinate to Fumarate

69

• ?Hydration of Fumarate to Malate

70

• ?Oxidation of Malate to Oxaloacetate

71
Summary

• Definition of TACAcetyl-CoA entered the cycle by
  combining with oxaloacetate to form citrate
  containing three carboxyls. Two carbon atoms
  emerged from the cycle as CO2 from the oxidation
  of isocitrate and a-ketoglutarate. The energy
  released by these oxidations was conserved in the
  reduction of three NAD and one FAD and the
  production of one ATP or GTP. At the end of the
  cycle a molecule of oxaloacetate was regenerated.
• Position of TAC reaction mitochondria

72
Four dehydrogenation
One substrate level osphorylation
TAC
Three key enzymes
Two decarboxylation

• One substrate level prosphorylation?
• Two decarboxylation?
• Three key enzymes?
• Four dehydrogenation

73

• Highlight of TAC

• Following a cycle
• Consumption one Acetyl-CoA
• Undergo four dehydrogenation,two
  decarboxylation,
• one substrate level
  prosphorylation
• Generation one FADH2,three NADHH,two CO2,
• one GTP
• Key enzymecitrate synthase, isocitrate
  dehydrogenase,
• a-ketoglutarate
  dehydrogenase complex.

• The whole cycle reaction is irreversible.

74

• intermediate product of TAC

• The intermediate products of TAC performed as a
  catalyst without change of its quantity.
  Oxaloacetate or other intermediate products can
  neither be synthesized directly from Acetyl-CoA,
  nor be oxidized directly to CO2 and H2O in TAC.

75
Apparently, Oxaloacetate which does not be
consumed in TAC could be used in recycling. In
fact
?. Various metabolic pathways and their
regulation in organism are linked and interacted
each other. Some intermediate products of TAC
could integrate metabolism of carbohydrate and
other material by converted into other
substances.
e.g.
76
Oxaloacetate must be replenished continuously
?. When the carbohydrate supply is insufficient,
it may cause circulatory disturbance of TAC. So
Acetyl-CoA could by generated by pyruvate which
is formed through the decarboxylization of malate
or Oxaloacetate.
77

• The source of oxaloacetate

78
3. Aerobic oxidation of carbohydrate is the main
method to get ATP of organism.
In oxidative phosphorylation, passage of two
electrons from NADH to O2 drives the formation of
about 2.5 ATP, and passage of two electrons from
FADH2 to O2 yields about 1.5 ATP.
79
Phase I (Cytoplasma)
Phase II (Mito matrix)
Phase III (Mito matrix)
80

• Aerobic oxidation of carbohydrate is the main
  method to get ATP of organism. The generation of
  energy is not only efficient but also gradually
  in this way. The energy of oxidations in the
  cycle is efficiently conserved by the formation
  of ATP.

81
TCA cycle has important physiological
significance in the metabolism of three major
nutrients

1. TCA cycle is the last metabolic pathway of three
   nutrients to provide reducing equivalents for the
   generation of ATP in oxidative phosphorylation
   through four dehydrogenations.
2. TCA cycle is a key point to communicate the
   metabolism of protein, carbohydrate and fat.

82
Glucogen Fat
Protein
?
Glucose Fatty acie Glycerine
Amino acid
?
Acetyl-CoA
Oxaloacetate
Citrate
Malate
a-Ketoglutarate
?
Succinate
CO2
Oxidative phosphorylation
Succinyl-CoA
2H
ADPPi
ATP
83
4. The regulation of aerobic oxidation of
carbohydrate is dependent on the requirement of
energy.
? Glycolytic pathway
Hexokinase pyruvate kinase Phosphofructokinase-1
Key Enzyme
? oxidative decarboxylation of pyruvate
Pyruvate dehydrogenase complex
citrate synthase a-ketoglutarate dehydrogenase
complex isocitrate dehydrogenase
? TCA cycle
84

• The regulation of Pyruvate dehydrogenase complex

• allosteric regulation

allosteric inhibitorAcetyl-CoANADHATP allosteri
c activatorAMPADPNAD
this enzyme activity is turned off when ample
fuel is available in the form of fatty acids and
acetyl-CoA and when the cells ATP/ADP and
NADH/NAD ratios are high.
85

• Covalent modification

glucagon
86
TCA cycle is regulated by substrate, products and
the activity of key enzymes.

• Three factors govern the rate of flux through the
  cycle substrate availability, inhibition by
  accumulating products, and allosteric feedback
  inhibition of the enzymes that catalyze early
  steps in the cycle.

87
1.There are three key enzymes in TCA cycle

• citrate synthase,
• Isocitrate dehydrogenase
• a-ketoglutarate dehydrogenase

88

• The regulation of TAC

Citrate
? Effect of ATP?ADP
citrate synthase
? inhibition by accumulating products
isocitrate dehydrogenase
?allosteric feedback inhibition of the enzymes
that catalyze early steps in the cycle.
Ca2
a-ketoglutarate dehydrogenase complex
? others,e.g. Ca2 activate enzymes
89
2.The rates of TCA cycle and the other reactions
of its upstream or downstream are integrated.

• Under normal conditions, the rate of glycolysis
  is matched to the rate of the citric acid cycle
  not only through its inhibition by high levels of
  ATP and NADH, which are common to both the
  glycolytic and respiratory stages of glucose
  oxidation, but also by the concentration of
  citrate which play a allosteric inhibition to
  PFK-1.
• The rate of oxidative phosphorylation play an
  important role in the progress of TCA cycle.

90
Because the activity of many enzymes in the
progress of oxidative phosphorylation is
regulated by the rates of ATP/ADP or ATP/AMP in
cells.
In vivo ATP concentration is 50 times of AMP.
After above reaction, the change of ATP/AMP are
much bigger than the change of ATP,it played an
effective regulation by signal amplification
91
5. The inhibiting effect of oxygen on the process
of fermentation

• Definition

Pasteur effect The inhibiting effect of oxygen
on the process of fermentation.

• Mechanism

• Under aerobic conditions, NADHH and pyruvate
  enter into the mitochondria, then enters the
  citric acid cycle, where it is completely
  oxidized.
• Under anaerobic conditions, pyruvate is reduced
  to lactate, accepting electrons from NADH and
  thereby regenerating the NAD necessary for
  glycolysis to continue.

92
Part IV
Other Metabolism Pathways of Glucose
93
1.Pentose phosphate pathway produces pentose
phosphates and NADPHH

• Definition

Pentose phosphate pathway is the progress of
glucose produces pentose phosphates and NADPHH,
then the pentose phosphates is converted into
Glyceraldehyde 3-phosphate and fructose
6-phosphate.
94

1. The progress of pentose phosphate pathway has two
   phases

• PositionCytosol

• The reaction has two phases

• Phase I The Oxidative Phase

Produces Pentose Phosphates, NADPHH and CO2

• Phase IIThe Nonoxidative Phase

Including a series of group transfer.
95
1.glucose 6-phosphate undergoes oxidation and to
form the pentose phosphates and NADPH
glucose 6-phosphate dehydrogenase
6-phosphogluconate dehydrogenase
96
NADP
NADPHH
NADP
NADPHH
Ribose 5-phosphate
G-6-P
CO2

• The glucose 6-phosphate dehydrogenase which
  catalyze the first step is the key enzyme of the
  pathway.
• H produced in two dehydrogenations were accepted
  by NADP to generate NADPH H .
• ribose phosphate generated in reaction is a very
  important intermediated product.

97
2.Enter the glycolysis by the group transfer
reaction

• The significance of phase II is the
  transformation of ribose to fructose
  6-phospherate and Glyceraldehyde 3-phosphate by a
  series of group transfer reaction, then enter the
  glycolysis. So, pentose phosphate pathway is also
  named pentose phosphate shunt.

98
Ribulose 5-phosphate (C5) 3
Ribose 5-phosphate C5
99
pentose phosphate pathway
Phase I
Phase II
100

• reaction formula

101
Characteristic of pentose phosphate pathway

• Hydrogen receptor of dehydrogenation is NADP ,
  to generate NADPHH?
• Transaldolase and transketolase catalyze the
  interconversion of three-, four-, five-, six-,
  and seven-carbon sugars, with the reversible
  conversion of six pentose phosphates to five
  hexose phosphates.
• The reaction provides specialized intermediated
  product ribose 5-phosphate.
• One CO2 and two NADPHH were generated by one
  G-6-P through one decarboxylation and two
  dehydrogenation in a cycle.

102

• 2. The pentose phospherate pathway is
• regulated mainly by the ratio of NADPH/NADP

• Glucose-6-phosphate dehydrogenase is the key
  enzyme of the pentose phosphate pathway, the
  activity of this enzyme decide the flow of
  glucose-6-phosphate which enter the pathway.
• The G-6-P-D is inhibited by a high ratio of
  NADPH/NADP and increased consumption of NADPH .
• Therefore, the flow of pentose phospherate
  pathway meets the needs of the cells for NADPH.

103

• 3. the significance of pentose phospherate is the
• generation of NADPH and ribose 5-phosphate

1.Provide ribose for biosynthesis of nucleotides.
2.Provide NADPH as hydrogen donor to participate
in various metabolic reactions
(1)NADPH is the hydrogen donor in various
anabolic (2)NADPH participate the hydroxylation
in vivo. (3)NADPH could keep the regeneration of
reduced glutathione (GSH).
104
oxidized glutathione
Reduced glutathione

• Reduced glutathione is an important antioxidant
  which protect protein or enzyme with SH group
  from the damage of oxidizing agents and peroxide
  in vivo.
• Reduced glutathione maintains the integrity of
  erythrocytes membrane.

105

• Favism
• some people are Glucose 6-Phosphate
  Dehydrogenase (G6PD) deficient. their
  erythrocytes will lyse after ingestion of the
  beans (containing divicine or other oxidizing
  agents), releasing free hemoglobin into the blood
  (acute hemolytic anemia).
• G6PD deficiency is a X-linked recessive
  genetic disease. X-linked diseases usually occur
  in males. Males have only one X chromosome. A
  single recessive gene on that X chromosome will
  cause the disease. The geographic distribution of
  G6PD deficiency is instructive. It is common in
  the South than in the northern population

106
Part V
Glycogenesis and Glycogenolysis
107
Structure of glycogen
shapebranched polymer
MW1,000,000 10,000,000
Reducing endone
Nonreducing endspoly
108
Distribution of glycogen
Hepatic glycogen the glycogen content of the
liver is up to 8 of the fresh weight.
Muscle glycogen the glycogen concentration
in muscle is 1-2.
Back
109
1. Most anabolism of glycogen occurred in liver
and muscle.

• Definition
• The synthesis progress of glycogen from
  monosaccharide is named glycogenesis.

• Monosaccharide
• Glucose (main), fructose, galactose

• Position
• Cytoplasma of liver, muscle

110
Glucose is converted to glucose 6-phosphate
ATP
Mg2
Glucokinase
111
Glucose-6-phosphate is isomerized to
glucose-1-phosphate
112
The generation of UDP-glucose
UDPG pyrophosphorylase
urdine
H2O
2Pi
UTP G-1-P UDPG PPi
113
The glucose in UDPG is attached to glycogen
primer
urdine
Glycogen synthase
UDP
Gn (glycogen)
114
The branching enzyme catalyze the formation of
new branches on glycogen
1218G
115
Scheme of the synthesis of glycogen
glucose
UTP
PPi
UDPG
Glycogen primer
Energy consumption need primer nonreducing end
UDP
Glycogen (1?4 glucose unit)
Branching enzyme
Back
116
2. The production of glycogen degradation
glucose could replenish the blood glucose

• Glycogen-degrading
• The progress that glycogen is degraded to
  glucose.

• Position
• Liver

• Production
• Glucose

117
Glycogen is phosphorolytic cleavaged to G-1-P
? ?
Gn
H3PO4
Rate-limiting enzyme
PHOSPHORYLASE
118
Nonreducing end
phosphorylase
Pi
Glucose-1-phospherate
119
The function of debranching enzyme
Debranching enzyme
Debranching enzyme has two activities a-1,4-
transglycosylase a-1,6- glycosidase
Debranching enzyme
120
G-1-P is converted to G-6-P
121
G-6-P is hydrolyzed to Glucose
Glucose -6 - phosphatase (liver)
This enzyme is deficient in brain and muscle
122
Scheme of the glycogen-degradation
Glycogen Gn1
Pi
phosphorylase
Gn
G-1-P
G-6-P
H2O
Glucose-6-phosphatase
Pi
Glucose
123
The synthesis and degradation of glycogen
glycogen Gn1
UDP
Glycogen Primer Gn
G-1-P
G-6-P
ADP
ATP
Glucose
124

• The synthesis and degradation of glycogen

125
Comparison of liver glycogen and muscle glycogen
liver glycogen Muscle glycogen
Storage 90-100g 200-500g
5 1-2
Raw material Monosaccharide/no-carbohydrate material Glucose
cleavage product Glucose lactate
function To maintain relatively stable of blood glucose To meet the energy requirement of muscles in strenuous exercise
consumption 12-18h after meal After heavy exercise
126
?.????????????????
3. Glycogen synthesis and glycogen degradation
are regulated by each other
Key enzyme of glycogen degradation
Key enzyme of glycogen degradation
phosphorylase
phosphorylase
P
P
127
Hormone regulate the metabolism by cAMP-protein
kinase
Cell membrane
Receptor
Protein kinase(active)
Protein kinase (inactive)
Unphosphorylated Protein kinase
covalent modification
Phosphorylation of integral protein
Change the process of physiology in cells
Cell membrane
128
Hormone regulate the synthesis and degradation
of liver glycogen
Adrenalin/Glucagon
Adrenalin/Glucagon
1?adenylcyclase(inactive)
1
adenylcyclase(active)
2?ATP
cAMP
R?cAMP
3?protein kinase(inactive)
Signifiance because the covalent modification of
enzyme is a enzymatic reaction, a little signal
(hormone) could make a large number of enzymes to
be modified through accelerating this enzymatic
reaction, then the signal is amplified. Such
regulation is quickly and efficiently
Protein kianse(active)
4
4?phosphorylase kinase(inactive)
Phosphorylase kinase(active)
5
5?phosphorylase b(inactive)
Phosphorylase a(active)
6
?108
6?glycogen
Glucose
G-1-P
blood
glucose
G-6-P
129
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130
Glucagon and adrenalin regulate the synthesis and
degradation of glycogen
Glucagon, adrenalin
Cascade amplification effect
??
131
The regulation of synthesis and degradation of
liver glycogen

• allosteric regulation
• G is an allosteric effector ? phosphorylase (a)
• The allosteric enzyme is susceptible to be
  inactive through dephosphorylation catalyzed by
  phosphoprotein phosphatase.
• Meanwhile, the glycogen synthase is activated
  through dephosphorylation catalyzed by
  phosphoprotein phosphatase.
• ResultG ?,the synthesis of glycogen?,the
  degradation
• of glycogen?

When the blood glucose increase
132
The synthesis and degradation of muscle glycogen

• Synthesis same to liver glycogen (without
  three-carbons pathway)
• Degradation different to liver glycogen,
  (without G6PE)
• glycogen?G-6-P ?glycolytic pathway
• Regulationadrenalin (mainly)
• AMP allosteric activate
  phosphorylase-b
• ATP and G-6-Pinhibit phosphorylase-b
  
• G-6-P allosteric activate
  glycogen synthase

133

• Summary of regulation

• There are two forms (active or inactive) of all
  key enzymes, the two kinds of forms could change
  in each other by phosphorylation and
  dephosphorylation.

• Bidirectional regulationsynthase and lytic
  enzyme were regulated separately. e.g. enhance
  the synthesis and decrease the degradation.

• Duel regulationallosteric regulation and
  covalent modificational regulation.

• There are cascade effect on the regulation of kcy
  enzyme.

• Difference of regulation on the liver and muscle
  glycogen e.g. glucagon degrade the liver
  glycogen,
• adrenalin degrade the muscle
  glycogen.

134

• 3. deficiencies of glycogen degrading enzymes
  lead to glycogen storage disease

glycogen storage diseases is an inherited
metabolism disease. Deficiencies of
glycogen-degrading enzymes usually lead to
accumulation of glycogen in the liver or other
organs.
135
Glycogen storage diseases
Type Enzyme deficiency Organ affected Structure of glycogen
? G-6-P Liver, kidney normal
? a1?4 or 1?6 glucosidase All organs normal
? Debranching enzyme Muscle, liver More branch,short peripheral carbs chain
? Branching enzyme All organs Less branch,long peripheral carbs chain
? Muscle phosphorylase muscle normal
? Liver phosphorylase Liver normal
? phosphofructokinase Muscle, erythrocyte normal
? Phosphorylase kinase Liver normal
136

• Part VI

Gluconeogenesis
137

• Definition

Gluconeogenesis is the synthesis progress of
glucose or glucogen from non-carbohydrate sources.

• Position

Cytoplasma and mitochondria of liver , kidney
cells.

• Substrance

Pyruvate, lactate, glycerine, glycogenic amino
acid.
138
1. Gluconeogenic pathway is not a reversible
reaction of glycolytic pathway completely
gluconeogenic pathway is the synthesis progress
of glucose from pyruvate.

• Progress

• Most reactions of gluconeogenic pathway and
  glycolytic pathway are shared and reversible.

• Three irreversible reactions catalyzed by three
  key enzymes in glycolysis must by bypassed in
  gluconeogenesis.

139
1. Pyruvate is converted to PEP by pyruvate
carboxylation bypass
oxalacetate
Pyruvate
PEP
? pyruvate carboxylase, coenzyme is biotin (in
mitochondria).
? PEP-carboxykinase ( mitochondrion, cytoplasma)
140
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141

• Oxaloacetate export to the cytosol from
  mitochondria

Out mitochondria
Malate
In mitochondria
Aspartate
Aapartate
Oxaloacetate
oxaloacetate
142
cytoplasma
mitocondria
Pyruvate
143

• The resource of NADHH in glyconeogenesis

The generation of glyceraldehyde-3-phosphate from
1,3-bisphosphoglycerate need NADHH in
glyconeogenesis.

• NADHH is provide from latate when the latate
  is the resource of glyconeogenesis.

LDH
pyruvate
Latate
NAD
NADHH
144

• If amino amid is the resource of glyconeogenesis,
  NADHH come from mitochondria where NADHH are
  derived from ß- oxadation of fatty acid or TAC.
  The transport of NADHH dependent on the
  conversion of oxaloacetate and malate.

oxaloacetate
oxaloacetate
Malate
Malate
NAD
NADHH
NAD
NADHH
cytoplasma
mitochondria
145
2. Conversion of Fructose 1,6-Bisphosphate to
Fructose 6-Phosphate
3. Conversion of Glucose 6-Phosphate to Glucose
146

• A set of forward and reverse reactions catalyzed
  by different enzymes are called substrate cycle.
  If the two kinds of enzyme activity is equal, the
  results of the cycle are that ATP energy is
  depleted, heat is produced and no net
  substrate-to-product conversion is achieved, so
  it is also called futile cycle. The two-enzyme
  cycle thus provides a means of controlling the
  direction of net metabolite flow.

147
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148
The non-carbs substances enter the
gluconeogenesis

• The substances of gluconeogenesis is converted to
  the intermediate products of carbohydrates
  metabolism.

-NH2
Glucogenic amino acid
a-oxoacid
Phospho dihydroxyacetone
Glycerine
a-phosphoglycerol
2H
Pyruvate
lactate

• Above intermediate products enter the
  gluconeogenesis pathway and generate to glucose
  or glycogen.

149
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150

• Question about TAC

• The intermediate products of TAC performed as a
  catalyst without change of its quantity.
  Oxaloacetate or other intermediate products can
  neither be synthesized directly from Acetyl-CoA,
  nor be oxidized directly to CO2 and H2O in TAC.

151
2. Glycolysis and Gluconeogenesis Are Regulated
Reciprocally through two substrate cycle.

• Glycolysis and gluconeogenesis are the two
  metabolic pathways in opposite direction. If the
  gluconeogenesis from pyruvate is carried out
  effectively, the glycosis must be inhibited. And
  vice versa.
• This coordination is dependent on the regulation
  of the two substrate cycle in pathway.

152
1. The first substrate cycle between
fructose-6-phosphate and Fructose
1,6-bisphosphate
153
2. The second substrate cycle between PEP and
pyruvate
PEP
Fructose 1,6-bisphosphate
ADP
Pyruvate kinase
oxaloacetate
ATP
alanine
Pyruvate
Acetyl-CoA
154
3. The physiological significance of
gluconeogenesis is to maintain the stable of
blood glucose.
1. The main function of gluconeogenesis
maintain the stable of blood glucose

• The maintenance of stable blood glucose is
  dependent on the gluconeogenesis from amino acid,
  glycerine when fasting or starvation.
• Under normal conditions, brain utilized energy
  derived from glucose because brain cells could
  not take energy from fatty acid erythrocytes get
  the energy through glycolysis totally in the
  absence of mitochondria and, bone marrow, nerves
  tissure are used to take glycolysis because of
  their active metabolism. Above mentioned glucose
  are generated through the gluconeogenesis.

155
The substrate of gluconeogenesis are lactate,
amino acid and glycerine.

• Lactate come from the muscle glycogenolysis
  related with exercise intensity.
• Amino acid and glycerine are the substrate of
  gluconeogenesis when in hungry.

156
2. Gluconeogenesis is an important pathway to
replenish and restore the storage of liver
glycogen
C3 pathway After meal, most glucose is broken
down to lactate or pyruvate which contain three
carbons outside the liver cells, then these C3
substrates enter the liver cells and generate to
glucogen by gluconeogenesis.
157
3. The enhance of renal gluconeogenesis is
helpful to the maintenance of acid-base balance

• Under long-term fasting and starve conditins, the
  renal gluconeogenesis is enhanced which is
  helpful to the maintenance of acid-base balance.
• The reason of this change maybe the metabolic
  acidosis
• pH?? PEP-carboxykinase??Gluconeogenesis?
• After aketoglutarate is consumed in
  glycolysis, the deamination of glutamine and
  glutamic acid will be enhanced. NH3 in renal
  tubular cells are excreted and bound with H in
  urine to decrease the H. This is good for the
  excreting of H and retention of Na to protect
  from acidosis.

158
4. Lactate cycle

• In muscle lactate can by produced by glycolysis.
  Gluconeogenic capacity of muscle is very low, so
  lactate diffused into blood and transported to
  the liver. In the liver, glucose is synthesized
  from lactate by gluconeogenesis. After glucose is
  released into blood, it can be taken up by
  muscle, which formed a cycle named Lactate cycle
  or Cori cycle.
• Because the enzymes in the liver and muscle are
  different, they could contribute to the formation
  of lactate cycle.

159

• Lactate cycle (Cori cycle)

Glucose
glucose/muscle glycogen
Glucose
gluconeogenesis
glycolysis
Pyruvate
Pyruvate
NADH
NADH
NAD
NAD
Lactate
Lactate
Lactate
Blood
Liver
muscle
Active gluconeogenesis With G-6-P
?
?
?
Low gluconeogenesis Without G-6-P
?
160

• Lactate cycle consumes energy

• 6 ATP are needed when 2 lactate are generated to
  1
• glucose.

• Significance

• Avoid waste of lactate

• Protect from acidosis caused by accumulation of
  lactate

161
Part VII
Metabolism of Other Monose
162

• Fructose, galactose and mannose enter the
  glycolysis through converting into intermediate
  products of glycolytic pathway.

163
Part VIII
The Definition, Level and Regulation of Blood
Glucose
164

• The definition and level of blood glucose

• Blood glucose the glucose in the blood

• The level of blood glucose

Normal blood glucose 3.896.11mmol/L
165

• The physiological significance of the
  maintenance of blood glucose level

Ensure the energy supply of some important
organs, especially the organs which is dependent
on glucose energy supply.

• The brain depend on glucose because they cannot
  oxidize alternative fuels.
• Erythrocytes depend on glycolysis because they
  have no mitochondria.
• Bone marrow and nerve tissue are used to utilized
  glucose because their active metabolism.

166
1. The resource and outlet of blood glucose is
relative balanced.
Blood glucose
167
2. The level of blood glucose is mainly regulated
by hormone

• The maintenance of stable levels of glucose in
  the blood is one of the most finely regulated
  homeostatic mechanisms that involves the liver,
  extrahepatic tissues, and several hormones.
• Different metabolic pathways among different
  organs could be regulated coordinately to meet
  the variable needs of body, it depend on the
  regulation of hormone.
• The key enzymes involved in glucose metabolisms
  are regulated by different kinds of hormone.

168
Decrease blood glucoseinsulin
The hormones regulate blood glucose
Increase blood glucose
glucagon glucocorticoids epinephrine
169
1. Insulin is the only hormone which can decrease
blood glucose.

• Insulin is the only hormone which can decrease
  blood glucose and promote synthesis of glycogen,
  lipids, and proteins.
• Insulin is released in response to hyperglycemia.

170

• Mechanism of insulin

1. Insulin enhance glucose transport into adipose
   tissue and muscle by recruitment of glucose
   transporters from the interior of the cells to
   the plasma membrane.
2. Insulin reduces the cAMP level in the liver by
   activating a cAMP-degrading phosphodiesterase. By
   stimulating the glucose-consuming pathways and
   inhibiting the glucose-producing pathways in the
   liver, insulin lower the blood glucose level.
3. Insulin activate pyruvate dehydrogenase by
   activating pyruvate dehydrogenase phosphatase, to
   accelerate oxidation of pyruvate to Acetyl-CoA,
   resulting the aerobic oxidation of carbohydrates.
   
4. Insulin inhibit gluconeogenesis in liver by
   decreasing the synthesis of PEP-carboxykinase and
   promoting the entrance of amino acid into muscle
   and protein synthesis.
5. Insulin slow the speed of fat mobilization
   through inhibiting the hormone-sensitive lipase
   in fat.

171
2. Different hormone increase blood glucose under
different conditions.

• 1.Glucagon is the main hormone which increase
• blood glucose in vivo.

Glucagon is released in response to hypoglycemia
or high level of amino acid in blood.
172

• Mechanism of glucagon

173

• Insulin and glucagon not only regulate blood
  glucose, but also play important role on the
  metabolism regulation of three nutriments.
• The change of carbohydrates, fat and amino acid
  metabolism is decided by the insulin/glucagon
  ratio.
• The secretion of two hormones is opposite.
• e.g. hyperglycemia stimulate the release of
  insulin, but inhibit the release of glucagon.

174
2. Glucocorticoids cause the increase of blood
glucose

• Mechanism of glucocorticoids

• ? They can increase gluconeogenesis by enhancing
  hepatic uptake of amino acids and increasing
  activity of aminotransferases and key enzymes of
  gluconeogenesis.
• ? They inhibit the uptake and utilization of
  glucose in extrahepatic tissues.

175
3. Epinephrine is stress hormone that increase
blood glucose

• Mechanism of epinephrine

Epinephrine is secreted as a result of stress
stimuli and lead to glycogenolysis in the liver
and muscle owing to stimulation of phosphorylase
via generation of cAMP.
176
3. Dysfunction of carbohydrate metabolism
abnormal blood glucose and diabetes.
Under normal conditions, there are a fine
mechanism for the regulation of glucose
metabolism to keep blood glucose from large
fluctuations and sustained increase after uptake
a large glucose.
A healthy individual could tolerate to
the uptake of a large glucose and keep blood
glucose in normal level, this is called glucose
tolerance.
177
Two common symptoms of carbohydrate metabolism
disorder in clinical

• Hypoglycemia
• Hyperglycemia

178
Hypoglycemia blood glucose concentration below
3.0mmol/L

• Hazards of hypoglycemia

• Hypoglycemia influence the function of brain
  because brain cells depend on the oxidation of
  glucose to supply energy. Hypoglycemia causes
  symptoms such as dizziness or light-headedness,
  weakness, palmus even faint which is called
  hypoglycemic shock. It can lead to death if we do
  not give the patient intravenous glucose
  supplement.

179

• The reasons of hypoglycemia

1. Dysfunction of pancreas hyperfunction of
   pancreas ß-cell, hypofunction of pancreas
   a-cells
2. Dysfunction of liver liver cancer, glycogen
   storage disease
3. Dyscrinism hypofunction of Pituitary,
   hypofunction of adrenal cortex
4. Tumor stomach cancer
5. Fasting and starve

180
2. hyperglycemia fasting blood glucose exceed
6.9mmol/L

• In clinical, fasting blood glucose exceed
  5.66.9mmol/L is called hyperglycemia.
• When blood glucose concentration exceed the
  tubular reabsorption capacity (renal glucose
  threshold), hyperglycemia caused glucosuria.
• Persistence hyperglycemia and glucosuria,
  especially fasting blood glucose and
  glucose-tolerance are higher than the normal
  range, it is often caused by diabetes mellitus.

181

• The reasons of hyperglycemia

1. Diabetes
2. Genetic defects in insulin receptor
3. chronic nephritis, nephrotic syndrome
4. Physiological hyperglycemia and glucosuria

182
3. Diabetes is a common disease of carbohydrate
metabolism disorder

• Diabetes, caused by a deficiency in the secretion
  or action of insulin, is a relatively common
  disease.

183

• Two types of diabetes

Type ? (insulin-dependent ) Type ?
(non-insulin-dependent )
184
Problems
1.The process of glutamate completely oxidized
into CO2 and H2O and the ATP ? 2.Which
metabolism pathway that G-6P could enter in liver
or muscle?
G(replenish blood glucose)
G-6-P
F-6-P (enter glycolysis)
6-Phosphoglucono-lactone (enter pentose
phosphate pathway)
G-1-P
UDPG
Gn(Glycogen synthesis)