Transcript ADP

Part Two
METABOLISM
Wu Yaosheng
Metabolism of Carbohydrate
Biological Oxidation
Metabolism of Lipids
Metabolism of Proteins
Metabolism of Nucleotides
Regulation of Metabolism
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目录
Chapter Four
Metabolism of
Carbohydrates
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目录
Main contents
1. Introduction
2. Glycolysis
3. Aerobic oxidation of glucose
4. Pentose phosphate pathway
5. Glycogenesis and glycogenolysis
6. Gluconeogenesis
7. Blood sugar and regulation
Disease cases
Concepts
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Questions
目录
Section One
Introduction
The physiological functions of saccharides
1. To be oxidized and to supply energy
This is the major function of saccharide
2. Work as remarkably versatile precursors
for biosynthetic reactions
such as amino acid, fat, cholesterol, nucleoside
3. Participate in the composition of tissue
cells in organism.
Such as glycoprotein, proteoglycan, glycolipid
1. Digestion and Absorption of
Carbohydrates
1.1 Digestion of Carbohydrates
In nature, starch from plants are the
major dietary carbohydrate source for
human. Other carbohydrate sources include
glycogen, maltose, sucrose, lactose and
glucose.
Digesting place:
Mainly in small intestine, less in mouth.
Process of digesting
Starch
Mouth
Stomach
Small
intestine
α-amylase in saliva
α-amylase in
pancreatic juice
maltose+maltotriose
（40%） （25%）
The surface
of the small
intestinal
epithelial
cells
α-limit dextrins+isomaltose
（30%） （5%）
α-limit dextrinase
α-glucosidase
Glucose
The cellulose existing abundant in
diet are useful for the human health
due to that they can stimulate the
moving of intestine, even though
they can not be digested because of
lacking of -glucosidase in human
intestine.
1.2 Absorption of Carbohydrates
(1) Absorption place
Upside part of small intestine
(2) Molecule absorbed
Monosaccharide, mainly glucose
(3) Mechanism of absorption
lumen
membrane
Intracellular
membrane
Small intestinal
epithelial cell
Portal vein
K+
Intestine
lumen
ATP
ADP+Pi
Na+pump
Na+
G
Na+-dependent glucose transporter, SGLT
1.4 Absorption route of Carbohydrates
Small intestine
lumen
SGLT
Small intestinal
epithelial cells
SGLT---- Na+ (Sodium)glucose transporter
Portal vein
GLUT, refer to glucose
transporter. There are five
kinds of GLUT having been
found
Various tissue
cells
Liver
GLUT
Blood circulation
2. The Fate of Absorbed Glucose
glycogen
Other substances
Transform
glycogenesis
Pentose
ribose
phosphate
pathway
+
NADPH+H+
ATP
glycogenolysis
Glucose
glycolysis
Aerobic
Pyruvate
Anaerobic
Digestion and
absorption
Starch
H2O and
CO2
Gluconeogenesis
Lactate, amino acid, glycerol
Lactate
Section Two
Anaerobic
degradation of
Glucose
Glycolysis
1. Basic Process of Glycolysis
* Definition of Glycolysis
The process in which a molecule of
glucose is degraded
in a series of
enzymatic reactions to yield two
molecules of pyruvate or lactate under
anaerobic condition is term glycolysis.
* The site of glycolysis is cytoplasm.
The basic process of glycolysis can be
divided into two stages:
The first stage
The reaction process from glucose to
pyruvate is called glycolytic pathway
The secondary stage
The reaction process from pyruvate to
lactate
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目录
Glu
ATP
1.1 Pyruvate Formation from Glucose
ADP
G-6-P
(1) Glucose is phosphorylated to be
glucose-6-phosphate
F-6-P
ATP
ADP
F-1,6-2P
3-PGA
DHAP
NAD+
NADH+H+
hexokinase
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
ADP
PEP
ATP
Pyruvate
Glucose-6phosphate
Glucose
One of key enzymes
Now it has been found that there are
four kinds of isoenyzme of hexokinase in
mammal animals called hexokinase I to
IV type, respectively. In liver, it is
hexokinase IV, namely glucokinase.
The characters of glucokinase are:
① The affinity to glucose is very low
(high Km, Km ~10 mmol/L, p131 error)
② It is regulated by hormones
Glu
ATP
⑵ Glucose-6-phosphate →Fructose6-phosphate
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
3-GAP
DHAP
Phosphohexose
isomerase
NAD+
NADH+H+
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
Glucose-6-phosphate
Fructose-6-phosphate
Glu
ATP
(3) fructose-6-phosphate →
Fructose-1,6-bisphosphate
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
3-GAP
DHAP
Phosphofructokinase-1
NAD+
NADH+H+
1,3-DPGA
ADP
Fructose-6-phosphate
ATP
Fructose-1,6-bisphosphate
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
One of key enzymes
Glu
ATP
(4) phosphohexose →2 molecules
of phosphotriose
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
aldolase
3-GAP
DHAP
NAD+
NADH+H+
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
Fructose-1,6bisphosphate
Dihydroxyacetone
phosphate, DHAP
Glyceraldehyde-3phosphate, 3-PGA
Glu
ATP
(5) Phosphotrioses interconverse
ADP
G-6-P
F-6-P
ATP
phosphotriose
isomerase
ADP
F-1,6-2P
3-GAP
DHAP
NAD+
NADH+H+
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
Dihydroxyacetone
phosphate
Glyceraldehyde-3phosphate
Glu
ATP
(6) glyceraldehyde-3-phosphate→1,3bisphosphoglycerate
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
Glyceraldehyde
-3-phosphaste
dehydrogenase
3-GAP
DHAP
NAD+
NADH+H+
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
Glyceraldehyde
-3-phosphaste
1,3-bisphosphoglycerate
Glu
(7) 1,3-bisphosphoglycerate→3phosphoglycerate
ATP
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
Phosphoglyc
erate kinase
3-GAP
DHAP
ADP
NAD+
1,3-bisphosphoglycerate
NADH+H+
ATP
3-phosphoglycerate
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
substrate level phosphorylation
Glu
ATP
(8) 3-phosphoglycerate→2phosphoglycerate
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
3-GAP
DHAP
Phosphoglycerate
mutase
NAD+
NADH+H+
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
3-phosphoglycerate
2-phosphoglycerate
Glu
ATP
(9) 2-phosphoglycerate
→phophoenolpyruvate, PEP
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
3-GAP
DHAP
enolase
NAD+
NADH+H+
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
2-phosphoglycerate
phophoenolpyruvate
Glu
(10) Phosphoenolpyruvate →
pyruvate, and yield ATP through
substrate level phosphorylation
ATP
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
Pyruvate
kinase
3-GAP
DHAP
NAD+
NADH+H+
ADP
1,3-DPGA
ADP
Phosphoenolpyruvate
pyruvate
ATP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
One of key enzymes
1.2 Conversion of Pyruvate to Lactate
COOH
NADH + H+
NAD+
CHOH
C=O
CH3
COOH
Lactate dehydrogenase, LDH
pyruvate
CH3
lactate
Here, the NADH+H+ in the reaction comes from
the six step in the above, the dehydrogenation
reaction of 3-phosphoglyceraldehyde
E1
Glu
G-6-P
F-6-P
ATP ADP
E2
ATP
F-1, 6-2P
ADP
DHAP
E1:hexokinase
3-GAP
NAD+
NADH+H+
E2: 6-PFK-1
1,3-DPG
E3: Pyruvate kinase
ADP
ATP
Glycolysis
metabolism
3-PGA
lactate
NAD+
2-PGA
NADH+H+
ATP ADP
Pyruvate
E3
PEP
glucose
Dihydroxyacetone
phosphate
G-6-P
The pathway of
glycolysis
Glyceraldehyde3-phosphate
1,3-Bisphospho
glycerate
3-Phosphoglycerate
F-6-P
2-Phosphoglycerate
F-1,6-bisphosphate
Phosphoenolpyruvate
pyruvate
lactate
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目录
Summary for glycolysis
(1) Reaction site：in cytoplasm
(2) It is a process to produce energy but
without the need for oxygen
(3) There are three irreversible reaction
steps
ATP
ADP
G
hexokinase
ATP
ADP
F-6-P
PEP
F-1,6-2P
PFK-1
ADP
G-6-P
ATP
Pyruvate kinase
pyruvate
(4) The manner to yield energy and the number
of ATP produced.
Manner：substrate level phosphorylation
The net number of yielding ATP ：
If to begin from Glucose,
2×2-2= 2ATP
If to begin from Glycogen, 2×2-1= 3ATP
(5) The fate of the final product lactate
To be released into blood stream, and then
to be taken into liver metabolized.
To be decomposed and utilized further
To go into Lactate cycle ( gluconeogenesis）
Except for glucose, other hexose
can converse to phosphohexose and
galactose
then go into glycolysis pathway.
Galactose
kinase
Mannose
hexokinase
Mannose-6phosphate
Galactose-1-phosphate
Glu
ATP
ADP
G-6-P
F-6-P
ATP
fructose
ADP
F-1,6-2P
pyruvate
mutase
Glucose-1phosphate
Entry of other carbohydrates into glycolysis
lactose
fructose
galactose-1-phosphate
uridylyl transferase
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目录
2. Regulation of Glycolysis
① hexokinase
Key enzymes
② 6-phosphofructokinase-1
③ pyruvate kinase
① allosteric regulation
Regulation models
② covalent modification
2.1 6-phosphofructokinase-1
(PFK-1)
* Allosteric regulation
Allosteric activators：AMP; ADP; F-1,6-2P; F-2,6-2P
Allosteric inhibitors： citric acid; ATP（high conc. ）
• F-1,6-2P can positively feedback regulate PFK-1
• There are two binding sites in PFK-1 for ATP：
① substrate-binding site in active center (low conc.)
② allosteric site outside active center (high conc. )
AMP
Glucagon
Citric acid
–
+
PFK-2
FBP-2
（active）
ATP
cAMP
（inactive）
6-PFK-2
ATP
F-6-P
activating
Phosphoprotein
phosphatase
PKA
F-2,6-2P
FBP-2
ATP
+
ADP
lactate
P
PFK-2
FBP-2
（inactive）
（active）
ADP
–/+
PFK-1
+ +
F-1,6-2P
AMP
Pi
P
Pi
+
–
Citric acid
目录
2.2 Pyruvate kinase
(1) Allosteric regulation
Allosteric activator：
fructose 1,6-bisphosphate
Allosteric inhibitors：
ATP, Alanine
(2) Covalent modification
Pi
Pyruvate kinase
Phosphoprotein
phosphatase
Pyruvate kinase
（active）
（inactive）
ADP
ATP
Glucagon
PKA, CaM kinase
PKA：protein kinase A
CaM：Calmodulin
P
2.3 Hexokinase
Glucose-6-phosphate
is
an
allosteric
inhibitor of hexokinase, except for
hexokinase IV, glucokinase.
Long chain acyl CoA is an allosteric inhibitor
of glucokinase
3. The significance of Glycolysis
(1) Glycolysis is the emergency energyyielding pathway.
(2) Glycolysis is the main way to produce
ATP in some tissues, even though the
oxygen supply is sufficient
In cells without mitochondria, red blood cells
In metabolism active cells, retina, testis, skin,
medulla of kidney.
Section Three
Aerobic Oxidation of Glucose
Concept
The process of complete oxidation
of glucose to CO2 and water with
release of energy as the form of ATP is
termed aerobic oxidation.
The place for aerobic oxidation：
cytoplasm, and mitochondria
1. Basic Process of Aerobic
Oxidation of Glucose
G（Gn）
Cytoplasm
First stage：Glycolytic pathway
Secondary stage：The oxidation
and decarboxylation of pyruvate
Third stage：Tricarboxylic cycle
and Oxidative phosphorylation
H2O
Acetyl CoA
mitoch
ondria
TAC
[O]
ATP
Pyruvate
ADP
NADH+H+
FADH2
CO2
1.1 Oxidation of Glucose to
Pyruvate
It is the same as the glycolytic pathway in
cytosol discussed above.
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目录
1.2 Oxidation of Pyruvate to lactate
After pyruvate is transported into
mitochondria, it will be oxidized and
decarboxylated to be acetyl Co A.
The total reaction:
NAD+ , HSCoA
CO2 , NADH + H+
Pyruvate
Pyruvate dehydrogenase
complex
Acetyl CoA
The fates of pyruvate in organism
Lactate
Alanine
Pyruvate
Acetyl CoA
Oxaloacetate
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目录
The composition of pyruvate
dehydrogenase complex
HSCoA
NAD+
enzymes
E1：pyruvate
dehydrogenase
E2：dihydrolipoyl
transacetylase
E3：dihydrolipoyl
dehydrogenase
coenzyme
TPP
lipoic acid(L
HSCoA
FAD, NAD+
S
)
S
1. Formation of hydroxyethyl-TPP
CO2
2. Yield of
acetyl
lipoamide
NADH+H+
5. Yield of
NADH+H+
NAD+
CoASH
3. Yield of
acetyl CoA
4. Formation of
lipoamide
目录
1.3 Tricarboxylic Acid Cycle, TAC
Introduction
Tricarboxylic Acid Cycle, TAC is called citric
acid cycle too, because that the first molecule for
the beginning of the cycle is citric acid with three
carboxyl groups. It was Krebs who first formally
put forward TAC theory, therefore the cycle was
called Krebs cycle.
Reaction location
All reactions related to TAC take place in mitochondria
H2O
H2O
②
①
NADH+H+
H2O
CoASH
②
NAD+
①citrate synthase
②aconitase
③isocitrate dehydrogenase
④α-ketoglutarate dehydrogenase complex
+
NAD
GTP
GDP ⑤succinyl CoA synthetase
Nucleoside diphosphate ⑥succinate
kinase
dehydrogenase
NADH+H+
⑦
⑦fumarase
③
⑧
H2O
ADP
FADH2
⑥
ATP
FAD
⑧malate dehydrogenase
GDP+Pi
GTP
NAD+
NADH+H+
④
CO2
⑤
CO2
CoASH
CoASH
目录
Summary for TAC
① Concept of TAC：It means the process in
which a molecule of acetyl-CoA combines
with the four-carbon dicarboxylic acid
oxaloacetate, resulting in the formation of a
six-carbon
tricarboxylic
acid,
citrate,
following a series of reactions in the course
of which two molecules of CO2 are released
and oxaloacetate is regenerated.
② The location of TAC is mitochondria
③ The key points of TAC
For each cycle of TAC，
– One molecule of acetyl CoA is consumed
– Undergo through four times of dehydrogenation,
two times of decarboxylation, one time of
substrate level phosphorylation
– Yield one molecule of FADH2, three molecules of
NADH+H+, two molecules of CO2, one molecule
of GTP.
– Key enyzmes：
citrate synthase
α-ketoglutarate dehydrogenase complex
isocitrate dehydrogenase
④ TAC is irreversible cycle
⑤ Intermediates in TAC and other
metabolism
TAC is the common final steps in the
breakdown of foodstuffs, such as
carbohydrates, lipids, and proteins.
TAC serves as the crossroad for the
interconversion among carbohydrates,
lipids, and non-essential amino acids, and
as a source of biosynthetic intermediates.
Oxaloacetate in TAC must be complemented
and renovated constantly
The source for oxaloacetate：
Acetyl CoA
CO2
Pyruvate
Pyruvate
carboxylase
oxaloacetate
citritic acid
Citric acid
lyase
Malate
dehydro
genase
NADH+H+
malate
NAD+
glutamate α-ketogutarate
Aspartate
transaminase
Aspartate
2. ATP Generated in the Aerobic
Oxidation of Glucose
When H+ + e are transported through
respiratory chain, they are completely
oxidized to H2O and to yield ATP by
coupled ADP phosphorylation.
NADH+H+
FADH2
[O]
[O]
H2O、3ATP
H2O、2ATP
ATP yielded in the Aerobic Oxidation of Glucose
Reaction
Coenzyme
First stage
Glucose→ G-6-P
ATP
-1
-1
F-6-P → F-1,6-DP
2× 3-GAP → 2× 1,3-DPGA
NAD+ 2× 3 or 2 × 2*
2×1
2×1
2× 1,3-DPGA → 2×3-PGA
2 × PEP → 2 × Pyruvate
Secondary
2× Pyruvate → 2× Acetyl CoA
stage
Third stage
NAD+
2×3
2×Isocitric acid → 2×α-ketoglutarate
NAD+
2 ×3
2×α-ketoglutarate → 2×Succinate CoA
NAD+
2×3
2×Succinate CoA → 2×Succinate
2×Succinate → 2×fumarate
2×malate → 2×oxaloacetate
2×1
FAD
2×2
NAD+
2×3
Net yield
38 (or 36) ATP
The result was calculated following old theory, now it is updated
3. The Regulation of Aerobic Oxidation
of Glucose
Key enzymes
① Glycolysis pathway: Hexokinase
Pyruvate kinase
6-phosphofructokinase-1
② Decarboxylation of pyruvate：
Pyruvate dehydrogenase complex
③ TAC：Citric acid synthase
α-ketoglutarate dehydrogenase complex
Isocitric acid dehydrogenase
3.1 The Regulation of Pyruvate
Dehydrogenase Complex
(1) Allosteric regulation
Allosteric inhibitor：acetyl CoA; NADH; ATP
Allosteric activator：AMP; ADP; NAD+; Ca2+
As [acetyl CoA]/[HSCoA] or [NADH]/[NAD+]，
its activity will be inhibited.
(2) Covalent modification regulation
⑵ 共价修饰调节
Acetyl CoA
Pyruvate
Protein kinase
Active pyruvate
dehydrogenase
complex
phosphatase
inactive pyruvate
dehydrogenase
complex
Acetyl CoA
Insulin
目录
3.2 The Regulation of
TAC
Acetyl CoA
– ATP
+ ADP
① The effect of ATP、ADP
Citric acid
synthase
Oxaloacetate
Citric
acid
NADH
Succinyl CoA
Citric acid
② Inhibited by products
Isocitrate
malate
③ allosteric inhibited
by intermediates
NADH
Isocitrate
dehydrogenase
FADH2
– ATP
+ ADP
Ca2+
α-ketoglutarate
α-ketoglutarate
dehydrogenase
complex
④ Others, for
example, Ca2+ can
activate various
enzymes.
+
Ca2+
Succinal CoA – Succinyl CoA NADH
GTP
ATP
Section Four
Pentose Phosphate Pathway
* Concept of pentose phosphate pathway
Pentose phosphate pathway is a process
in which ribose-5-phosphate and NADPH+H+
are yielded accompanying the degradation of
glucose, and then ribose-5 phosphate can
turn to glyceraldehyde -3- phosphate and
fructose-6-phosphate further.
nicotinamide adenine dinucleotide phosphate
( NADPH , reduced form)
1. Basic Process of PPP
* Location in cell：in cytoplasm
* Two stages
 first stage：The oxidative phase
to yield pentose phosphate, NADPH+H+
and CO2
 secondary stage: Non-oxidative phase,
including the transfer of a series of groups
1.1 The oxidative phase
H
C
OH
H
C
OH
HO
C
H
H
C
OH
H
C
G-6-P
dehydrogenase
C=O
NADP+
O
CH2O
NADPH+H+
⑴
H
C
OH
HO
C
H
H
C
OH
H
C
P
CH2O
Glucose-6-phosphate
H 2O
O
P
6-phosphogluconolactone
H
C
OH
H
HO
C
H
H
C
OH
H
C
OH
CH2O
P
6-phosphogluconate
CH2OH
G-6-PD
NADP+
CO
COO—
CO2
NADPH+H+
⑵
C=O
C
O
H
C
OH
H
C
OH
CH2O
P
Ribulose-5-phosphate
Ribose-5-phosphate
NADP+
NADPH+H+
NADP+
NADPH+H+
Ribose-5-phosphate
G-6-P
CO2
• Glurose-6-phosphate dehydrogenase (G6PD) is
the first key enzyme for the pathway.
• All hydrogen atoms coming from two times of
dehydrogenation are accepted by NADP+ to
generate NADPH + H+
• Ribose-5-phosphate is a very important
intermediate molecule during the pentose
phosphate pathway.
1.2 Non-oxidative phase
Groups transfer
• Pentose-5-phosphate can interconvert with
three, four, five, six, seven-carbon sugars
under the catalysis of transketolase and
transaldolase.
Among them, glyceraldehyde-3phosphate and fructose-6-phosphate can go
into glycolysis pathway, therefore, PPP can
be called pentose phosphate shunt.
Non-oxidative phase
Ribulose-5-phosphate(C5) ×3
Xylulose-5-P
C5
Ribose-5-P
C5
Sedoheptulose-7-P
C7
Glycerald
ehyde -3P
C3
Erythrose-4-P
C4
Fructose-6-P
C6
Xylulose-5-P
C5
Glyceraldehyde-3P
C3
Fructose-6-P
C6
3NADP+
G6PD
3NADP+3H+
6-phosphogluconolactone (C6)×3
First phase
6-phosphogluconate (C6)×3
3NADP+
3NADP+3H+
G6PD
CO2
Ribulose-5P(C5) ×3
Xylulose-5P
C5
3-GAP
C3
Ribose-5P
C5
Sedoheptulose-7P
C7
Erythrose-4P
C4
F-6-P
C6
Xylulose-5P
C5
3-GAP
C3
F-6-P
C6
Secondary phase
Pentose phosphate pathway
G-6-P (C6)×3
The sum of total reactions in pentose
phosphate pathway are
3×Glucose-6-Phosphate+ 6 NADP+
2×F-6-P+3-GAP+6NADPH+H++3CO2
2. The Significance of pentose
Phosphate Pathway
2.1 To supply ribose-5-phosphate for
nucleotide and nucleic acid biosynthesis
2.2 To produce NADPH for reductive
synthesis such as fatty acid and steroid
biosynthesis
To produce NADPH
(1) NADPH is the donor of hydrogen for various
anabolic metabolism in organism
(2) NADPH can participate in the hydroxylation
reaction, involving biosynthesis or
biotransformation in organism
(3) NADPH can keep the reduction of GSH
A
2G-SH
NADP+
AH2
G-S-S-G
GSH
NADPH+H+
reducase
Section Five
Glycogen Formation
and Degradation
Glycogen
They are the major storage model of
saccharide in animal, and are the main
energy source which can be quickly utilized.
• Organs in which can store glycogen
and physiological significance
Muscle：muscle glycogen，180 ~ 300g，
mainly supply to muscle contraction
Liver：hepatic glycogen，70 ~ 100g，to keep
blood sugar level constant
• Structure of glycogen
1. 93% of glucose units are
joined by α-1,4glucosidic bonds, 7% of
glucosyl residues are
joined by α-1,6glucosidic bonds
2. About each ten glucosyl
residues, a branch
occurs. More branches ,
higher solubility.
3. Each chain ends in a
reduced terminal,
benefiting the
degradation by enzyme
目录
1. Glycogen Formation ( glycogenesis )
Definition of glycogenesis
It is the process to synthesize
glycogen from glucose.
Synthesis sites in organism
Organ sites：mainly in liver and muscle
Cellular site：cytoplasm
Pathway of glycogen synthesis
(1) Glucose is phosphorylated to G-6-P
ATP
Glucose
ADP
Glucose-6-phosphate
hexokinase;
glucokinase（liver）
(2) G-6-P turn to G-1-P
G-6-P
Phosphoglucomutase
G-1-P
Phosphogluco
mutase
Glucose-6-phosphate
Glucose-1-phosphate
(3) G-1-P turn to UDPG
CH2OH
H
H
OH
O H
HO
O
H
+
H
P
P
P
uridine
P
UTP
OH
G-1-P
CH2OH
H
H
OH
UDPGpyrophosphorylase
HO
PPi
O H
H
O
H
P
P
uridine
尿苷
OH
( uridine diphosphate glucose , UDPG )
2Pi+energy
* UDPG can be seen as active glucose donor
Uridine diphosphate
glucose , UDPG structure
Active glucose
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(4) Formation of α-1,4-glucosidic bond
Gn + UDPG
glycogen synthase
Gn+1 + UDP
One more glucose is added to the glycogen
primer or glycogen molecule
UDP
ATP
Nucleoside
diphosphate kinase
UTP
ADP
(5) The formation of branch of glycogen
α-1,4 glycosidic
bond
α
-1,4-糖苷键
分 支 酶
(branching enzyme)
α-1,6 glycosidic
bond
α-1,6-糖苷键
目录
Glycogen synthesis
UDP-glucose
pyrophosphorylase
G
G-6-P
hexokinase
G-1-P
Phosphoglucomutase
UDP-G + PPi
UTP Glycogen
synthase
Gn
Gn+1
Enzymes
-UDP-glucose pyrophosphorylase
-Glycogen synthase (key enzyme)
-Branching enzyme [amylo-(1-41-6)
Transglycosylase]
Notes
It needs primer before the synthesis of Gn
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2. Glycogen Degradation
( Glycogenolysis )
* Definition of glycogenolysis
Generally, it refers the process of hepatic
glycogen hydrolyzed to release glucose.
* Cellular site：in cytoplasm
(1) Glycogen suffer phosphorolysis
Gn+1
phosphorylase
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Gn + G-1-P
目录
(2) Debranching enzyme
① transfer glycosyl residues
② hydrolyzing -1,6glycosidic bond
(debranching enzyme)
phosphorylase
transferase
α-1,6
glucosidase
目录
(3) G-1-P turn to G-6-P
Glucose-1phosphate
Glucose-6phosphate
Phosphoglucomutase
(4) G-6-P is hydrolyzed to yield glucose
glucose-6-phosphaste
Glucose
glucose-6-phosphatase
（liver，kidney）
Attention: there are no glucose-6-phosphatase in
skeleton muscle, so glycogen couldn’t be used to
replenish blood sugar because of no free G released
into blood from muscle glycogen.
Summary for glycogenesis and glycogenolysis
(1) Reaction site：in cytoplasm
(2) The fates of G-6-P metabolism
G（to replenish blood sugar）
6-phosphogluconolactone
（into PPP）
G-6-P
F-6-P
（into glycolysis）
G-1-P
UDPG
glucuronate
（into glucuronate pathway)
Gn（to synthesize
glycogen）
The total chart for glycogenesis and glycogenolysis
Gn+1
UDP
Gn
Pi
Gn synthase
UDPG
PPi
Gn
Phosphorylase
UDPG pyrophosphorylase
UTP
G-1-P
Phosphoglucomutase
Glucose-6-phosphatase(liver）
G-6-P
G
Hexo(gluco)kinase
3. The Regulation of Glycogensis and
Glycogenolysis
Key enzyme
① Glycogenesis：Gn synthase
② Glycogenolysis：Gn phosphorylase
The important characters of these two enzymes：
* The covalent modification and allosteric
regulation as rapid regulation models
* There are two types of enzyme with active or
inactive (low active) forms interconverting
mutually through phosphorylation or
dephosphorylation
3.1 Phosphorylase
ATP
Phosphorylase b
kinase
Phosphorylase b
(dephosphorylated,
inactive )
Pi
ADP
Phosphorylase a
( phosphorylated,
active )
Protein phosphatase I
3.2 Glycogen Synthase
Protein phosphatase
Glycogen synthase b
(phosphorylated,
inactive )
ADP
Pi
Glycogen synthase a
(dephosphorylated,
inactive )
Protein kinase A
ATP
hormones（glucagon 、epinephrine）+ receptor
Adenyly cyclase
（inactive）
Adenyly cyclase
（active）
ATP
cAMP
Pi
Phosphorylase b
kinase
PKA
PKA
(inactive)
(active)
Phosphoprotein
phosphatase-1
Phosphorylase
b kinase-P
–
Gn synthase
Gn synthase-P
active
Pi
inactive
Phosphorylase b
Phosphorylase a-P
inactive
Phosphoprotein
Phosphatase-1
Pi
active
Phosphoprotein
phosphatase-1
–
–
Phosphoprotein
Phosphatase inhibitor-P
PKA（active）
Phosphoprotein
Phosphatase inhibitor
4. The Significance of Glycogenesis and
Glycogenolysis
After a meal, the excessive glucose will store in liver
as glycogen.
After fasting, liver glycogen is degraded into glucose
and released to blood for keeping the blood sugar
level
Liver glycogen can store energy and regulate the
blood sugar level.
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5. glycogen storage diseases
Glycogen storage diseases are a group of
inherited disorders characterized by
deposition of an abnormal type or quantity of
glycogen in some tissues.
Section Six
Gluconeogenesis
* Definition
Gluconeogenesis is a process to synthesize
glucose or glycogen from noncarbohydrate
precursors.
* Cellular site:
In cytoplasm and mitochondria in liver or
kidney.
* Raw material
Glycerol, glucogenic amino, lactate, and
other organic acids.
Glu
1.The Basic Process of
Gluconeogenesis
ATP
ADP
G-6-P
F-6-P
ATP
ADP
F-1,6-2P
3-GAP
DHAP
NAD+
NADH+H+
1,3-DPGA
ADP
ATP
3-PGA
2-PGA
PEP
ADP
ATP
Pyruvate
The main pathway for
gluconeogenesis is essentially a
reversal of glycolysis, but there
are three energy barriers
obstructing a simple reversal of
glycolysis
1.1 The Conversion of Pyruvate to
Phosphoenolpyruvate (PEP)
ATP
pyruvate
CO2
ADP+Pi
GTP
GDP
oxaloacetate
①
PEP
② CO2
① Pyruvate carboxylase, coenyzme is biotin.
Reaction occurs in mitochondria.
② Phosphoenol pyruvate carboxykinase (PEP
carboxykinase ) in mitochondria and
cytoplasm
Process of Gluconeogenesis
目录
PEP
cytoplasm
GDP + CO2
PEP carboxykinase
GTP
Aspartate
Oxaloacetate
Malate
Malate
Aspartate
NAD+
α-ketoglutarate
NADH + H+
Glutamate
Oxaloacetate
ADP + Pi
ATP + CO2
mitochondria
Pyruvate carboxylase
Pyruvate
Pyruvate
1.2 F-1,6-DP turns to F-6-P
Pi
F-6-P
F-1,6-DP
Fructose-1,6-diphosphatase
1.3 G-6-P is hydrolyzed to glucose
Pi
G-6-P
glucose-6-phosphatase
Glucose
2. The Cori Cycle (Lactate cycle )
LIVER
MUSCLE
Glucose
Glucose
Gluconeogenesis
Pyruvate
Lactate
Dehydrogenase
Lactate
Blood
Glycolysis
Pyruvate NADH
NADH
+H+
Lactate
Dehydrogenase
NAD+
Lactate
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+H+
NAD+
目录
The significances of Cori Cycle
1) To avoid the lose of lactate and get the
reuse of muscle lactate ( lactate in muscle
could be used to synthesize glucose)
2) To prevent the build up of lactate in muscle
Glucogen
in muscle
Glucose
in blood
gluconeogenesis
glycolysis
Lactate
in blood
Synthesis
of glucogen
Glucogen
in liver
Degradation
of glucogen
Glucogen
in muscle
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3. Regulation of Gluconeogenesis
G-6-Pase
G-6-P
G
ADP
F-1,6-DPase-1
HK
Pi
F-1,6-DP
ADP
Pi
ATP
F-6-P
F-1,6-DPase-1
ATP
ADP+Pi
Py carboxylase
GTP
PEP carboxylkinase
oxaloacetate
GDP+Pi
CO2+ATP
PEP
pyruvate
ADP
Py kinase
ATP
+CO2
4. The Significance of Glyconeogenesis
(1) To maintain blood glucose levels stable
during starvation or during vigorous
exercise.
It is more important for the functions
of brain or erythrocytes.
(2) To replenish liver glycogen
(3) To regulate acid-base equilibrium.
Section Seven
Blood Glucose and Its
Regulation
1. Blood Sugar Level
* Blood sugar refers the level of glucose
in blood.
Normal blood sugar concentration:
3.89~6.11mmol/L
The income and outcome of blood sugar
Dietary
supply
Digestion and
absorption
Oxidation
CO2 + H2O
Gn synthesis
degradation
Liver
glycogen
glyconeogenesis
Noncarbohydrates
Blood
sugar
PP Pathway
liver (muscle) Gn
Other sugar
Lipid, AA synthesis
Fat, AA
2. Regulation of Blood Glucose
Concentration
* Mainly, the regulation depends on
hormones
Hormones
Decrease blood sugar:
insulin
Increase blood sugar:
glucagon,
glucocorticoids,
epinephrine ( adrenalin )
2.1 Insulin
—— the unique a hormone to decrease blood
level in body
Mechanism of insulin action
① Effects on membrane actively transport
② Effects on glucose utilization
③ Effects on gluconeogenesis
④ Decrease lipolysis and stimulates the
uptake of neutral AA into muscle for protein
biosynthesis
2.2 Glucagon
——One of the hormones to increase blood
sugar level
Mechanism of glucagon action
① Improve glycogenolysis, inhibit glycogen
synthesis
② Inhibit glycolysis, improve gluconeogenesis
③ Activate the triacylglyceride mobilization
2.3 Epinephrine (adrenalin )
——A hormone for increasing blood sugar in
stress
Target tissues: liver and muscle.
To stimulate glucogenolysis to produce glucose
in liver and lactate in muscle;
To stimulate gluconeogenesis;
To enhance the transport of glucogenic amino
acids to liver for gluconeogenesis
2.4 Glucocorticoids
——One of the hormones to increase blood
sugar
Mechanism of glucocorticoid action
To stimulate the gluconeogenesis
To inhibit the utilization of glucose by inhibiting
pyruvate dehydrogenase complex
To promote lipolysis for increasing free fatty
acids level in blood
3. Abnormal Blood Sugar Level
3.1 Hyperglycemia
Definition of hyperglycemia
It is termed hyperglycemia when
the blood sugar concentration in fasting
is higher than 7.22~7.78 mmol/L in
clinic.
Renal threshold for glucose
When blood sugar conc. is higher than 8.89
~10.00 mmol/L, it is over the ability of renal tubular
to reabsorb glucose, resulting in glucose appearing
in urine. Therefore, this blood sugar level is termed
renal threshold for glucose.
The case which glucose presents in urine is
called glycosuria
The reasons for glycosuria:
Emotional, alimentary, symptomatic and
renal glycosuria, insulin absolutely
deficiency or relatively deficiency, etc.
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Diabetes mellitus, DM
There two types for diabetes mellitus
Ⅰtype ---- insulin-dependent diabetes
mellitus
Ⅱtype ---- non-insulin dependent diabetes
mellitus
3.2 hypoglycemia
Definition of hypoglycemia
It refers the case when blood sugar conc.
in fasting is lower than 3.33~3.89 mmol/L
The impact of hypoglycemia to body
The functions of brain cells would be
affected, then various symptoms such as be
light in the head swirl, accidie, atony, heartthrob, more severely coma would appear.
The pathogeny of hypoglycemia
① Relate to pancreas (the excessive of islet
β-cell functions, or the deficiency of islet αcell functions ）
② Relate to liver（liver cancer, glycogen
storage disease, etc）
③ abnormal secretory action ( pituitary
function deficiency, adrenal gland cortex
function deficiency, etc. ）
④ tumor
⑤ starvation, or unavailable to take food
The disease related to the metabolism of galactose---Galactosemia
What’s it: It is a genetic disease caused by an inability to
convert galactose to glucose. Toxic substances
accumulate such as galactitol, formed by the reduction of
galactose
Symptom: fail to thrive, vomit or diarrhea after drinking
milk, and often enlarged liver and jaundice. The
formation of cataracts , mental retardation and an early
death
Reasons: due to a deficiency of the galactose-1phosphate uridylyl transferase
hence cannot metabolize galactose.
Treating: by prescribing a galactose-free diet which
causes all the symptoms to regress except mental
retardation which may be irreversible.
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Disease cases
1. Diabetes mellitus (糖尿病)
2. Hypoglycemia (低血糖症)
3. Galactosemia (半乳糖血症)
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Concepts
1 Glycolysis
2 Gluconeogenesis
3 The Cori Cycle ( lactate cycle )
4 Pentose Phosphate Pathway
5 Glycogen
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Questions
1 As you know, which kinds of sugar in daily
life belong to monosaccharide? Which ones
belong to disaccharide? Which ones belong to
polysaccharide?
2 What are the key enzymes for the glycolysis
pathway? The location in cells?
3 Which kinds of substances can be turned to
glucose through gluconeugensis pathway?
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4 How many ATP could be produced when one
of molecule of glucose be metabolized by
glycolysis pathway or by aerobic oxidization
pathway?
5 What are the significances of pentose
phosphate pathway ?
6 In which organ, glycogen can be degraded to
glucose ? Why?
7 What is the key enzyme for glycogen synthesis
or glycogen degradation, respectively?
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Thank you
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