chap 4 metabolism of carbohydrates
DESCRIPTION
Chap 4 Metabolism of Carbohydrates. Substance metabolism. Relationship of each metabolism. External substance → internal subtance. Assimilation. Micromolecule → Biomacromolecule. Anabolism. Endergonic reaction. Metabolism. Substance metabolism. Energy metabolism. Exergonic reaction. - PowerPoint PPT PresentationTRANSCRIPT
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目录
Chap 4Chap 4
Metabolism of Metabolism of CarbohydratesCarbohydrates
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目录
Substance metabolism
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目录
Relationship of each metabolism
MetabMetabolismolism
AssimilationAssimilation
DissimilationDissimilation
External substance External substance →→ internal subtance internal subtance
Endergonic Endergonic reactionreaction
Exergonic Exergonic reactionreaction
BiomacromoleculeBiomacromolecule→→MicromoleculeMicromolecule
Internal substance Internal substance →→ External substance External substance
Energy Energy metabolismmetabolism
Substance Substance metabolismmetabolism
Catabolism
MicromoleculeMicromolecule→→BiomacromoleculeBiomacromolecule
Anabolism
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Carbohydrates:Carbohydrates: Carbohydrates are polyhydroxy aldehydes or ketones,or substances that yield such compounds on hydrolysis.
Definition of carbohydrate (saccharide)Definition of carbohydrate (saccharide)
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Carbohydrates are classified Carbohydrates are classified into four types according to their into four types according to their hydrolysates:hydrolysates:
monosaccharidemonosaccharide
oligosaccharideoligosaccharide
polysaccharidepolysaccharide
glycoconjugateglycoconjugate
classes and structure of carbohydrates:classes and structure of carbohydrates:
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OH
OH H
H OH
H OH
O
OH
O
OHHHH
OHOH
H OH
H
CH2OH
glucose( aldohexose )
fructose( ketohexose )
OH
O
H OH
OH H
H OH
H OH
monosaccharide monosaccharide It’s the simplest of the carbohydrates that could not be hydrolyzed any more.
O
OHOH
HOH2C
HH
OH H
CH2OH
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O
OHH
HOH
HOH
H OH
H
CH2OH
O
HH H H
OH OH
OHHOH2C
OH
O
H OH
OH H
OH H
H OH
galactose( aldohexose )
ribose( aldopentose )
OH
H OH
H OH
OH
O
H
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The common disaccharides:
maltose : glucose — glucose
sucrose : glucose — fructose
lactose : glucose — galactose
oligosaccharide 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.
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The common polysaccharides :
starch
glycogen
cellulose
polysacchride polysacchride The polysaccharides are sugar polymers containingmore than 20 or so monosaccharide units, and somehave hundreds or thousands of units.
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• Starch Starch —— The most important storage polysaccharides are starch in plant cells
Starch granules
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• Glycogen Glycogen —— glycogen are stored forms of fuel in animal cells
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microfibrilmicrofibril fiberfiberIndividual cellulose Individual cellulose
moleculemolecule
hydrogen bondhydrogen bond
• cellulose cellulose —— the skeleton of plants
ß1-4 linkage
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glycolipid : a compound that consists of a lipid and a
carbohydrateglycoprotein : have one or several oligosaccharides of varying complexity joined covalently to a protein.
The common glycoconjugates :
glycoconjugate glycoconjugate the informational carbohydrate is covalently joined to a protein or a lipid to form a glycoconjugate, which is the biologically active molecule.
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Part IPart I
IntroductionIntroduction
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The main function of carbohydrates is to provide your body with energy and carbon.
e.g. Carbohydrate provides
material for synthesis of amino
acid, nucleotide, coenzyme, fatty
acid, or other metabolic
intermediate.
Structural elements of cells and tissues
Source of material for anabolism
e.g. Carbohydrates are
components of glycoprotein,
proteoglycans and glycolipids.
1. The main physiological function of 1. The main physiological function of carbohydrate: Oxidation of fuelcarbohydrate: Oxidation of fuel1. The main physiological function of 1. The main physiological function of carbohydrate: Oxidation of fuelcarbohydrate: Oxidation of fuel
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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 site : most in the small intestine,
some in the mouse
2. Digestion and absorption of carbohydrates2. Digestion and absorption of carbohydrates2. Digestion and absorption of carbohydrates2. Digestion and absorption of carbohydrates
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Starch
Maltose + maltotriose(40%) (25%)
α-limit dextrin + isomaltose (30%) (5%)
Glucose
α-amylase in saliva
α-glucosidase α-limit dextrinase
brush border of Intestinal epithelial
cells
Oral cavity
Enteric cavity
α-amylase in pancreatic
Process of digestion : Process of digestion :
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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.
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absorption position : The upper small intestine
Absorption Type :monosaccharide
absorption of carbohydratesabsorption of carbohydrates
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ADP+Pi
ATP
G
Na+
K+
Na+
PUMP
Mucosal cells of IntestinalLum
enPortal
Na+-dependent glucose transporter, SGLT
Brush
border
cellular inner membrane
Absorption mechanismAbsorption mechanism
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Glucose are transported into cells
This process is dependent on glucose transporter (GLUT).
Lumen of small
intestinal
Intestinal epithelial cells
portal
liverCirculation
SGLT
A variety of tissue cells
GLUT
3.Overview of carbohydrate metabolism3.Overview of carbohydrate metabolism3.Overview of carbohydrate metabolism3.Overview of carbohydrate metabolism
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ExtracellularExtracellular
Polysaccharide Polysaccharide and and
oligosaccharideoligosaccharide
intracellularintracellular
glycogenglycogen
Phosphorylase
Activation
hydrolysis
Transferase
Debranching enzyme
Branched-chain break
Phosphorylase
Activationhydrolysis
monosaccharide
(glucose)
intestinal ( amylase 、 oligase)
α 、 β-amylase ExtracellularExtracellular
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目录
Blood glucose
Carbs in food Digestion
absorption
glycogen Bread down
Non-sugar substances
Gluconeogenesis
Synthesis of
glycogen liver (muscle)
glycogen PPP
Other carbs anabolism
Fat, amino acid
glycolysis
Pyruvate
aerobicconditions CO2 + H2O
Provide energy
The sources and outlet of blood glucoseThe sources and outlet of blood glucoseThe sources and outlet of blood glucoseThe sources and outlet of blood glucose
anaerobicconditions lactate
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目录
Part IIPart II
GlycolysisGlycolysis
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Glycolysis:Glycolysis: A process in which glucose A process in which glucose
is partially broken down to two is partially broken down to two
molecules of pyruvate (it is converted molecules of pyruvate (it is converted
into lactate finally ) by cells in into lactate finally ) by cells in
enzyme reactions that do not need enzyme reactions that do not need
oxygen. Glycolysis is also called oxygen. Glycolysis is also called
anaerobic oxidation.anaerobic oxidation.
Position of glycolysisPosition of glycolysis :: cytoplasm
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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.
1. Glycolysis Has Two Phases:1. Glycolysis Has Two Phases:
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1. Phosphorylation of Glucose
Phase I------ glycolytic pathway:Phase I------ glycolytic pathway: The six-carbon glucose break down
into two molecules of the three-carbon
pyruvate
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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:①Low affinity to glucose;
②Regulated by hormone;
Glucokinase play a critical role in the maintenance
of blood glucose and metabolism of carbohydrates.
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2. Conversion of Glucose 6-Phosphate to Fructose 6-Phosphate
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3. Phosphorylation of Fructose 6-Phosphate to Fructose 1,6-Bisphosphate
6-phosphfructokinase-1
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4. Cleavage of Fructose 1,6-Bisphosphate
++
Aldolase
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5. Interconversion of the Triose Phosphates
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6. Oxidation of Glyceraldehyde 3-Phosphate to 1,3-Bisphosphoglycerate
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7. Phosphoryl Transfer from 1,3-7. Phosphoryl Transfer from 1,3-Bisphosphoglycerate to ADPBisphosphoglycerate to ADP
The formation of ATP by phosphorylgroup transfer from a substrate such as 1,3-bisphosphoglycerateis referred to as a substrate-levelsubstrate-levelphosphorylationphosphorylation
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8. Conversion of 3-Phosphoglycerate to 2-Phosphoglycerate
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9. Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate
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ADP ATP K+ Mg2+
pyruvate kinase
10. Transfer of the Phosphoryl Group
from Phosphoenolpyruvate to ADP
Phosphoenolpyruvate
COOH
C
CH2
PPO
Pyruvate
COOH
C=O
CH3
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NADH+H+ needed in this reaction is
provided by Oxidation of Glyceraldehyde 3-
Phosphate in step 6 of glycolytic pathway.
Pyruvate
Lactate
Lactate dehydrogenase (LDH)
NADH + H+ NAD+ COOH
CHOH
CH3
COOH
C=O
CH3
Phase II:Phase II: Pyruvate is converted to lactate.
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E1:Hexokinase
E2: Phosphofructokinase-1E3:Pyruvate kinase
NAD+
lactate
Glycolysis
Glu G-6-P F-6-P F-1, 6-2PATP ADP ATP ADP
2×1,3-Bisphosphoglycerate
2× 3-Phosphoglycerate
2× 2-Phosphoglycerate
2×pyruvate
Dihydroxyacetone phosphate
Glyceraldehyde 3-phosphate
NAD+
NADH+H+
ADP ATP
ADP ATP2× Phosphoenolpyruvate
E2E1
E3
NADH+H+
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Position of glycolysisPosition of glycolysis :: cytoplasmcytoplasm Glycolysis is an anaerobic process through which Glycolysis is an anaerobic process through which
ATP is synthesized .ATP is synthesized . There are three irreversible steps in the process.There are three irreversible steps in the process.
G G-6-P
ATP ADP
Hexokinase
ATP ADP
F-6-P F-1,6-2P Phosphofructokinase-1
ADP ATP
PEP Pyruvate Pyruvate
kinase
Summary of glycolysisSummary of glycolysis
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Method and Quantity of energy-producing:Method and Quantity of energy-producing:
MethodMethod : : substrate-level Phosphorylationsubstrate-level Phosphorylation
Quantity of ATPQuantity of ATP :: From GFrom G 2×2-2= 2ATP2×2-2= 2ATP
From GnFrom Gn 2×2-1= 3ATP2×2-1= 3ATP Fates of lactate:Fates of lactate:
Lactate is released into blood and metabolized in liverLactate is released into blood and metabolized in liver
DecompositionDecomposition
Cori cycleCori cycle (( glyconeogenesisglyconeogenesis ))
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目录
Fructosehexokinase
Glu
G-6-P
F-6-P
F-1,6-2P
ATP
ADP
ATP
ADP
Pyruvae
galactose
UDP-galactose
Glucose1-phosphate
galactokinase
mutase
Mannose
Mannose 6-phosphate
hexokinasemutase
Many hexose besides glucose meet their catabolic fate in glycolysis, after being transformed into hexosephosphate
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Key Enzyme
s
① Hexokinase
② Phosphofructokinase-1
③ Pyruvate kinase
Method of
regulation
① allosteric regulation
② covalent modification
2. Regulation of Glycolysis: 3 key enzymes 2. Regulation of Glycolysis: 3 key enzymes
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1.Phosphofructokinase-1 (PFK-1) is the most 1.Phosphofructokinase-1 (PFK-1) is the most important enzyme to regulate the yield of glycolysisimportant enzyme to regulate the yield of glycolysis
Allosteric regulation
allosteric activator : AMP; ADP;
F-1,6-2P; F-2,6-
2P
allosteric inhibitor : citrate; ATP ( High leve
l )
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ATP regulate the acitivity of ATP regulate the acitivity of Phosphofructokinase-1 (PFK-1)Phosphofructokinase-1 (PFK-1)
ATP binding siteATP binding site RegulationRegulation
substrate-binding site in active centersubstrate-binding site in active center
(( low levellow level ))activationactivation
allosteric regulation site allosteric regulation site
beside active centerbeside active center (( high levelhigh level ))inhibitioninhibition
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Fructose 2,6-bisphosphate is the strongest allosteric Fructose 2,6-bisphosphate is the strongest allosteric
activator of Phosphofructokinase-1activator of Phosphofructokinase-1
When fructose 2,6-bisphosphate binds to its When fructose 2,6-bisphosphate binds to its
allosteric site on PFK-1, it increases that enzyme’s allosteric site on PFK-1, it increases that enzyme’s
affinity for its substrate, fructose 6-phosphate, and affinity for its substrate, fructose 6-phosphate, and
reduces its affinity for the allosteric inhibitors ATP reduces its affinity for the allosteric inhibitors ATP
and citrate.and citrate.
Fructose 2,6-bisphosphate regulate the activity Fructose 2,6-bisphosphate regulate the activity of Phosphofructokinase-1 (PFK-1)of Phosphofructokinase-1 (PFK-1)
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F-6-P
F-1,6-2P
ATP
ADP PFK-1
Phosphoprotein phosphatase
Pi
PKA
ATP
ADP
Pi
Glucagon
ATP cAMP
Activate
F-2,6-2P
+
+
+
–/+
AMP
+
Citrate
––
AMP
+
Citrate
––
PFK-2( active )
FBP-2( inactive )
6-PFK-2
PFK-2( inactive )
FBP-2( active )
P P
FBPase-2
PKA : protein kinase A
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目录
GlucogenGlucogen Fat Fat ProteinProtein GlucoseGlucose Fatty acieFatty acie + + Glycerine Glycerine
Amino acidAmino acid
Acetyl-CoAAcetyl-CoA
OxaloacetaOxaloacetatete
CitrateCitrate
MalateMalate
SuccinatSuccinatee
Succinyl-CoASuccinyl-CoA
α-α-KetoglutaratKetoglutarat
ee
2H +
ADP +Pi
ATP
Ⅱ
ⅢCO2
Oxidative Oxidative phosphorylationphosphorylation
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2. Pyruvate kinase is the second regulation point of 2. Pyruvate kinase is the second regulation point of glycolysisglycolysis
Allosteric regulation
allosteric activator : F-1,6-2P
allosteric inhibitor : Alanine; ATP.
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Covalent modification regulation
Pyruvate kinase
Pyruvate kinase
ATP ADP
Pi phosphoprotein phosphatase
( inactive ) ( active )
Glucagon PKA, CaM kinase
P
PKA : protein kinase A
CaM: calmodulin
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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 it’s transcription.
3. Hexokinase is regulated by feedback suppression3. Hexokinase is regulated by feedback suppression
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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.① Cells without mitochondria : erythrocytes
② Metabolic active cells : leucocyte 、 myeloid cell
3. The main physiological function of 3. The main physiological function of glycolysis: provide energy quickly under glycolysis: provide energy quickly under anaerobic conditions anaerobic conditions
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Part IIIPart III
Aerobic Oxidation Aerobic Oxidation of Carbohydrateof Carbohydrate
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DefinitionDefinition
The aerobic oxidation of carbohydrates is referred to glucose is oxidized to H2O and CO2 under aerobic conditions. It’s the main energy supply mode.
PositionPosition ::cytoplasm and cytoplasm and mitochondriamitochondria
GlycolysisGlycolysis
(( cytoplasmcytoplasm ))
oxidative oxidative phosphorylationphosphorylation
(( mitochondriamitochondria ))
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目录
Phase I : Glytolytic
pathway
Phase II : Oxidative decarboxylation of pyruvatePhase III : TAC cycle
G ( Gn )
Phase IV: Oxidative phosphorylation
Pyrutate
Acetyl-CoA
CO2NADH+H+
FADH2
H2O [O]
ATP ADP
TAC
cytoplasma
mitochondria
1. There are four phases in the process of 1. There are four phases in the process of aerobic oxidation of carbohydratesaerobic oxidation of carbohydrates
CitrateCitrate
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目录
1. Glucose break down into two molecules of the 1. Glucose break down into two molecules of the three-carbon pyruvate in glycolytic pathwaythree-carbon pyruvate in glycolytic pathway
Pyruvate
Acetyl-CoA
NAD+ , HSCoA CO2 , NADH + H+
pyruvate dehydrogenase complex
Overall reaction :
2. Pyruvate is oxidized to Acetyl-CoA and CO2 in 2. Pyruvate is oxidized to Acetyl-CoA and CO2 in mitochondriamitochondria
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目录
The composition of pyruvate dehydrogenase complex
E1 : pyruvate dehydrogenase
E2 : dihydrolipoyl transacetylase
E3 : dihydrolipoyl
dehydrogenase
HSCoA
NAD+
TPP lipoate ( )HSCoA
FAD, NAD+
S
SL
enzymes
Coenzymes
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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.
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CO2
CoASH
NAD+
NADH+H+
5. Generation of NADH+H+
1.Generation of -hydroxyethyl-TPP
2.Generation of Acyl lipoyllysine
3.Generatin of Acetyl-CoA
4. Generation of lipoyllysine
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目录
Tricarboxylic Acid Cycle (TAC)Tricarboxylic Acid Cycle (TAC) is also named is also named
citric acid cyclecitric acid cycle ,, because the first intermediate because the first intermediate
product is citric acid containing three carboxylor, product is citric acid containing three carboxylor,
or the or the Krebs cycleKrebs cycle (after its discoverer, Hans (after its discoverer, Hans
Krebs). Krebs).
overview
Position of reaction Position of reaction :: mitochondriamitochondria
2. TCA is a circulation response system based 2. TCA is a circulation response system based on the formation of citric acid as starting on the formation of citric acid as starting materialmaterial
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目录
1. The Citric Acid Cycle Has Eight Steps1. The Citric Acid Cycle Has Eight Steps
1. The condensation of acetyl-CoA with oxaloacetate to 1. The condensation of acetyl-CoA with oxaloacetate to
form citrate.form citrate.
2.2. Formation of Isocitrate via cis-Aconitate. Formation of Isocitrate via cis-Aconitate.
3. Oxidation of Isocitrate to α-Ketoglutarate and CO2.3. Oxidation of Isocitrate to α-Ketoglutarate and CO2.
4. Oxidation of α-Ketoglutarate to Succinyl-CoA and 4. Oxidation of α-Ketoglutarate to Succinyl-CoA and
CO2.CO2.
5. Conversion of Succinyl-CoA to Succinate.5. Conversion of Succinyl-CoA to Succinate.
6. Oxidation of Succinate to Fumarate.6. Oxidation of Succinate to Fumarate.
7. Hydration of Fumarate to Malate.7. Hydration of Fumarate to Malate.
8. Oxidation of Malate to Oxaloacetate8. Oxidation of Malate to Oxaloacetate
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CoASH
NADH+H+
NAD+
COCO22
NAD+
NADH+H+
COCO
22GTPGTPGDP+PiGDP+PiFAD
FADH2
NADH+H+
NAD+
H2O
H2O
H2O
CoASHCoASH
⑧
① ②
③
④
⑤
⑥
⑦
②
H2O
①citrate synthase
②aconitase
③isocitrate dehydrogenase
④α-ketoglutarate dehydrogenase complex
⑤succinyl-CoA synthetase
⑥succinate dehydrogenase
⑦fumarase
⑧malate dehydrogenase
GTP GDP
ATPADP
nucleoside diphosphate kinase
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目录
⑴ ⑴ Formation of Citrate:Formation of Citrate:
Inreversible reactionInreversible reaction
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⑵ ⑵ Formation of IsocitrateFormation of Isocitrate
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⑶ ⑶ Oxidation of Isocitrate to α-Ketoglutarate Oxidation of Isocitrate to α-Ketoglutarate ::
Inreversible reactionInreversible reaction
MgMg2+2+
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⑷⑷Oxidation of α-Ketoglutarate to Succinyl-CoA Oxidation of α-Ketoglutarate to Succinyl-CoA
Inreversible reactionInreversible reaction
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⑸⑸substrate-level phosphorylationsubstrate-level phosphorylation ::Conversion of Succinyl-CoA to SuccinateConversion of Succinyl-CoA to Succinate
The only substrate-level The only substrate-level phosphorylation reaction which phosphorylation reaction which produced GTP in TACproduced GTP in TAC
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⑹ ⑹ Oxidation of Succinate to Fumarate:Oxidation of Succinate to Fumarate:
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⑺⑺Hydration of Fumarate to MalateHydration of Fumarate to Malate ::
HH22OO
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⑻⑻Oxidation of Malate to OxaloacetateOxidation of Malate to Oxaloacetate ::
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SummarySummary ::
Definition of TACDefinition of TAC :: Acetyl-CoA entered the cycle by combining Acetyl-CoA entered the cycle by combining
with oxaloacetate to form citrate containing three carboxyls. Two with oxaloacetate to form citrate containing three carboxyls. Two
carbon atoms emerged from the cycle as CO2 from the oxidation of carbon atoms emerged from the cycle as CO2 from the oxidation of
isocitrate and isocitrate and αα-ketoglutarate. The energy released by these -ketoglutarate. The energy released by these
oxidations was conserved in the reduction of three NAD+ and one 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 FAD and the production of one ATP or GTP. At the end of the cycle
a molecule of oxaloacetate was regenerated.a molecule of oxaloacetate was regenerated.
Position of TAC reaction : Position of TAC reaction : mitochondriamitochondria
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目录
One substrate level prosphorylation 、 Two decarboxylation 、 Three key enzymes 、 Four dehydrogenation
Four Four dehydrogenationdehydrogenation One substrate level One substrate level
osphorylationosphorylation
Two Two decarboxylationdecarboxylation
Three keyThree key enzymesenzymes
TAC
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Following a cycle :Following a cycle :
• Consumption: Consumption: one Acetyl-CoAone Acetyl-CoA ;;• Undergo: Undergo: four dehydrogenationfour dehydrogenation ,, two decarboxylationtwo decarboxylation , , one substrate level prosphorylationone substrate level prosphorylation ;;• Generation: Generation: one FADH2one FADH2 ,, three NADH+H+three NADH+H+ ,, two CO2two CO2 , , one GTPone GTP ;;• Key enzymeKey enzyme :: citrate synthasecitrate synthase , , isocitrate dehydrogenase,isocitrate dehydrogenase,
α-ketoglutarate dehydrogenase complex.α-ketoglutarate dehydrogenase complex.
The whole cycle reaction is irreversible.
Highlight of TAC :
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目录
The intermediate products of TAC performed The intermediate products of TAC performed
as a catalystas a catalyst without change of it’s quantity. without change of it’s quantity.
Oxaloacetate or other intermediate products can Oxaloacetate or other intermediate products can
neither be synthesized directly from Acetyl-CoA, neither be synthesized directly from Acetyl-CoA,
nor be oxidized directly to CO2 and H2O in TAC.nor be oxidized directly to CO2 and H2O in TAC.
intermediate product of TAC:
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Apparently , Oxaloacetate which does not be consumed in TAC could be used in recycling.
In fact:
e.g. Oxaloacetate aspartate
α-ketoglutarate glumatic acid
citrate fatty acid
Succinyl-CoA porphyrin
Ⅰ. 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.
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目录
Ⅱ. 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.
Oxaloacetate oxaloacetic decarboxylase
Pyruvate
CO2
Malate malic enzyme
Pyruvate
CO2 NAD+ NADH + H+
Oxaloacetate must be replenished continuouslyOxaloacetate must be replenished continuously
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目录
Oxaloacetat
Oxaloacetat
ee
CitrateCitrateCitrate lyaseCitrate lyase
Acetyl-CoA
PyruvatePyruvate pyruvate pyruvate carboxylasecarboxylase
CO2
MalateMalate
malate malate dehydrogenasedehydrogenase
NADH+H+ NAD+
AspartateAspartateGOTGOT
α-ketoglutarateGlu
The source of oxaloacetate :
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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.
NADH+H+ H2O 、 2.5ATP [O]
H2O 、 1.5ATP FADH2
[O]
3. Aerobic oxidation of carbohydrate is the main 3. Aerobic oxidation of carbohydrate is the main method to get ATP of organism. method to get ATP of organism.
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Phase I(Cytoplasma)
Phase III(Mito matrix)
Phase II(Mito matrix)
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Aerobic oxidation of carbohydrate is the main method Aerobic oxidation of carbohydrate is the main method
to get ATP of organism. The generation of energy is to get ATP of organism. The generation of energy is
not only efficient but also gradually in this way. The not only efficient but also gradually in this way. The
energy of oxidations in the cycle is efficiently energy of oxidations in the cycle is efficiently
conserved by the formation of ATP.conserved by the formation of ATP.
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目录
TCA cycle has important TCA cycle has important physiological significance in the physiological significance in the metabolism of three major nutrients metabolism of three major nutrients
1.1. TCA cycleTCA cycle is the last metabolic pathway of three is the last metabolic pathway of three
nutrients to provide reducing equivalents for the nutrients to provide reducing equivalents for the
generation of ATP in oxidative phosphorylation generation of ATP in oxidative phosphorylation
through four dehydrogenations.through four dehydrogenations.
2.2. TCA cycle is a key point to communicate the TCA cycle is a key point to communicate the
metabolism of protein, carbohydrate and fat.metabolism of protein, carbohydrate and fat.
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目录
GlucogenGlucogen Fat Fat ProteinProtein GlucoseGlucose Fatty acieFatty acie + + Glycerine Glycerine
Amino acidAmino acid
Acetyl-CoAAcetyl-CoA
OxaloacetaOxaloacetatete
CitrateCitrate
MalateMalate
SuccinatSuccinatee
Succinyl-CoASuccinyl-CoA
α-α-KetoglutaratKetoglutarat
ee
2H +
ADP +Pi
ATP
Ⅱ
ⅢCO2
Oxidative Oxidative phosphorylationphosphorylation
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目录
KeyEnzyme
① Glycolytic pathway :
② oxidative decarboxylation of pyruvate :③ TCA cycle :
Hexokinasepyruvate kinasePhosphofructokinase-1
citrate synthaseα-ketoglutarate dehydrogenase complexisocitrate dehydrogenase
4. The regulation of aerobic oxidation of 4. The regulation of aerobic oxidation of carbohydrate is dependent on the requirement carbohydrate is dependent on the requirement of energy.of energy.
Pyruvate dehydrogenase complex
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The regulation of Pyruvate dehydrogenase complex
allosteric regulation
allosteric inhibitor : Acetyl-CoA ; NADH ;
ATP
allosteric activator : AMP ; ADP ; NAD+
this enzyme activity is turned off when ample fuel is available
in the form of fatty acids and acetyl-CoA and when the cell’s
[ATP]/[ADP] and [NADH]/[NAD+] ratios are high.
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Covalent modificationglucagonglucagon
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TCATCA cycle is regulated by substrate, cycle is regulated by substrate, products and the activity of key products and the activity of key enzymes.enzymes.
Three factors govern the rate of flux through Three factors govern the rate of flux through
the cycle: substrate availability, inhibition by the cycle: substrate availability, inhibition by
accumulating products, and allosteric accumulating products, and allosteric
feedback inhibition of the enzymes that feedback inhibition of the enzymes that
catalyze early steps in the cycle.catalyze early steps in the cycle.
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11 .. There are three key enzymes in TCA There are three key enzymes in TCA cycle:cycle:
citrate synthase, citrate synthase,
Isocitrate dehydrogenaseIsocitrate dehydrogenase
αα-ketoglutarate dehydrogenase-ketoglutarate dehydrogenase
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目录
Acetyl-CoA
Citrate Oxaloacetate
Succiny-CoA
α--Ketoglutarate
Isocitrate
Malate NADH
FADH2
GTP ATP
isocitratedehydrogenase
citratesynthase
α-ketoglutarate dehydrogenase complex
– ATP
+ ADP
ADP +
ATP – CitrateCitrate Succiny-CoA NADH
– Succiny-CoA NADH
+ Ca2+
Ca2+
① Effect of ATP 、 ADP
② inhibition by accumulating products
③allosteric feedback inhibition of the enzymes that catalyze early steps in the cycle.
④ others , e.g. Ca2+ activate enzymes
The regulation of TAC
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22 .. The rates of TCAThe rates of TCA cycle and the other reactions of cycle and the other reactions of its upstream or downstream are integrated.its upstream or downstream are integrated.
Under normal conditions, the rate of glycolysis is matched to the Under normal conditions, the rate of glycolysis is matched to the
rate of the citric acid cycle not only through its inhibition by high rate of the citric acid cycle not only through its inhibition by high
levels of ATP and NADH, which are common to both the levels of ATP and NADH, which are common to both the
glycolytic and respiratory stages of glucose oxidation, but also by glycolytic and respiratory stages of glucose oxidation, but also by
the concentration of citrate which play a the concentration of citrate which play a allosteric inhibitiallosteric inhibition to on to
PFK-1.PFK-1.
The rate of oxidative phosphorylation play an important role in The rate of oxidative phosphorylation play an important role in
the progress of TCA cycle.the progress of TCA cycle.
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目录
2ADP ATP+AMP
adenylate kinase
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
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.
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Definition
Mechanism Under aerobic conditions, NADH+H+ 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.
Pasteur effect: The inhibiting effect of oxygen on the process of fermentation.
5. The inhibiting effect of oxygen on the process 5. The inhibiting effect of oxygen on the process of fermentationof fermentation
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Part IVPart IV
Other Metabolism Other Metabolism Pathways of GlucosePathways of Glucose
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目录
Definition
Pentose phosphate pathway is the progress
of glucose produces pentose phosphates and
NADPH+H+, then the pentose phosphates is
converted into Glyceraldehyde 3-phosphate and
fructose 6-phosphate.
1.Pentose phosphate pathway 1.Pentose phosphate pathway produces pentose phosphates produces pentose phosphates and NADPH+Hand NADPH+H++
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目录
PositionPosition :: CytosolCytosol
Phase I: The Oxidative Phase
1. The progress of pentose phosphate pathway has two phases:
The reaction has two phases:
Phase II : The Nonoxidative Phase
Produces Pentose Phosphates, NADPH+H+ and CO2
Including a series of group transfer.
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目录
NADPH+H+
NADP+
⑴
H2O
NADP+ CO2
NADPH+H+
⑵
glucose 6-phosphatedehydrogenase
6-phosphogluconatedehydrogenase
C
C
C
C
COO—
CH2O
H
OH
OH
OHH
H
HO
H
PP
6-Phosphogluconate
HH
COCO
HH
CH2OH
C=O
C
C
CH2O
OH
OHH
H
PPRibulose5-phosphate
CH2OH
C O
glucose 6-phosphate
C
C
C
C
C
CH2O
H
OH
OH
OH
H
H
HO
H
H
O
PP
6-Phosphoglucono-lactone
C
C
C
C
C=O
CH2O
H
OH
OH
H
H
HO
H
O
PP
1 . glucose 6-phosphate undergoes oxidation and to form the pentose phosphates and NADPH
Ribose5-phosphate
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目录
The The glucose 6-phosphate dehydrogenase glucose 6-phosphate dehydrogenase which which catalyze the first step is the key enzyme of the catalyze the first step is the key enzyme of the pathway.pathway.
H+ produced in two dehydrogenations were H+ produced in two dehydrogenations were accepted by accepted by NADPNADP+ + to generate to generate NADPH + HNADPH + H++ . .
ribose phosphate generated in reaction is a very ribose phosphate generated in reaction is a very important intermediated product.important intermediated product.
G-6-PRibose
5-phosphate
NADP+ NADPH+H+ NADP+ NADPH+H+
CO2
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The significance of phase II is the transformation The significance of phase II is the transformation
of ribose to fructose 6-phospherate and of ribose to fructose 6-phospherate and
Glyceraldehyde 3-phosphate by a series of group Glyceraldehyde 3-phosphate by a series of group
transfer reaction, then enter the glycolysis. So, transfer reaction, then enter the glycolysis. So,
pentose phosphate pathway is also named pentose phosphate pathway is also named pentose pentose
phosphate shunt.phosphate shunt.
2 . Enter the glycolysis by the group transfer reaction
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Ribulose 5-phosphate (C5) ×3
Ribose5-phosphate
C5Xylulose 5-phospha
te
C5
Xylulose 5-phosphate
C5
Sedoheptulose7-phosphate
C7
Glyceraldehyde3-phosphate
C3
Erythrose4-phosphate
C4
Fructose6-phosphate
C6
Fructose6-phosphate
C6
Glyceraldehyde3-phosphate
C3
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目录
pentose phosphate pathway Phase I
Phase II
glucose 6-phosphate(C6)×3
6-Phosphoglucono-lactone(C6)×3
6-Phosphogluconate(C6)×3
Ribulose 5-phosphate(C5) ×3
Ribose 5-phosphate C5
3NADP+
3NADP+3H+
6-phosphogluconate dehydrogenase3NADP+
3NADP+3H+
glucose 6-phosphate dehydrogenaseglucose 6-phosphate dehydrogenase
CO2
Xylulose 5-phosphate C5c
Sedoheptulose7-phosphate C7
Glyceraldehyde3-phosphate C3
Erythrose4-phosphate C4
Fructose6-phosphate C6
Fructose6-phosphate C6
Glyceraldehyde3-phosphate C3
Xylulose 5-phosphate C5c
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目录
reaction formula:
3×glucose 6-phosphate + 6 NADP+
2×Fructose 6-phosphate +
Glyceraldehyde 3-phosphate +
6NADPH+H+
+3CO2
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目录
Hydrogen receptor of dehydrogenation is Hydrogen receptor of dehydrogenation is NADPNADP++ , , to generateto generate
NADPH+HNADPH+H++ 。 。 Transaldolase and transketolase catalyze the interconversion of three-, Transaldolase and transketolase catalyze the interconversion of three-,
four-, five-, six-, and seven-carbon sugars, with the reversible conversion four-, five-, six-, and seven-carbon sugars, with the reversible conversion
of six pentose phosphates to five hexose phosphates.of six pentose phosphates to five hexose phosphates.
The reaction provides specialized intermediated product: ribose 5-The reaction provides specialized intermediated product: ribose 5-
phosphate.phosphate.
One CO2One CO2 and and two NADPH+H+two NADPH+H+ were generated by one G-6-P through were generated by one G-6-P through
one decarboxylation and two dehydrogenation in a cycleone decarboxylation and two dehydrogenation in a cycle.
CharacteristicCharacteristic of of pentose phosphate pathwaypentose phosphate pathway::CharacteristicCharacteristic of of pentose phosphate pathwaypentose phosphate pathway::
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目录
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.
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目录
3. the significance of pentose phospherate is the
generation of NADPH and ribose 5-phosphate
2 . Provide NADPH as hydrogen donor to participate in various metabolic reactions
1 . Provide ribose for biosynthesis of nucleotides.
( 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).
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目录
2G-SH G-S-S-G
NADP+ NADPH+H+
A AH2
oxidized glutathioneReduced 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.
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目录
FavismFavism :: 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
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目录
Glycogenesis and Glycogenesis and GlycogenolysisGlycogenolysis
Part VPart V
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目录
Nonreducing ends : polyReducing
end
Nonreducing ends
shape : branched polymer
MW : 1,000,000 ~ 10,000,000
Reducing end : one
Structure of glycogenStructure of glycogenStructure of glycogenStructure of glycogen
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目录
Distribution of glycogenDistribution of glycogenDistribution of glycogenDistribution 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
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目录
Position: Cytoplasma of liver, muscle …
1. Most anabolism of glycogen 1. Most anabolism of glycogen occurred in liver and muscle.occurred in liver and muscle.1. Most anabolism of glycogen 1. Most anabolism of glycogen occurred in liver and muscle.occurred in liver and muscle.
Definition: The synthesis progress of glycogen from monosaccharide is named glycogenesis.
Monosaccharide: Glucose (main), fructose, galactose …
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Glucose is converted to glucose 6-phosphateGlucose is converted to glucose 6-phosphateGlucose is converted to glucose 6-phosphateGlucose is converted to glucose 6-phosphate
ATP ADP
Glucokinase
Mg2+
glucose
O H
HH
H
OHOH
H OH
OH
CH2OH
glucose-6-phosphate
O H
HH
H
OHOH
H OH
OH
CH2OPO3H2
Glucose + ATP glucose-6-phosphate+ADP
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Glucose-6-phosphate Glucose-1-phosphate
Glucose-6-phosphate is isomerized to Glucose-6-phosphate is isomerized to glucose-1-phosphateglucose-1-phosphate
Glucose-6-phosphate is isomerized to Glucose-6-phosphate is isomerized to glucose-1-phosphateglucose-1-phosphate
OH
OH
OP
OHO
CH2
OHOH
OH
O
glucose-1-phosphate
phosphoglucomutase
PO
OH
OHO
OCH2
OHOH
OH
OH
glucose-6-phosphate
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The generation of UDP-glucoseThe generation of UDP-glucoseThe generation of UDP-glucoseThe generation of UDP-glucose
O H
HH
H
OHOH
H OH
O
CH2OH
P
O
OH
OH
glucose-1-phosphate
UTPUDPG
pyrophosphorylase
UTP+ G-1-P UDPG+ PPi
H2O
2Pi
O H
HH
H
OHOH
H OH
O
CH2OH
P
O
OH
O ÄòÜÕP
O
OH
O
UDPG(uridine diposphate glucose)
PPi
urdine
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The glucose in UDPG is attached toThe glucose in UDPG is attached to glycogen primer glycogen primer
The glucose in UDPG is attached toThe glucose in UDPG is attached to glycogen primer glycogen primer
ÄòÜÕPP
O H
HH
H
OHOH
H OH
CH2OH
UDPG
ROH O
O H
HH
H
OH
H OH
CH2OH
O
OH
HH
H
OH
H OH
CH2OH
Gn(glycogen primer)
RO O
O H
HH
H
OH
H OH
CH2OH
O
OH
HH
H
OH
H OH
CH2OH
O H
HH
H
OHOH
H OH
CH2OH
Glycogen synthase
Gn+
(glycogen)
UDP
urdine
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目录
The branching enzyme catalyze the formation of The branching enzyme catalyze the formation of new branches on glycogennew branches on glycogen
The branching enzyme catalyze the formation of The branching enzyme catalyze the formation of new branches on glycogennew branches on glycogen
Glycogen primer
Glycogen synthase
Branching enzyme
Rate-limiting enzyme
12~18G
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目录
Scheme of the synthesis Scheme of the synthesis of glycogenof glycogen
Scheme of the synthesis Scheme of the synthesis of glycogenof glycogen
Energy consumptionEnergy consumption
need primerneed primer
nonreducing endnonreducing end
glucose
G-1-P
Glycogen (1→4 and 1→6 glucose unit)
G-6-P
ATPADP
UDPG
UTP
PPi
Glycogen (1→4 glucose unit)
Glycogen primer
UDP
Back
Branching enzymeBranching enzyme
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目录
2. The production of glycogen degradation: 2. The production of glycogen degradation:
glucose could replenish the blood glucoseglucose could replenish the blood glucose 2. The production of glycogen degradation: 2. The production of glycogen degradation:
glucose could replenish the blood glucoseglucose could replenish the blood glucose
Position: Liver
Production: Glucose
Glycogen-degrading The progress that glycogen is degraded to glucose.
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Glycogen is phosphorolytic cleavaged to G-1-PGlycogen is phosphorolytic cleavaged to G-1-PGlycogen is phosphorolytic cleavaged to G-1-PGlycogen is phosphorolytic cleavaged to G-1-P
PHOSPHORYLASE Rate-limiting enzyme
糖 原 Gn
糖 原 Gn-1
H3PO4
OH
OH
OP
OHO
CH2
OHOH
OH
O
glucose-1-phosphate
Gn+ H3PO4
G-1-P + Gn-1
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PiNonreducing end
Glucose-1-phospherate
phosphorylase
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目录
The function of The function of debranching debranching
enzymeenzyme
The function of The function of debranching debranching
enzymeenzyme
G
G-1-P
Pi
Debranching enzymeDebranching enzyme has two activities:α-1,4- transglycosylaseα-1,6- glycosidase
Debranching enzyme
Debranching enzyme
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G-1-P is converted to G-6-PG-1-P is converted to G-6-PG-1-P is converted to G-6-PG-1-P is converted to G-6-P
OH
OH
OP
OHO
CH2
OHOH
OH
O
glucose-1-phosphate
PO
OH
OHO
OCH2
OHOH
OH
OHglycophosphomutase
glucose-6-phosphate
G-1-P G-6-P
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G-6-P is hydrolyzed to GlucoseG-6-P is hydrolyzed to Glucose G-6-P is hydrolyzed to GlucoseG-6-P is hydrolyzed to Glucose
glucose
O H
HH
H
OHOH
H OH
OH
CH2OH
glucose-6-phosphate
O H
HH
H
OHOH
H OH
OH
CH2OPO3H2 H3PO4H2O
Glucose -6 - phosphatase
( liver )
G-6-P+ H2O Glucose + H3PO4
This enzyme is deficient in brain and muscle
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目录
Scheme of Scheme of the glycogen-the glycogen-degradationdegradation
Scheme of Scheme of the glycogen-the glycogen-degradationdegradation
GlycogenGn+1
G-1-P
Pi
Gn
phosphorylase
G-6-P
glucophosphomutase
Glucose
H2O
PiGlucose-6-phosphatase
Catabiosis of carbohydrate
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目录
The synthesis and degradation of glycogen
UDPG pyrophosphorylase
G-1-P UTP
UDPG
PPi
Gn+1 UDP
G-6-P G
Glycogen synthase
glucophosphomutase
Hexokinase (glucokinase)
Gn
Pi
phosphorylase
Glucose-6-phosphatase(liver)
Gn
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目录
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
Comparison of liver glycogen and muscle Comparison of liver glycogen and muscle glycogenglycogen
Comparison of liver glycogen and muscle Comparison of liver glycogen and muscle glycogenglycogen
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目录
三三 .. 糖原合成与分解受到彼此相反的调节糖原合成与分解受到彼此相反的调节
Key enzyme of Key enzyme of glycogen degradationglycogen degradation
Glycogen synthaseGlycogen synthase
Key enzyme of Key enzyme of glycogen synthesisglycogen synthesis
Glycogen synthase
Glycogen synthase PPinactiveinactive
activeactive
3. Glycogen synthesis and glycogen 3. Glycogen synthesis and glycogen
degradation are regulated by each otherdegradation are regulated by each other 3. Glycogen synthesis and glycogen 3. Glycogen synthesis and glycogen
degradation are regulated by each otherdegradation are regulated by each other
phosphorylase
PP
Key enzyme of Key enzyme of glycogen degradationglycogen degradation
phosphorylase
PPphosphorylase
PhosphorylasePhosphorylase
Key enzyme of Key enzyme of glycogen degradationglycogen degradation
activeactive
inactiveinactivephosphorylase
PP
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目录
ATP cAMP+PPi
Phosphorylation of integral protein
Change the process of physiology in cells
Cell membraneCell membrane
Cell membraneCell membrane
cR
Protein kinase ( inactive )
c + R cAMP
Protein kinase ( active )
Receptor cyclase
Hormone
G Protein
Unphosphorylated Protein kinase
ATP ADPPhosphorylatedProtein kinase
Hormone regulate the metabolism by cAMP-protein kinaseHormone regulate the metabolism by cAMP-protein kinase
covalent covalent modificationmodification
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目录
Hormone Hormone regulate the regulate the
synthesis and synthesis and degradation of degradation of liver glycogenliver glycogen
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
Adrenalin/Glucagon
1 、 adenylcyclase ( inactive ) adenylcyclase ( activ
e )2 、 ATP
cAMP
R 、 cAMP
3 、 protein kinase ( inactive
)Protein kianse ( activ
e )
4 、 phosphorylase kinase ( inactive )Phosphorylase kinase
( active )
5 、 phosphorylase b ( inactive ) Phosphorylase a ( activ
e )
6 、 glycogen
G-6-P
G-1-P
glucoseblood
Adrenalin/Glucagon
1
3
2102
104
106
108
Glucose
ATP ADP
ATP ADP
4
5
6
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目录
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目录
Glucagon and adrenalin Glucagon and adrenalin regulate the synthesis regulate the synthesis and degradation of and degradation of glycogenglycogen
Glucagon and adrenalin Glucagon and adrenalin regulate the synthesis regulate the synthesis and degradation of and degradation of glycogenglycogen
Glucagon, adrenalin
adenylcyclase adenylcyclase+
ATP cAMP+
Protein kinase Protein kinase+
Glycogen synthase Glycogen synthase+
Phosphorylase b kinase
Phosphorylase b kinase
+
Phosphorylase b Phosphorylase a+
Enhance the degradation of glycogen
Decrease the synthesis of glycogenCascadeamplification effect 返回
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目录
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.
Result : G , the synthesis of glycogen , the degradation
of glycogen
The regulation of synthesis and degradation of liver glycogen
The regulation of synthesis and degradation of liver glycogen
When the blood glucose When the blood glucose increaseincrease
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The synthesis and degradation of muscle glycogen
Synthesis: same to liver glycogen (without three-carbons Synthesis: same to liver glycogen (without three-carbons pathway)pathway)
Degradation: different to liver glycogen, (without G6PE)Degradation: different to liver glycogen, (without G6PE)
glycogenglycogenG-6-P G-6-P glycolytic pathwayglycolytic pathway RegulationRegulation :: adrenalin (mainly)adrenalin (mainly)
AMP: AMP: allosteric activatallosteric activate e phosphorylasephosphorylase-b-b
ATP and G-6-PATP and G-6-P :: inhibit inhibit phosphorylasephosphorylase-b -b
G-6-P: allosteric activate glycogen synthaseG-6-P: allosteric activate glycogen synthase
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Summary of regulation:
Bidirectional regulation : synthase and lytic enzyme were regulated separately. e.g. enhance the synthesis and decrease the degradation.
Duel regulation : allosteric regulation and covalent modificational regulation.
Difference of regulation on the liver and muscle glycogen: e.g. glucagon degrade the liver glycogen,
adrenalin degrade the muscle glycogen.
There are cascade effect on the regulation of kcy enzyme.
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.
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3. deficiencies of glycogen degrading 3. deficiencies of glycogen degrading enzymes lead to glycogen storage disease 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.
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目录
TypeType Enzyme deficiencyEnzyme deficiency Organ affectedOrgan affected Structure of Structure of glycogenglycogen
ⅠⅠ G-6-PG-6-P Liver, kidneyLiver, kidney normalnormal
ⅡⅡ α1→4 or 1→6 glucosidaseα1→4 or 1→6 glucosidase All organsAll organs normalnormal
ⅢⅢ Debranching enzymeDebranching enzyme Muscle, liverMuscle, liver More More branchbranch ,, short short peripheral carbs peripheral carbs chainchain
ⅣⅣ Branching enzymeBranching enzyme All organsAll organs Less Less branchbranch ,, long long peripheral carbs peripheral carbs chainchain
ⅤⅤ Muscle phosphorylaseMuscle phosphorylase musclemuscle normalnormal
ⅥⅥ Liver phosphorylaseLiver phosphorylase LiverLiver normalnormal
ⅦⅦ phosphofructokinasephosphofructokinase Muscle, Muscle, erythrocyteerythrocyte
normalnormal
ⅧⅧ Phosphorylase kinasePhosphorylase kinase Liver Liver normalnormal
Glycogen storage diseases
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目录
Part VIPart VI
GluconeogenesisGluconeogenesis
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目录
Gluconeogenesis is the synthesis progress of
glucose or glucogen from non-carbohydrate
sources.
Position :
Substrance :
Definition :
Cytoplasma and mitochondria of liver , kidney cells.
Pyruvate, lactate, glycerine, glycogenic amino acid.
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Progress :
Three irreversible reactions catalyzed by three key enzymes in glycolysis must by bypassed in gluconeogenesis.
Most reactions of gluconeogenic pathway and glycolytic pathway are shared and reversible.
gluconeogenic pathway is the synthesis
progress of glucose from pyruvate.
1. Gluconeogenic pathway is 1. Gluconeogenic pathway is not a reversible reaction of not a reversible reaction of glycolytic pathway completelyglycolytic pathway completely
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目录
1. Pyruvate is converted to PEP by pyruvate 1. Pyruvate is converted to PEP by pyruvate carboxylation bypasscarboxylation bypass
Pyruvate oxalacetate PEP
ATP ADP+Pi
CO2 ①
GTP GDP
CO2 ②
① pyruvate carboxylase, coenzyme is biotin (in
mitochondria).
② PEP-carboxykinase ( mitochondrion,
cytoplasma)
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目录
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Oxaloacetate export to the cytosol from Oxaloacetate export to the cytosol from mitochondriamitochondria
Out mitochondria Malate Malate Oxaloacetate oxalozcetate
Oxaloacetate Aspartate In mitochondria Aapartate oxaloacetate
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目录
Pyruvate
Pyruvate
oxaloacetate
pyruvic carboxylaseATP + CO2
ADP + Pi
Malate
NADH + H+
NAD+
Aspartate
glutamate
α-ketoglutarate
Aspartate Malateoxaloacetate
PEP
PEP-carboxykinaseGTP
GDP + CO2
mitocondria
cytoplasma
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目录
The resource of NADH+HThe resource of NADH+H++ in glyconeogenesis in glyconeogenesis:
The generation of glyceraldehyde-3-phosphate
from 1,3-bisphosphoglycerate need NADH+H+ in
glyconeogenesis.
NADH+H+ is provide from latate when the latate is
the resource of glyconeogenesis.
Latate pyruvateLDH
NAD+ NADH+H+
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目录
If amino amid is the resource of glyconeogenesis,
NADH+H+ come from mitochondria where NADH+H+
are derived from β- oxadation of fatty acid or TAC. The
transport of NADH+H+ dependent on the conversion of
oxaloacetate and malate.
Malate
mitochondria
Malateoxaloac
etate
NAD+ NADH+H+NAD+NADH+H+
cytoplasma
oxaloacetate
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2. Conversion of Fructose 1,6-Bisphosphate to 2. Conversion of Fructose 1,6-Bisphosphate to Fructose 6-PhosphateFructose 6-Phosphate
Fructose 1,6-Bisphosphate
Fructose 6-Phosphate
Pi
fructose 1,6-bisphosphatase
(FBPase-1)
3. Conversion of Glucose 6-Phosphate to Glucose3. Conversion of Glucose 6-Phosphate to Glucose
Glucose 6-Phosphate GlucosePi
glucose 6-phosphatase
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A set of forward and reverse reactions catalyzed by different enzymes are called substrate cyclesubstrate 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 cyclefutile cycle. The two-enzyme cycle thus provides a means of controlling the direction of net metabolite flow.
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Fructose 6-Phosphate Fructose 1,6-Bisphosphate
PFK-1
FBPase-1
ADP ATP
Pi
Glucose 6-Phosphate Glucose
glucose 6-phosphatase
hexokinase ATP ADP
Pi
PEP
Pyruvate
oxaloacetate
Pyruvate kinase
pyruvic carboxylase
ADP ATP
CO2+ATP
ADP+Pi GTP
PEP-carboxykinase
GDP+Pi
+CO2
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The non-carbs substances enter the The non-carbs substances enter the gluconeogenesis gluconeogenesis
The substances of gluconeogenesis is converted to the intermediate products of carbohydrates metabolism.
Glucogenic amino acid α-oxoacid-NH2
Glycerine α-phosphoglycerol
Phosphodihydroxyacetone
lactate Pyruvate2H
Above intermediate products enter the gluconeogenesis
pathway and generate to glucose or glycogen.
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The intermediate products of TAC performed The intermediate products of TAC performed
as a catalystas a catalyst without change of it’s quantity. without change of it’s quantity.
Oxaloacetate or other intermediate products can Oxaloacetate or other intermediate products can
neither be synthesized directly from Acetyl-CoA, neither be synthesized directly from Acetyl-CoA,
nor be oxidized directly to CO2 and H2O in TAC.nor be oxidized directly to CO2 and H2O in TAC.
Question about TAC
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Glycolysis and gluconeogenesis are the two metabolic Glycolysis and gluconeogenesis are the two metabolic
pathways in opposite direction. If the gluconeogenesis pathways in opposite direction. If the gluconeogenesis
from pyruvate is carried out effectively, the glycosis from pyruvate is carried out effectively, the glycosis
must be inhibited. And vice versamust be inhibited. And vice versa. This coordination is dependent on the regulation of This coordination is dependent on the regulation of
the two substrate cycle in pathway.the two substrate cycle in pathway.
2. Glycolysis and Gluconeogenesis Are 2. Glycolysis and Gluconeogenesis Are Regulated Regulated Reciprocally through two substrate Reciprocally through two substrate cycle.cycle.
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1. The first substrate cycle: between fructose-6-phosphate and Fructose 1,6-bisphosphate
Frustose-6-phospherate
Fructose 1,6-bisphosphate
ATP
ADP
PFK-1
Pi
FBPase-1
fructose 2,6-bisphosphate
AMP
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2. The second substrate cycle: between PEP and pyruvate
PEP
Pyruvate
ATP
ADPPyruvate kinase
Fructose 1,6-bisphosphate
alanine
Acetyl-CoA
oxaloacetate
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1. The main function of gluconeogenesis: 1. The main function of gluconeogenesis: maintain the stable of blood glucosemaintain 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.
3. The physiological significance of 3. The physiological significance of gluconeogenesis is to maintain the stable gluconeogenesis is to maintain the stable of blood glucose.of blood glucose.
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The substrate of gluconeogenesis are The substrate of gluconeogenesis are lactate, amino acid and glycerine.lactate, amino acid and glycerine.
Lactate come from the muscle glycogenolysis related Lactate come from the muscle glycogenolysis related
with exercise intensity. with exercise intensity.
Amino acid and glycerine are the substrate of Amino acid and glycerine are the substrate of
gluconeogenesis when in hungry.gluconeogenesis when in hungry.
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2. Gluconeogenesis is an important pathway to 2. Gluconeogenesis is an important pathway to replenish and restore the storage of liver glycogenreplenish 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.
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Under long-term fasting and starve conditins, the renal Under long-term fasting and starve conditins, the renal gluconeogenesis is enhanced which is helpful to the gluconeogenesis is enhanced which is helpful to the maintenance of acid-base balance.maintenance of acid-base balance.
The reason of this change maybe the metabolic acidosis: The reason of this change maybe the metabolic acidosis: pHpH↓→ ↓→ PEP-carboxykinasePEP-carboxykinase↑↑→Gluconeogenesis→Gluconeogenesis↑↑
After After αα–ketoglutarate is consumed in glycolysis, the –ketoglutarate is consumed in glycolysis, the deamination of glutamine and glutamic acid will be deamination of glutamine and glutamic acid will be enhanced. NHenhanced. NH33 in renal tubular cells are excreted and in renal tubular cells are excreted and bound with Hbound with H++ in urine to decrease the H in urine to decrease the H++. This is good for . This is good for the excreting of Hthe excreting of H++ and retention of Na and retention of Na++ to protect from to protect from acidosis.acidosis.
3. The enhance of renal gluconeogenesis is helpful to 3. The enhance of renal gluconeogenesis is helpful to the maintenance of acid-base balancethe maintenance of acid-base balance
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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 cycleLactate cycle or Cori cycleCori cycle. Because the enzymes in the liver and muscle are different,
they could contribute to the formation of lactate cycle.
44. Lactate cycle:. Lactate cycle:
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Active gluconeogenesisWith G-6-P【 】
Lactate cycle (Cori cycle)
Liver muscle
Glucose Glucose glucose/muscle
glycogen
glycolysis
Pyruvate
Lactate
NADH
NAD+
LactateLactateNAD+
NADH
Pyruvate
gluconeogenesis
Blood
Low gluconeogenesisWithout G-6-P【 】
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Significance:Avoid waste of lactate
Protect from acidosis caused by accumulation of lactate
Lactate cycle consumes energy:
6 ATP are needed when 2 lactate are generated to 1 glucose.
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Part VIIPart VII
Metabolism of Other MonoseMetabolism of Other Monose
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Fructose, galactoseFructose, galactose and and mannosemannose enter the enter the
glycolysis through converting into glycolysis through converting into
intermediate products of glycolytic pathway.intermediate products of glycolytic pathway.
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Part VIIIPart VIII
The Definition, Level and The Definition, Level and Regulation of Blood GlucoseRegulation of Blood Glucose
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Blood glucose: the glucose in the blood
The level of blood glucose:
The definition and level of blood glucose
Normal blood glucose : 3.89~6.11mmol/L
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The physiological significance of the The physiological significance of the maintenance of blood glucose levelmaintenance 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.
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Blood glucose
Food carbs Digestion/absorption
Liver glycogen
lysis
Non-carbohydrate substrate
gluconeogenesis
oxidation, lysis
CO2 + H2O
Glycogen synthesis
liver(muscle) glycogen
Pentose phosphate pathwayOther carbs
Anabolism of fat, amino acid
Fat, amino acid
1. The resource and outlet of blood glucose is
relative balanced.
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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.
2. The level of blood glucose is mainly regulated by hormone
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The hormones regulate blood
glucose
Decrease blood glucose : insulin
Increase blood
glucose :glucagon
glucocorticoids
epinephrine
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Insulin is the only hormone which can decrease blood Insulin is the only hormone which can decrease blood
glucose and promote synthesis of glycogen, lipids, and glucose and promote synthesis of glycogen, lipids, and
proteins.proteins.
Insulin is released in response to hyperglycemia.Insulin is released in response to hyperglycemia.
1. Insulin is the only hormone which can 1. Insulin is the only hormone which can decrease blood glucose.decrease blood glucose.
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①① Insulin enhance glucose transport into adipose tissue and muscle Insulin enhance glucose transport into adipose tissue and muscle by recruitment of glucose transporters from the interior of the by recruitment of glucose transporters from the interior of the cells to the plasma membrane.cells to the plasma membrane.
②② Insulin reduces the cAMP level in the liver by activating a cAMP-Insulin reduces the cAMP level in the liver by activating a cAMP-degrading phosphodiesterase. By stimulating the glucose-degrading phosphodiesterase. By stimulating the glucose-consuming pathways and inhibiting the glucose-producing consuming pathways and inhibiting the glucose-producing pathways in the liver, insulin lower the blood glucose level.pathways in the liver, insulin lower the blood glucose level.
③③ Insulin activate pyruvate dehydrogenase by activating pyruvate Insulin activate pyruvate dehydrogenase by activating pyruvate dehydrogenase phosphatase, to accelerate oxidation of pyruvate to dehydrogenase phosphatase, to accelerate oxidation of pyruvate to Acetyl-CoA, resulting the aerobic oxidation of carbohydrates.Acetyl-CoA, resulting the aerobic oxidation of carbohydrates.
④④ Insulin inhibit gluconeogenesis in liver by decreasing the synthesis Insulin inhibit gluconeogenesis in liver by decreasing the synthesis of PEP-carboxykinase and promoting the entrance of amino acid of PEP-carboxykinase and promoting the entrance of amino acid into muscle and protein synthesis.into muscle and protein synthesis.
⑤⑤ Insulin slow the speed of fat mobilization through inhibiting the Insulin slow the speed of fat mobilization through inhibiting the hormone-sensitive lipase in fat.hormone-sensitive lipase in fat.
Mechanism of insulin
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2. Different hormone increase blood 2. Different hormone increase blood glucose under different conditions.glucose under different conditions.
11 .. Glucagon is the main hormone which increase Glucagon is the main hormone which increase blood glucose in vivo.blood glucose in vivo.
Glucagon is released in response to hypoglycemia or
high level of amino acid in blood.
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Mechanism of glucagon
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Insulin and glucagon not only regulate blood Insulin and glucagon not only regulate blood glucose, but also play important role on the metabolism glucose, but also play important role on the metabolism regulation of three nutriments.regulation of three nutriments.
The change of carbohydrates, fat and amino acid The change of carbohydrates, fat and amino acid metabolism is decided by the insulin/glucagon ratio.metabolism is decided by the insulin/glucagon ratio.
The secretion of two hormones is opposite. The secretion of two hormones is opposite.
e.g. hyperglycemia stimulate the release of insulin, e.g. hyperglycemia stimulate the release of insulin, but inhibit the release of glucagon.but inhibit the release of glucagon.
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2. Glucocorticoids cause the increase of blood glucose2. Glucocorticoids cause the increase of blood glucose
① ① They can increase gluconeogenesis by enhancing They can increase gluconeogenesis by enhancing hepatic uptake of amino acids and increasing hepatic uptake of amino acids and increasing activity of aminotransferases and key enzymes of activity of aminotransferases and key enzymes of gluconeogenesis.gluconeogenesis.
② ② They inhibit the uptake and utilization of glucose in They inhibit the uptake and utilization of glucose in
extrahepatic tissues.extrahepatic tissues.
Mechanism of glucocorticoids
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3. Epinephrine is stress hormone that increase 3. Epinephrine is stress hormone that increase blood glucoseblood 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.
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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.
3. Dysfunction of carbohydrate metabolism: abnormal blood glucose and diabetes.
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Two common symptoms of carbohydrate Two common symptoms of carbohydrate
metabolism disorder in clinical:metabolism disorder in clinical:
Hypoglycemia Hypoglycemia
Hyperglycemia Hyperglycemia
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1.1. Hypoglycemia: blood glucose concentration Hypoglycemia: blood glucose concentration
below 3.0mmol/Lbelow 3.0mmol/L
Hypoglycemia influence the function of brain Hypoglycemia influence the function of brain
because brain cells depend on the oxidation of glucose to because brain cells depend on the oxidation of glucose to
supply energy.supply energy. Hypoglycemia causes symptoms such as Hypoglycemia causes symptoms such as
dizziness or light-headedness, weakness, palmus even faint dizziness or light-headedness, weakness, palmus even faint
which is called hypoglycemic shock. It can lead to death if which is called hypoglycemic shock. It can lead to death if
we do not give the patient intravenous glucose we do not give the patient intravenous glucose
supplement.supplement.
Hazards of hypoglycemia: Hazards of hypoglycemia:
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①① Dysfunction of pancreas: hyperfunction Dysfunction of pancreas: hyperfunction
of pancreas β-cell, hypofunction of of pancreas β-cell, hypofunction of
pancreas α-cells;pancreas α-cells;
②② Dysfunction of liver: liver cancer, Dysfunction of liver: liver cancer,
glycogen storage disease;glycogen storage disease;
③③ Dyscrinism: hypofunction of Pituitary, Dyscrinism: hypofunction of Pituitary,
hypofunction of adrenal cortex;hypofunction of adrenal cortex;
④④ Tumor: stomach cancer;Tumor: stomach cancer;
⑤⑤ Fasting and starve; Fasting and starve;
The reasons of hypoglycemia:The reasons of hypoglycemia:
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2. hyperglycemia: fasting blood glucose exceed 2. hyperglycemia: fasting blood glucose exceed 6.9mmol/L 6.9mmol/L
In clinical, fasting blood glucose exceed 5.6In clinical, fasting blood glucose exceed 5.6 ~~6.9mmol/L is called hyperglycemia.6.9mmol/L is called hyperglycemia.
When blood glucose concentration exceed the tubular When blood glucose concentration exceed the tubular
reabsorption capacity (renal glucose threshold), reabsorption capacity (renal glucose threshold),
hyperglycemia caused glucosuria.hyperglycemia caused glucosuria.
Persistence hyperglycemia and glucosuria, especially Persistence hyperglycemia and glucosuria, especially
fasting blood glucose and glucose-tolerance are higher fasting blood glucose and glucose-tolerance are higher
than the normal range, it is often caused by diabetes than the normal range, it is often caused by diabetes
mellitus.mellitus.
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①① Diabetes;Diabetes;
②② Genetic defects in insulin receptor; Genetic defects in insulin receptor;
③③ chronic nephritis, nephrotic syndromechronic nephritis, nephrotic syndrome
④④ Physiological hyperglycemia and Physiological hyperglycemia and
glucosuria; glucosuria;
The reasons of hyperglycemiaThe reasons of hyperglycemia ::
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3. Diabetes is a common disease of 3. Diabetes is a common disease of carbohydrate metabolism disordercarbohydrate metabolism disorder
DiabetesDiabetes, caused by a deficiency in the , caused by a deficiency in the
secretion or action of insulin, is a relatively secretion or action of insulin, is a relatively
common disease. common disease.
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Type Ⅰ (insulin-dependent )
Type Ⅱ (non-insulin-
dependent )
Two types of diabetes:
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G ( replenish blood glucose )
G-6-P F-6-P( enter glycolysis )
G-1-P
Gn ( Glycogen synthesis )
UDPG
6-Phosphoglucono-lactone( enter pentose phosphate
pathway )
Problems:
1.The process of glutamate 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?