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目目 Chap 4 Chap 4 Metabolism of Metabolism of Carbohydrates Carbohydrates

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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 Presentation

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Page 1: Chap 4 Metabolism of Carbohydrates

目录

Chap 4Chap 4

Metabolism of Metabolism of CarbohydratesCarbohydrates

Page 2: Chap 4 Metabolism of Carbohydrates

目录

Substance metabolism

Page 3: Chap 4 Metabolism of Carbohydrates

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

Page 4: Chap 4 Metabolism of Carbohydrates

目录

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

Definition of carbohydrate (saccharide)Definition of carbohydrate (saccharide)

Page 5: Chap 4 Metabolism of Carbohydrates

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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:

Page 6: Chap 4 Metabolism of Carbohydrates

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

Page 7: Chap 4 Metabolism of Carbohydrates

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

Page 8: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 9: Chap 4 Metabolism of Carbohydrates

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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.

Page 10: Chap 4 Metabolism of Carbohydrates

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

Starch granules

Page 11: Chap 4 Metabolism of Carbohydrates

• Glycogen Glycogen —— glycogen are stored forms of fuel in animal cells

Page 12: Chap 4 Metabolism of Carbohydrates

microfibrilmicrofibril fiberfiberIndividual cellulose Individual cellulose

moleculemolecule

hydrogen bondhydrogen bond

• cellulose cellulose —— the skeleton of plants

ß1-4 linkage

Page 13: Chap 4 Metabolism of Carbohydrates

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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.

Page 14: Chap 4 Metabolism of Carbohydrates

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Part IPart I

IntroductionIntroduction

Page 15: Chap 4 Metabolism of Carbohydrates

目录

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

Page 16: Chap 4 Metabolism of Carbohydrates

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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

Page 17: Chap 4 Metabolism 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 :

Page 18: Chap 4 Metabolism of Carbohydrates

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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.

Page 19: Chap 4 Metabolism of Carbohydrates

目录

absorption position : The upper small intestine

Absorption Type :monosaccharide

absorption of carbohydratesabsorption of carbohydrates

Page 20: Chap 4 Metabolism 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

Page 21: Chap 4 Metabolism of Carbohydrates

目录

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

Page 22: Chap 4 Metabolism of Carbohydrates

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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

Page 23: Chap 4 Metabolism of Carbohydrates

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

Page 24: Chap 4 Metabolism of Carbohydrates

目录

Part IIPart II

GlycolysisGlycolysis

Page 25: Chap 4 Metabolism of Carbohydrates

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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

Page 26: Chap 4 Metabolism of Carbohydrates

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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:

Page 27: Chap 4 Metabolism of Carbohydrates

目录

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

Page 28: Chap 4 Metabolism of Carbohydrates

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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.

Page 29: Chap 4 Metabolism of Carbohydrates

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2. Conversion of Glucose 6-Phosphate to Fructose 6-Phosphate

Page 30: Chap 4 Metabolism of Carbohydrates

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3. Phosphorylation of Fructose 6-Phosphate to Fructose 1,6-Bisphosphate

6-phosphfructokinase-1

Page 31: Chap 4 Metabolism of Carbohydrates

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4. Cleavage of Fructose 1,6-Bisphosphate

++

Aldolase

Page 32: Chap 4 Metabolism of Carbohydrates

目录

5. Interconversion of the Triose Phosphates

Page 33: Chap 4 Metabolism of Carbohydrates

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6. Oxidation of Glyceraldehyde 3-Phosphate to 1,3-Bisphosphoglycerate

Page 34: Chap 4 Metabolism of Carbohydrates

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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

Page 35: Chap 4 Metabolism of Carbohydrates

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8. Conversion of 3-Phosphoglycerate to 2-Phosphoglycerate

Page 36: Chap 4 Metabolism of Carbohydrates

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9. Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate

Page 37: Chap 4 Metabolism of Carbohydrates

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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

Page 38: Chap 4 Metabolism of Carbohydrates

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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.

Page 39: Chap 4 Metabolism of Carbohydrates

目录

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+

Page 40: Chap 4 Metabolism of Carbohydrates

目录

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

Page 41: Chap 4 Metabolism of Carbohydrates

目录

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 ))

Page 42: Chap 4 Metabolism of Carbohydrates

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

Page 43: Chap 4 Metabolism of Carbohydrates

目录

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

Page 44: Chap 4 Metabolism of Carbohydrates

目录

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 )

Page 45: Chap 4 Metabolism of Carbohydrates

目录

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

Page 46: Chap 4 Metabolism of Carbohydrates

目录

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)

Page 47: Chap 4 Metabolism of Carbohydrates

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

Page 48: Chap 4 Metabolism of Carbohydrates

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

ⅢCO2

Oxidative Oxidative phosphorylationphosphorylation

Page 49: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 50: Chap 4 Metabolism of Carbohydrates

目录

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

Page 51: Chap 4 Metabolism of Carbohydrates

目录

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

Page 52: Chap 4 Metabolism of Carbohydrates

目录

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

Page 53: Chap 4 Metabolism of Carbohydrates

目录

Part IIIPart III

Aerobic Oxidation Aerobic Oxidation of Carbohydrateof Carbohydrate

Page 54: Chap 4 Metabolism of Carbohydrates

目录

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 ))

Page 55: Chap 4 Metabolism of Carbohydrates

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

Page 56: Chap 4 Metabolism of Carbohydrates

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

Page 57: Chap 4 Metabolism of Carbohydrates

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

Page 58: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 59: Chap 4 Metabolism of Carbohydrates

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

Page 60: Chap 4 Metabolism of Carbohydrates

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

Page 61: Chap 4 Metabolism of Carbohydrates

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

Page 62: Chap 4 Metabolism of Carbohydrates

CoASH

NADH+H+

NAD+

COCO22

NAD+

NADH+H+

COCO

22GTPGTPGDP+PiGDP+PiFAD

FADH2

NADH+H+

NAD+

H2O

H2O

H2O

CoASHCoASH

① 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

Page 63: Chap 4 Metabolism of Carbohydrates

目录

⑴ ⑴ Formation of Citrate:Formation of Citrate:

Inreversible reactionInreversible reaction

Page 64: Chap 4 Metabolism of Carbohydrates

目录

⑵ ⑵ Formation of IsocitrateFormation of Isocitrate

Page 65: Chap 4 Metabolism of Carbohydrates

目录

⑶ ⑶ Oxidation of Isocitrate to α-Ketoglutarate Oxidation of Isocitrate to α-Ketoglutarate ::

Inreversible reactionInreversible reaction

MgMg2+2+

Page 66: Chap 4 Metabolism of Carbohydrates

目录

⑷⑷Oxidation of α-Ketoglutarate to Succinyl-CoA Oxidation of α-Ketoglutarate to Succinyl-CoA

Inreversible reactionInreversible reaction

Page 67: Chap 4 Metabolism of Carbohydrates

目录

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

Page 68: Chap 4 Metabolism of Carbohydrates

目录

⑹ ⑹ Oxidation of Succinate to Fumarate:Oxidation of Succinate to Fumarate:

Page 69: Chap 4 Metabolism of Carbohydrates

目录

⑺⑺Hydration of Fumarate to MalateHydration of Fumarate to Malate ::

HH22OO

Page 70: Chap 4 Metabolism of Carbohydrates

目录

⑻⑻Oxidation of Malate to OxaloacetateOxidation of Malate to Oxaloacetate ::

Page 71: Chap 4 Metabolism of Carbohydrates

目录

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

Page 72: Chap 4 Metabolism of Carbohydrates

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

Page 73: Chap 4 Metabolism of Carbohydrates

目录

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 :

Page 74: Chap 4 Metabolism of Carbohydrates

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:

Page 75: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 76: Chap 4 Metabolism of Carbohydrates

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

Page 77: Chap 4 Metabolism of Carbohydrates

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 :

Page 78: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 79: Chap 4 Metabolism of Carbohydrates

目录

Phase I(Cytoplasma)

Phase III(Mito matrix)

Phase II(Mito matrix)

Page 80: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 81: Chap 4 Metabolism of Carbohydrates

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.

Page 82: Chap 4 Metabolism of Carbohydrates

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

ⅢCO2

Oxidative Oxidative phosphorylationphosphorylation

Page 83: Chap 4 Metabolism of Carbohydrates

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

Page 84: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 85: Chap 4 Metabolism of Carbohydrates

目录

Covalent modificationglucagonglucagon

Page 86: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 87: Chap 4 Metabolism of Carbohydrates

目录

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

Page 88: Chap 4 Metabolism of Carbohydrates

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

Page 89: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 90: Chap 4 Metabolism of Carbohydrates

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.

Page 91: Chap 4 Metabolism of Carbohydrates

目录

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

Page 92: Chap 4 Metabolism of Carbohydrates

目录

Part IVPart IV

Other Metabolism Other Metabolism Pathways of GlucosePathways of Glucose

Page 93: Chap 4 Metabolism of Carbohydrates

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++

Page 94: Chap 4 Metabolism of Carbohydrates

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.

Page 95: Chap 4 Metabolism of Carbohydrates

目录

NADPH+H+

NADP+

H2O

NADP+ CO2

NADPH+H+

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

Page 96: Chap 4 Metabolism of Carbohydrates

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

Page 97: Chap 4 Metabolism of Carbohydrates

目录

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

Page 98: Chap 4 Metabolism of Carbohydrates

目录

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

Page 99: Chap 4 Metabolism of Carbohydrates

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

Page 100: Chap 4 Metabolism of Carbohydrates

目录

reaction formula:

3×glucose 6-phosphate + 6 NADP+

2×Fructose 6-phosphate +

Glyceraldehyde 3-phosphate +

6NADPH+H+

+3CO2

Page 101: Chap 4 Metabolism of Carbohydrates

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::

Page 102: Chap 4 Metabolism of Carbohydrates

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.

Page 103: Chap 4 Metabolism of Carbohydrates

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).

Page 104: Chap 4 Metabolism of Carbohydrates

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.

Page 105: Chap 4 Metabolism of Carbohydrates

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

Page 106: Chap 4 Metabolism of Carbohydrates

目录

Glycogenesis and Glycogenesis and GlycogenolysisGlycogenolysis

Part VPart V

Page 107: Chap 4 Metabolism of Carbohydrates

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

Page 108: Chap 4 Metabolism of Carbohydrates

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

Page 109: Chap 4 Metabolism of Carbohydrates

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 …

Page 110: Chap 4 Metabolism of Carbohydrates

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

Page 111: Chap 4 Metabolism of Carbohydrates

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

Page 112: Chap 4 Metabolism of Carbohydrates

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

Page 113: Chap 4 Metabolism of Carbohydrates

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

Page 114: Chap 4 Metabolism of Carbohydrates

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

Page 115: Chap 4 Metabolism of Carbohydrates

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

Page 116: Chap 4 Metabolism of Carbohydrates

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.

Page 117: Chap 4 Metabolism of Carbohydrates

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

Page 118: Chap 4 Metabolism of Carbohydrates

PiNonreducing end

Glucose-1-phospherate

phosphorylase

Page 119: Chap 4 Metabolism of Carbohydrates

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

Page 120: Chap 4 Metabolism of Carbohydrates

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

Page 121: Chap 4 Metabolism of Carbohydrates

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

Page 122: Chap 4 Metabolism of Carbohydrates

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

Page 123: Chap 4 Metabolism of Carbohydrates

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

Page 124: Chap 4 Metabolism of Carbohydrates

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

Page 125: Chap 4 Metabolism of Carbohydrates

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

Page 126: Chap 4 Metabolism of Carbohydrates

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

Page 127: Chap 4 Metabolism of Carbohydrates

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

Page 128: Chap 4 Metabolism of Carbohydrates

目录

Page 129: Chap 4 Metabolism of Carbohydrates

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

Page 130: Chap 4 Metabolism of Carbohydrates

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

Page 131: Chap 4 Metabolism of Carbohydrates

目录

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

Page 132: Chap 4 Metabolism of Carbohydrates

目录

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.

Page 133: Chap 4 Metabolism of Carbohydrates

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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.

Page 134: Chap 4 Metabolism of Carbohydrates

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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

Page 135: Chap 4 Metabolism of Carbohydrates

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Part VIPart VI

GluconeogenesisGluconeogenesis

Page 136: Chap 4 Metabolism of Carbohydrates

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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.

Page 137: Chap 4 Metabolism of Carbohydrates

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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

Page 138: Chap 4 Metabolism of Carbohydrates

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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)

Page 139: Chap 4 Metabolism of Carbohydrates

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Page 140: Chap 4 Metabolism of Carbohydrates

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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

Page 141: Chap 4 Metabolism of Carbohydrates

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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

Page 142: Chap 4 Metabolism of Carbohydrates

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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+

Page 143: Chap 4 Metabolism of Carbohydrates

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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

Page 144: Chap 4 Metabolism of Carbohydrates

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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

Page 145: Chap 4 Metabolism of Carbohydrates

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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.

Page 146: Chap 4 Metabolism of Carbohydrates

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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

Page 147: Chap 4 Metabolism of Carbohydrates

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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.

Page 148: Chap 4 Metabolism of Carbohydrates
Page 149: Chap 4 Metabolism of Carbohydrates

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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

Page 150: Chap 4 Metabolism of Carbohydrates

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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.

Page 151: Chap 4 Metabolism of Carbohydrates

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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

Page 152: Chap 4 Metabolism of Carbohydrates

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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

Page 153: Chap 4 Metabolism of Carbohydrates

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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.

Page 154: Chap 4 Metabolism of Carbohydrates

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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.

Page 155: Chap 4 Metabolism of Carbohydrates

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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.

Page 156: Chap 4 Metabolism of Carbohydrates

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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

Page 157: Chap 4 Metabolism of Carbohydrates

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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:

Page 158: Chap 4 Metabolism of Carbohydrates

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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【 】

Page 159: Chap 4 Metabolism of Carbohydrates

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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.

Page 160: Chap 4 Metabolism of Carbohydrates

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Part VIIPart VII

Metabolism of Other MonoseMetabolism of Other Monose

Page 161: Chap 4 Metabolism of Carbohydrates

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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.

Page 162: Chap 4 Metabolism of Carbohydrates

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Part VIIIPart VIII

The Definition, Level and The Definition, Level and Regulation of Blood GlucoseRegulation of Blood Glucose

Page 163: Chap 4 Metabolism of Carbohydrates

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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

Page 164: Chap 4 Metabolism of Carbohydrates

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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.

Page 165: Chap 4 Metabolism of Carbohydrates

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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.

Page 166: Chap 4 Metabolism of Carbohydrates

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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

Page 167: Chap 4 Metabolism of Carbohydrates

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The hormones regulate blood

glucose

Decrease blood glucose : insulin

Increase blood

glucose :glucagon

glucocorticoids

epinephrine

Page 168: Chap 4 Metabolism of Carbohydrates

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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.

Page 169: Chap 4 Metabolism of Carbohydrates

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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

Page 170: Chap 4 Metabolism of Carbohydrates

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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.

Page 171: Chap 4 Metabolism of Carbohydrates

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Mechanism of glucagon

Page 172: Chap 4 Metabolism of Carbohydrates

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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.

Page 173: Chap 4 Metabolism of Carbohydrates

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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

Page 174: Chap 4 Metabolism of Carbohydrates

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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.

Page 175: Chap 4 Metabolism of Carbohydrates

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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.

Page 176: Chap 4 Metabolism of Carbohydrates

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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

Page 177: Chap 4 Metabolism of Carbohydrates

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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:

Page 178: Chap 4 Metabolism of Carbohydrates

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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:

Page 179: Chap 4 Metabolism of Carbohydrates

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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.

Page 180: Chap 4 Metabolism of Carbohydrates

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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 ::

Page 181: Chap 4 Metabolism of Carbohydrates

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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.

Page 182: Chap 4 Metabolism of Carbohydrates

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Type Ⅰ (insulin-dependent )

Type Ⅱ (non-insulin-

dependent )

Two types of diabetes:

Page 183: Chap 4 Metabolism of Carbohydrates

目录

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?