Wu Yaosheng Part Two METABOLISM. 目 录目 录 制作：吴耀生 Metabolism of Carbohydrate...

Wu Yaosheng

Part Two

METABOLISM

制作：吴耀生 目 录

Metabolism of Carbohydrate

Biological Oxidation

Metabolism of Lipids

Metabolism of Proteins

Metabolism of Nucleotides

Regulation of Metabolism

制作：吴耀生 目 录

Metabolism of Carbohydrates

Chapter Four

制作：吴耀生 目 录

Main contents 1. Introduction

2. Glycolysis 3. Aerobic oxidation of glucose 4. Pentose phosphate pathway

5. Glycogenesis and glycogenolysis 6. Gluconeogenesis

7. Blood sugar and regulation

Disease cases

Questions

Concepts

Section One

Introduction

The physiological functions of saccharidesThe physiological functions of saccharides

1. To be oxidized and to supply energy

such as amino acid, fat, cholesterol, nucleoside

3. Participate in the composition of tissue cells in organism.

This is the major function of saccharide

2. Work as remarkably versatile precursors for biosynthetic reactions

Such as glycoprotein, proteoglycan, glycolipid

1. Digestion and Absorption of Carbohydrates

1.1 Digestion of Carbohydrates

In nature, starch from plants are the major dietary carbohydrate source for human. Other carbohydrate sources include glycogen, maltose, sucrose, lactose and glucose.

Digesting place: Mainly in small intestine, less in mouth.

Starch

maltose+maltotriose （ 40% ） （ 25% ）

α-limit dextrins+isomaltose （ 30% ） （ 5% ）

Glucose

α-amylase in saliva

α-glucosidase α-limit dextrinase

Process of digesting

The surface of the small intestinal epithelial cells

Stomach

Mouth

Small intestine

α-amylase in pancreatic juice

The cellulose existing abundant in diet are useful for the human health due to that they can stimulate the moving of intestine, even though they can not be digested because of lacking of -glucosidase in human intestine.

(1) Absorption place Upside part of small intestine

(2) Molecule absorbed Monosaccharide, mainly glucose

1.2 Absorption of Carbohydrates

ADP+Pi

ATP

G

Na+

K+

Na+pump

Small intestinal epithelial cell

Intestine lumen

Portal vein

(3) Mechanism of absorption

Na+-dependent glucose transporter, SGLT

lumen membrane

Intracellular membrane

Small intestine lumen

Small intestinal epithelial cells

Portal vein

Liver

Blood circulation

SGLT

Various tissue cells

GLUT

GLUT, refer to glucose transporter. There are five kinds of GLUT having been found

1.4 Absorption route of Carbohydrates

SGLT---- Na+ (Sodium)-glucose transporter

2. The Fate of Absorbed Glucose 2. The Fate of Absorbed Glucose

Glucose

glycolysis Pyruvate

Aerobic

Anaerobic

H2O and CO2

Lactate

Gluconeogenesis

Lactate, amino acid, glycerol

glycogen

glycogenolysis glycogenesis

Pentose phosphate pathway

ribose + NADPH+H+

Starch

Digestion and absorption

ATP Transform

Other substances

Section Two

Glycolysis

Anaerobic degradation of

Glucose

1. Basic Process of Glycolysis

* Definition of Glycolysis

* The site of glycolysis is cytoplasm.

The process in which a molecule of glucose is degraded in a series of enzymatic reactions to yield two molecules of pyruvate or lactate under anaerobic condition is term glycolysis.

制作：吴耀生目 录

The first stage

The secondary stage

The basic process of glycolysis can be divided into two stages:

The reaction process from glucose to pyruvate is called glycolytic pathway

The reaction process from pyruvate to lactate

(1) Glucose is phosphorylated to be glucose-6-phosphate

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-PGA

NAD+

NADH+H+

ADPATP

ADPATP

PEP

1.1 Pyruvate Formation from Glucose1.1 Pyruvate Formation from Glucose

Glucose Glucose-6-phosphate

hexokinase

One of key enzymes

Now it has been found that there are four kinds of isoenyzme of hexokinase in mammal animals called hexokinase I to IV type, respectively. In liver, it is hexokinase IV, namely glucokinase.

The characters of glucokinase are:① The affinity to glucose is very low (hi

gh Km, Km ~10 mmol/L, p131 error)② It is regulated by hormones

⑵ Glucose-6-phosphate →Fructose-6-phosphate

Glucose-6-phosphate Fructose-6-phosphate

Phosphohexose isomerase

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

(3) fructose-6-phosphate → Fructose-1,6-bisphosphate

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

Fructose-6-phosphate Fructose-1,6-bisphosphate

Phosphofructokinase-1

One of key enzymes

Fructose-1,6-bisphosphate

Dihydroxyacetone phosphate, DHAP

Glyceraldehyde-3-phosphate, 3-PGA

aldolase

(4) phosphohexose →2 molecules of phosphotriose

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

(5) Phosphotrioses interconverse

phosphotriose isomerase

Dihydroxyacetone phosphate

Glyceraldehyde-3-phosphate

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

(6) glyceraldehyde-3-phosphate→1,3-bisphosphoglycerate

Glyceraldehyde-3-phosphastedehydrogenase

Glyceraldehyde-3-phosphaste

1,3-bisphosphoglycerate

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

(7) 1,3-(7) 1,3-bisphosphoglyceratebisphosphoglycerate→3-→3-phosphoglyceratephosphoglycerate

substrate level phosphorylation

Phosphoglycerate kinase

ADP ATP1,3-bisphosphoglycerate

3-phosphoglycerate

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

(8) 3-phosphoglycerate→2-phosphoglycerate

3-phosphoglycerate 2-phosphoglycerate

Phosphoglycerate mutase

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

(9) 2-phosphoglycerate →phophoenolpyruvate, PEP

2-phosphoglycerate phophoenolpyruvate

enolase

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

(10) Phosphoenolpyruvate → pyruvate, and yield ATP through substrate level phosphorylation

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

Phosphoenolpyruvate pyruvate

ATP

ADP

Pyruvate kinase

One of key enzymes

pyruvate lactate

Here, the NADH+H+ in the reaction comes

from the six step in the above, the

dehydrogenation reaction of 3-

phosphoglyceraldehyde

Lactate dehydrogenase, LDH

NADH + H+ NAD+ COOH

CHOH

CH3

COOH

C=O

CH3

1.2 Conversion of Pyruvate to Lactate1.2 Conversion of Pyruvate to Lactate

E1:hexokinase

E2: 6-PFK-1

E3: Pyruvate kinase

NAD+

lactate

Glyco

lysis metab

olism

E2E1

E3

NADH+H+

Glu G-6-P F-6-P F-1, 6-2PATP ADP ATP ADP

1,3-DPG

3-PGA

2-PGA

Pyruvate

DHAP 3-GAPNAD+

NADH+H+

ADP ATP

ADP ATPPEP

制作：吴耀生目 录

The pathway of glycolysis

glucose

G-6-P

F-6-P

F-1,6-bisphosphate

Dihydroxyacetone phosphate

Glyceraldehyde-3-phosphate

1,3-Bisphosphoglycerate

3-Phosphoglycerate

2-Phosphoglycerate

Phospho-enolpyruvate

pyruvate

lacta

te

Summary for glycolysis(1) Reaction site： in cytoplasm (2) It is a process to produce energy but withou

t the need for oxygen(3) There are three irreversible reaction steps

G G-6-P ATP ADP

hexokinase ATP ADP

F-6-P F-1,6-2P PFK-1

ADP ATP

PEP pyruvate Pyruvate kinase

(4) The manner to yield energy and the number of ATP produced.

Manner： substrate level phosphorylationThe net number of yielding ATP ：If to begin from Glucose, 2×2-2= 2ATPIf to begin from Glycogen, 2×2-1= 3ATP

(5) The fate of the final product lactate To be released into blood stream, and then to

be taken into liver metabolized.To be decomposed and utilized further To go into Lactate cycle ( gluconeogenesis）

fructose hexokinase

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

pyruvate

galactose

Galactose-1-phosphate

Glucose-1-phosphate

Galactose kinase

mutase

Mannose

Mannose-6-phosphate

hexokinasemutase

Except for glucose, other hexose can converse to phosphohexose and then go into glycolysis pathway.

制作：吴耀生目 录

Entry of other carbohydrates into glycolysis

fructose

lactose

galactose-1-phosphate uridylyl transferase

2. Regulation of Glycolysis

Key enzymes

① hexokinase

② 6-phosphofructokinase-1

③ pyruvate kinase

Regulation models

① allosteric regulation

② covalent modification

2.1 6-phosphofructokinase-1 (PFK-1)

* Allosteric regulation

Allosteric activators ： AMP; ADP; F-1,6-2P; F-2,6-2P

Allosteric inhibitors ： citric acid; ATP （ high conc. ）

• There are two binding sites in PFK-1 for ATP：① substrate-binding site in active center (low conc.)② allosteric site outside active center (high conc. )

• F-1,6-2P can positively feedback regulate PFK-1

F-6-P

ATP

ADP PFK-1

Phosphoprotein phosphatase

Pi

PKA

ATP

ADP

Pi

Glucagon

ATP cAMP

activating

F-2,6-2P

+

+

+

–/+

AMP

+

Citric acid

––

AMP

+

Citric acid

––

PFK-2（ active ）

FBP-2（ inactive ）

6-PFK-2

PFK-2（ inactive ）

FBP-2（ active ）

P P

FBP-2

目 录F-1,6-2P lactate

2.2 Pyruvate kinase

(1) Allosteric regulation

Allosteric inhibitors ：ATP, Alanine

Allosteric activator ：fructose 1,6-bisphosphate

(2) Covalent modification

Pyruvate kinase

ATP ADP

Pi Phosphoprotein phosphatase

（ inactive ） （ active ）

Glucagon PKA, CaM kinase

Pyruvate kinase P

PKA ： protein kinase ACaM ： Calmodulin

2.3 Hexokinase

Glucose-6-phosphate is an allosteric inhibitor of hexokinase, except for hexokinase IV, glucokinase.

Long chain acyl CoA is an allosteric inhibitor of glucokinase

(1) Glycolysis is the emergency energy-yielding pathway.

(2) Glycolysis is the main way to produce ATP in some tissues, even though the oxygen supply is sufficient

In cells without mitochondria, red blood cells

In metabolism active cells, retina, testis, skin, medulla of kidney.

3. The significance of Glycolysis

Section Three

Aerobic Oxidation of Glucose

The process of complete oxidation of glucose to CO2 and water with release of energy as the form of ATP is termed aerobic oxidation.

The place for aerobic oxidation ： cytoplasm, and mitochondria

Concept

1. Basic Process of Aerobic Oxidation of Glucose

First stage ： Glycolytic pathway

Secondary stage ： The oxidation and decarboxylation of pyruvate

Third stage ： Tricarboxylic cycle and Oxidative phosphorylation

G （ Gn ）

Pyruvate

Acetyl CoA

CO2 NADH+H+

FADH2

H2O [O]

ATP ADP

TAC

Cytoplasm

mitochondria

制作：吴耀生目 录

1.1 Oxidation of Glucose to Pyruvate

It is the same as the glycolytic pathway in cytosol discussed above.

After pyruvate is transported into mitochondria, it will be oxidized and decarboxylated to be acetyl Co A.

Pyruvate

Acetyl CoA

NAD+ , HSCoA CO2 , NADH + H+

Pyruvate dehydrogenase complex

The total reaction:

1.2 Oxidation of Pyruvate to lactate

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The fates of pyruvate in organism

Acetyl CoA Lactate

Alanine Oxaloacetate

Pyruvate

The composition of pyruvate dehydrogenase complex

enzymes

E1 ： pyruvate dehydrogenaseE2 ： dihydrolipoyl transacetylaseE3 ： dihydrolipoyl dehydrogenase

HSCoA

NAD+

coenzyme

TPPlipoic acid( )HSCoAFAD, NAD+

S

SL

5. Yield of NADH+H+

1. Formation of -hydroxyethyl-TPP

2. Yield of acetyl lipoamide

3. Yield of acetyl CoA

4. Formation of lipoamide

目 录

CoASH

CO2

NAD+

NADH+H+

Tricarboxylic Acid Cycle, TAC is called citric acid cycle too, because that the first molecule for the beginning of the cycle is citric acid with three carboxyl groups. It was Krebs who first formally put forward TAC theory, therefore the cycle was called Krebs cycle.

All reactions related to TAC take place in mitochondria

1.3 1.3 TTricarboxylic ricarboxylic AAcid cid CCycle, ycle, TACTAC

Introduction

Reaction location

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 dehydrogenase⑦fumarase

⑧malate dehydrogenase

GTP GDP

ATPADP

Nucleoside diphosphate kinase

目 录

Summary for TAC

① Concept of TAC ： It means the process in which a molecule of acetyl-CoA combines with the four-carbon dicarboxylic acid oxaloacetate, resulting in the formation of a six-carbon tricarboxylic acid, citrate, following a series of reactions in the course of which two molecules of CO2 are released and oxaloacetate is regenerated.

② The location of TAC is mitochondria

③ The key points of TAC For each cycle of TAC ，

– One molecule of acetyl CoA is consumed – Undergo through four times of dehydrogenation, t

wo times of decarboxylation, one time of substrate level phosphorylation

– Yield one molecule of FADH2, three molecules of NADH+H+, two molecules of CO2, one molecule of GTP.

– Key enyzmes ： citrate synthase

α-ketoglutarate dehydrogenase complex isocitrate dehydrogenase

④ TAC is irreversible cycle

⑤ Intermediates in TAC and other metabolism

TAC is the common final steps in the breakdown of foodstuffs, such as carbohydrates, lipids, and proteins.

TAC serves as the crossroad for the interconversion among carbohydrates, lipids, and non-essential amino acids, and as a source of biosynthetic intermediates.

Oxaloacetate in TAC must be complemented anOxaloacetate in TAC must be complemented and renovated constantlyd renovated constantly

oxaloacetateoxaloacetate

citritic acid citritic acid Citric acid Citric acid lyase lyase

Acetyl CoA

Pyruvate Pyruvate Pyruvate carPyruvate carboxylase boxylase

CO2

malate malate

Malate dMalate dehydrogeehydrogenasenase

NADH+H+ NAD+

Aspartate Aspartate Aspartate traAspartate transaminase nsaminase

α-ketogutarate glutamate

The source for oxaloacetate ：

When H+ + e are transported through respiratory chain, they are completely oxidized to H2O and to yield ATP by coupled ADP phosphorylation.

NADH+H+ H2O 、 3ATP [O]

H2O 、 2ATP FADH2

[O]

2. ATP Generated in the 2. ATP Generated in the Aerobic Oxidation of Glucose Aerobic Oxidation of Glucose

Net yield 38 (or 36) ATP

ATP yielded in the Aerobic Oxidation of ATP yielded in the Aerobic Oxidation of Glucose Glucose

The result was calculated following old theory, now it is updated

Reaction Coenzyme ATP

Glucose→ G-6-P - 1

F-6-P → F-1,6-DP - 1

2×3-GAP → 2× 1,3-DPGA NAD+ 2× 3 or 2 × 2*

22 ×PEP → × Pyruvate 2 × 1

2× Pyruvate → 2× Acetyl CoA 2 × 3 NAD+

2×Isocitric acid→2×α-ketoglutarate 2 × 3 NAD+

2 × 1 →2× 1,3-DPGA 2×3-PGA

Secondary stage

Firs

t sta

ge

Th

ird

sta

ge

2 × 3 NAD+ → 2×Succinate CoA2×α-ketoglutarate

2 × 1 →2×Succinate CoA 2×Succinate

FAD 2 × 2 →2×Succinate 2×fumarate

NAD+ 2 × 3 →2×malate 2×oxaloacetate

3. The Regulation of Aerobic Oxidation of Glucose

① Glycolysis pathway: Hexokinase

② Decarboxylation of pyruvate ： Pyruvate dehydrogenase complex

③ TAC ： Citric acid synthase

Pyruvate kinase6-phosphofructokinase-1

α-ketoglutarate dehydrogenase complexIsocitric acid dehydrogenase

Key

en

zym

es

3.1 The Regulation of Pyruvate Dehydrogenase Complex

(1) Allosteric regulation

Allosteric inhibitor ： acetyl CoA; NADH; ATP

Allosteric activator ： AMP; ADP; NAD+; Ca2+

As [acetyl CoA]/[HSCoA] or [NADH]/[NAD+] ，its activity will be inhibited.

⑵ 共价修饰调节

目 录

Pyruvate

Acetyl CoA

Acetyl CoA

Protein kinase

phosphataseActive pyruvate dehydrogenase complex

Insulin

inactive pyruvate dehydrogenase complex

(2) Covalent modification regulation

Acetyl CoA

Citric acid Oxaloacetate

Succinal CoA

α-ketoglutarate

Isocitrate malate NADH

FADH2

GTP ATP

Isocitrate dehydrogenase

Citric acid synthase

α-ketoglutarate dehydrogenase complex

–ATP

+ADP

ADP +

ATP –Citric acid Succinyl CoA

NADH

– Succinyl CoA NADH

+Ca2+

Ca2+

① The effect of ATP 、 ADP

② Inhibited by products

③ allosteric inhibited by intermediates

④ Others, for example, Ca2+ can activate various enzymes.

3.2 The Regulation of TAC

Section

FourPentose Phosphate Pathway

* Concept of pentose phosphate pathway

Pentose phosphate pathway is a process in which ribose-5-phosphate and NADPH+H+ are yielded accompanying the degradation of glucose, and then ribose-5 phosphate can turn to glyceraldehyde -3- phosphate and fructose-6-phosphate further.

nicotinamide adenine dinucleotide phosphate ( NADPH , reduced form)

* Location in cell ： in cytoplasm

first stage ： The oxidative phase to yield pentose phosphate, NADPH+H+ and CO2

1. Basic Process of PPP

* Two stages

secondary stage: Non-oxidative phase, including the transfer of a series of groups

C

C

C

C

COO—

CH2O

H

OH

OH

OHH

H

HO

H

PP6-phosphogluconate

CH2OH

C=O

C

C

CH2O

OH

OHH

H

PPRibulose-5-phosphate

NADPH+H+

NADP+

⑴

H2O

NADP+ CO2

NADPH+H+

⑵

G-6-PD

HH

COCO

HH

CH2OH

C O

Glucose-6-phosphate

C

C

C

C

C

CH2O

H

OH

OH

OH

H

H

HO

H

H

O

PP6-phosphogluconolactone

C

C

C

C

C=O

CH2O

H

OH

OH

H

H

HO

H

O

PP

1.1 The oxidative phase

Ribose-5-phosphate

G-6-P dehydrogenase

• Glurose-6-phosphate dehydrogenase (G6PD) is the first key enzyme for the pathway.

• All hydrogen atoms coming from two times of dehydrogenation are accepted by NADP+ to generate NADPH + H+

• Ribose-5-phosphate is a very important intermediate molecule during the pentose phosphate pathway.

G-6-P Ribose-5-phosphate

NADP+ NADPH+H+ NADP+ NADPH+H+

CO2

• Pentose-5-phosphate can interconvert with three, four, five, six, seven-carbon sugars under the catalysis of transketolase and transaldolase.

Among them, glyceraldehyde-3-phosphate and fructose-6-phosphate can go into glycolysis pathway, therefore, PPP can be called pentose phosphate shunt.

1.2 Non-oxidative phase

Groups transfer

Ribulose-5-phosphate(C5) ×3

Ribose-5-P C5

Xylulose-5-P C5

Xylulose-5-P C5

Sedoheptulose-7-P C7

Glyceraldehyde-3P C3

Erythrose-4-P C4

Fructose-6-P C6

Fructose-6-P C6

Glyceraldehyde -3P

C3

Non-oxidative phase

Pen

tose p

hosp

hate

p

ath

way First

phase

Xylulose-5P C5

Xylulose-5P C5

Sedoheptulose-7P C7

3-GAP C3

Erythrose-4P C4

F-6-P C6

F-6-P C6

3-GAP C3

G-6-P (C6)×3

6-phosphogluconolactone (C6)×3

6-phosphogluconate (C6)×3

Ribulose-5P(C5) ×3

Ribose-5P C5

3NADP+

3NADP+3H+ G6PD

3NADP+

3NADP+3H+ G6PD

CO2

Secon

dary

p

hase

The sum of total reactions in pentose phosphate pathway are

3×Glucose-6-Phosphate+ 6 NADP+

2×F-6-P+3-GAP+6NADPH+H++3CO2

2. The Significance of pentose Phosphate Pathway

2.1 To supply ribose-5-phosphate for nucleotide and nucleic acid biosynthesis

2.2 To produce NADPH for reductive synthesis such as fatty acid and steroid biosynthesis

(1) NADPH is the donor of hydrogen for various anabolic metabolism in organism

(2) NADPH can participate in the hydroxylation reaction, involving biosynthesis or biotransformation in organism(3) NADPH can keep the reduction of

GSH

To produce NADPH

2G-SH G-S-S-G

NADP+ NADPH+H+

A AH2

GSH reducase

Section Five

Glycogen Formation and Degradation

They are the major storage model of saccharide in animal, and are the main energy source which can be quickly utilized.

Muscle ： muscle glycogen ， 180 ~ 300g ， mainly supply to muscle contraction

Liver ： hepatic glycogen ， 70 ~ 100g ， to keep blood sugar level constant

Glycogen

• Organs in which can store glycogen and physiological significance

1. 93% of glucose units are joined by α-1,4-glucosidic bonds, 7% of glucosyl residues are joined by α-1,6-glucosidic bonds

2. About each ten glucosyl residues, a branch occurs. More branches , higher solubility.

3. Each chain ends in a reduced terminal, benefiting the degradation by enzyme

• Structure of glycogen

目 录

1. Glycogen Formation ( glycogenesis )

Synthesis sites in organism

Definition of glycogenesis

It is the process to synthesize glycogen from glucose.

Organ sites：mainly in liver and muscleCellular site： cytoplasm

(1) Glucose is phosphorylated to G-6-P

Glucose

Glucose-6-phosphate

ATP ADP

hexokinase;glucokinase （ liver ）

Pathway of glycogen synthesis

G-1-P Phosphoglucomutase

G-6-P

(2) G-6-P turn to G-1-P

Glucose-6-phosphate Glucose-1-phosphate

Phosphoglucomutase

* UDPG can be seen as active glucose donor

++UTP

uridine P P P

PPi

UDPGpyrophosphorylase

(3) G-1-P turn to UDPG

2Pi+energy

G-1-P

OH

HOOH

H OHH OH

HO

H

CH2OH

H

PPP

( uridine diphosphate glucose , UDPG )

OH

HOOH

H OHH OH

HO

H

CH2OH

H

PPP 尿苷P 尿苷PP uridine

制作：吴耀生目 录

Uridine diphosphate glucose , UDPG structure

Active glucose

UDP UTP

ADP ATP

Nucleoside diphosphate kinase

(4) Formation of α-1,4-glucosidic bond

Gn + UDPG

Gn+1 + UDP glycogen synthase

One more glucose is added to the glycogen primer or glycogen molecule

(5) The formation of branch of glycogen

分 支 酶 (branching enzyme)

α-1,6- 糖苷键

α-1,4- 糖苷键

目 录

α-1,4 glycosidic bond

α-1,6 glycosidic bond

制作：吴耀生目 录

Glycogen synthesisUDP-glucosepyrophosphorylase

G G-6-P G-1-P UDP-G + PPi

Gn

Gn+1

hexokinase Phospho-glucomutase

UTP Glycogen synthase

Enzymes-UDP-glucose pyrophosphorylase-Glycogen synthase (key enzyme)-Branching enzyme [amylo-(1-41-6) Transglycosylase]NotesIt needs primer before the synthesis of Gn

2. Glycogen Degradation ( Glycogenolysis )

* Definition of glycogenolysis

* Cellular site ： in cytoplasm

Generally, it refers the process of hepatic glycogen hydrolyzed to release glucose.

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(1) Glycogen suffer phosphorolysis

Gn+1 Gn + G-1-Pphosphorylase

(debranching enzyme)

(2) Debranching enzyme ① transfer glycosyl residues

② hydrolyzing -1,6-glycosid

ic bond

phosphorylase

transferase α-1,6 glucosidase

目 录

Glucose-1-phosphate

Glucose-6-phosphatePhosphoglucomutase

(3) G-1-P turn to G-6-P

(4) G-6-P is hydrolyzed to yield glucose

glucose-6-phosphatase（ liver， kidney）

Glucose glucose-6-phosphaste

Attention: there are no glucose-6-phosphatase in skeleton muscle, so glycogen couldn’t be used to replenish blood sugar because of no free G released into blood from muscle glycogen.

(2) The fates of G-6-P metabolism G （ to replenish blood sugar ）

G-6-P F-6-P（ into glycolysis ）

G-1-P

Gn （ to synthesize glycogen ）

UDPG

6-phosphogluconolactone（ into PPP ）

glucuronate（ into glucuronate pathway)

Summary for glycogenesis and glycogenolysis

(1) Reaction site ： in cytoplasm

The total chart for glycogenesis and glycogenolysis

UDPG pyrophosphorylase

G-1-P UTP

UDPG

PPi

Gn+1 UDP

G-6-P G

Gn synthase

Phosphoglucomutase

Hexo(gluco)kinase

Gn

Pi

Phosphorylase

Glucose-6-phosphatase(liver ）

Gn

3. The Regulation of Glycogensis and Glycogenolysis

Key enzyme

① Glycogenesis ： Gn synthase

② Glycogenolysis ： Gn phosphorylase

The important characters of these two enzymes：* The covalent modification and allosteric regulatio

n as rapid regulation models * There are two types of enzyme with active or inacti

ve (low active) forms interconverting mutually through phosphorylation or dephosphorylation

3.1 Phosphorylase

Phosphorylase b(dephosphorylated, inactive )

Phosphorylase a( phosphorylated, active )

Protein phosphatase IPi

Phosphorylase b kinase

ADPATP

3.2 Glycogen Synthase

Glycogen synthase b(phosphorylated, inactive )

Glycogen synthase a(dephosphorylated, inactive )

Protein kinase AADP ATP

Protein phosphatasePi

Adenyly cyclase （ inactive ）

hormones （ glucagon 、 epinephrine ） + receptor

cAMP

PKA(inactive)

Phosphorylase b kinase

Gn synthase Gn synthase-P

PKA(active)

Phosphorylase b Phosphorylase a-P

Phosphorylase b kinase-P

Pi

Phosphoprotein phosphatase-1

Pi PhosphoproteinPhosphatase-1

Pi Phosphoprotein phosphatase-1

–

–

–PhosphoproteinPhosphatase inhibitor-P

PhosphoproteinPhosphatase inhibitor

PKA （ active ）

Adenyly cyclase （ active ）

ATP

inactiveactive inactive active

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4. The Significance of Glycogenesis and Glycogenolysis

After a meal, the excessive glucose will store in liver as glycogen.

After fasting, liver glycogen is degraded into glucose and released to blood for keeping the blood sugar level

Liver glycogen can store energy and regulate the blood sugar level.

5. glycogen storage diseases

Glycogen storage diseases are a group of inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in some tissues.

Section Six

Gluconeogenesis

Gluconeogenesis is a process to synthesize glucose or glycogen from noncarbohydrate precursors.

* Cellular site:

* Raw material

* Definition

In cytoplasm and mitochondria in liver or kidney.

Glycerol, glucogenic amino, lactate, and other organic acids.

1.The Basic Process of Gluconeogenesis

Glu

G-6-P

F-6-P

F-1,6-2P

ATP

ADP

ATP

ADP

1,3-DPGA

3-PGA

2-PGA

Pyruvate

DHAP 3-GAP

NAD+

NADH+H+

ADPATP

ADPATP

PEP

The main pathway for gluconeogenesis is essentially a reversal of glycolysis, but there are three energy barriers obstructing a simple reversal of glycolysis

1.1 The Conversion of Pyruvate to Phosphoenolpyruvate (PEP)

pyruvate oxaloacetate PEP ATP ADP+Pi

CO2 ①

GTP GDP

CO2 ②

① Pyruvate carboxylase, coenyzme is biotin. Reaction occurs in mitochondria.

② Phosphoenol pyruvate carboxykinase (PEP carboxykinase ) in mitochondria and cytoplasm

目 录

Process of Gluconeogenesis

Pyruvate

Pyruvate

Oxaloacetate

Pyruvate carboxylase ATP + CO2

ADP + Pi

Malate

NADH + H+

NAD+

Aspartate

Glutamate

α-ketoglutarate

Aspartate Malate

Oxaloacetate

PEP

PEP carboxykinase GTP

GDP + CO2

mitochondria

cytoplasm

1.2 F-1,6-DP turns to F-6-P

F-1,6-DP F-6-P Fructose-1,6-diphosphatase

1.3 G-6-P is hydrolyzed to glucose

G-6-P Glucose glucose-6-phosphatase

Pi

Pi

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2. The Cori Cycle (Lactate cycle )

LIVER

Glucose

Pyruvate

Lactate

Lactate Dehydro-genase

NADH+H+

NAD+

Gluconeo-genesis

MUSCLE

Glucose

Pyruvate

Lactate

Lactate Dehydro-genase

NADH+H+

NAD+

GlycolysisBlood

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The significances of Cori Cycle 1) To avoid the lose of lactate and get the reuse of muscle lactate ( lactate in muscle could be used to synthesize glucose)2) To prevent the build up of lactate in muscle

Glucogen in muscle

Glucogen in muscle

Lactate in blood

Glucogen in liver

Glucose in blood

glycolysis

gluconeogenesisDegradation of glucogen

Synthesis of glucogen

3. Regulation of Gluconeogenesis

F-6-P F-1,6-DP

F-1,6-DPase-1

F-1,6-DPase-1

ADP ATP

Pi

G-6-P G

G-6-Pase

HK ATP ADP

Pi

PEP

pyruvate

oxaloacetate

Py kinase

Py carboxylase

ADP ATP

CO2+ATP

ADP+Pi GTP

PEP carboxylkinase GDP+Pi

+CO2

4. The Significance of Glyconeogenesis

(1) To maintain blood glucose levels stable during starvation or during vigorous exercise. It is more important for the functions of brain or erythrocytes.

(2) To replenish liver glycogen

(3) To regulate acid-base equilibrium.

Section Seven

Blood Glucose and Its Regulation

* Blood sugar refers the level of glucose in blood.

Normal blood sugar concentration:3.89~6.11mmol/L

1. Blood Sugar Level

Blood sugar

Dietary supply Digestion and

absorption

Liver glycogen

degradation

Noncarbohydrates

glyconeogenesis

Oxidation

CO2 + H2O

Gn synthesis liver (muscle) Gn

PP Pathway Other sugar

Lipid, AA synthesis

Fat, AA

The income and outcome of blood sugar

2. Regulation of Blood Glucose Concentration

HormonesDecrease blood sugar: insulin

Increase blood sugar:

glucagon,

glucocorticoids,

epinephrine ( adrenalin )

* Mainly, the regulation depends on hormones

2.1 Insulin

① Effects on membrane actively transport

② Effects on glucose utilization

③ Effects on gluconeogenesis

④ Decrease lipolysis and stimulates the uptake of neutral AA into muscle for protein biosynthesis

—— the unique a hormone to decrease blood level in body

Mechanism of insulin action

2.2 Glucagon

① Improve glycogenolysis, inhibit glycogen synthesis

② Inhibit glycolysis, improve gluconeogenesis

③ Activate the triacylglyceride mobilization

——One of the hormones to increase blood sugar level

Mechanism of glucagon action

——A hormone for increasing blood sugar in stress

2.3 Epinephrine (adrenalin )

To stimulate glucogenolysis to produce glucose in liver and lactate in muscle;

Target tissues: liver and muscle.

To stimulate gluconeogenesis;

To enhance the transport of glucogenic amino acids to liver for gluconeogenesis

2.4 Glucocorticoids

To stimulate the gluconeogenesis

——One of the hormones to increase blood sugar

To inhibit the utilization of glucose by inhibiting pyruvate dehydrogenase complex

Mechanism of glucocorticoid action

To promote lipolysis for increasing free fatty acids level in blood

3. Abnormal Blood Sugar Level

3.1 Hyperglycemia

Definition of hyperglycemia

It is termed hyperglycemia when the blood sugar concentration in fasting is higher than 7.22~7.78 mmol/L in clinic.

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Renal threshold for glucose

When blood sugar conc. is higher than 8.89 ~10.00 mmol/L, it is over the ability of renal tubular to reabsorb glucose, resulting in glucose appearing in urine. Therefore, this blood sugar level is termed renal threshold for glucose.

The case which glucose presents in urine is called glycosuria

The reasons for glycosuria:

Emotional, alimentary, symptomatic and renal glycosuria, insulin absolutely deficiency or relatively deficiency, etc.

Diabetes mellitus, DM

Ⅰtype ---- insulin-dependent diabetes mellitusⅡtype ---- non-insulin dependent diabetes mellitus

There two types for diabetes mellitus

3.2 hypoglycemia

Definition of hypoglycemia

The impact of hypoglycemia to body

It refers the case when blood sugar conc. in fasting is lower than 3.33~3.89 mmol/L

The functions of brain cells would be affected, then various symptoms such as be light in the head swirl, accidie, atony, heart-throb, more severely coma would appear.

① Relate to pancreas (the excessive of islet β-cell functions, or the deficiency of islet α-cell functions ）② Relate to liver （ liver cancer, glycogen storage disease, etc ）③ abnormal secretory action ( pituitary function deficiency, adrenal gland cortex function deficiency, etc. ）④ tumor ⑤ starvation, or unavailable to take food

The pathogeny of hypoglycemia

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The disease related to the metabolism of galactose----GalactosemiaWhat’s it: It is a genetic disease caused by an inability to convert galactose to glucose. Toxic substances accumulate such as galactitol, formed by the reduction of galactoseSymptom: fail to thrive, vomit or diarrhea after drinking milk, and often enlarged liver and jaundice. The formation of cataracts , mental retardation and an early death Reasons: due to a deficiency of the galactose-1-phosphate uridylyl transferase hence cannot metabolize galactose. Treating: by prescribing a galactose-free diet which causes all the symptoms to regress except mental retardation which may be irreversible.

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1. Diabetes mellitus ( 糖尿病 )

Disease cases

2. Hypoglycemia ( 低血糖症 )

3. Galactosemia ( 半乳糖血症 )

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Concepts

5 Glycogen

4 Pentose Phosphate Pathway

3 The Cori Cycle ( lactate cycle )

2 Gluconeogenesis

1 Glycolysis

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Questions

3 Which kinds of substances can be turned to glucose through gluconeugensis pathway?

2 What are the key enzymes for the glycolysis pathway? The location in cells?

1 As you know, which kinds of sugar in daily life belong to monosaccharide? Which ones belong to disaccharide? Which ones belong to polysaccharide?

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4 How many ATP could be produced when one of molecule of glucose be metabolized by glycolysis pathway or by aerobic oxidization pathway?

7 What is the key enzyme for glycogen synthesis or glycogen degradation, respectively?

6 In which organ, glycogen can be degraded to glucose ? Why?

5 What are the significances of pentose phosphate pathway ?

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Thank you