Part Two METABOLISM. Metabolism of Carbohydrate Biological Oxidation Metabolism of Lipids Metabolism...

Part Two

METABOLISM

Metabolism of Carbohydrate

Biological Oxidation

Metabolism of Lipids

Metabolism of Proteins

Metabolism of Nucleotides

Regulation of Metabolism

Substance synthesis and decompose

Metabolism of Carbohydrates

Chapter Four

Carbohydrates are aldehyde or ketone derivatives of polyhydric alcohols

Carbohydrate chemistry

1. Concept of Carbohydrate

hydroxy group

They are classified as followsThey are classified as follows

MonosaccharideMonosaccharide

DisaccharidesDisaccharides

OligosaccharideOligosaccharide

PolysaccharidePolysaccharide

GlycoconjugateGlycoconjugate

2. Category and naming 2. Category and naming

glucose——hexoaldoses fructose——hexoketoses

(1) MonosaccharideMonosaccharide

Mannose, glucose, galactose——hexoaldose

two molecules of monosaccharide maltose, sucrose, lactose.

(2) Disaccharides Disaccharides

lactose

sucrose

Sugars with four, five, six or seven carbons are called tetroses, pentose, hexoses and heptoses respectively.

Yield a lot of monosaccharides when hydrolyzed starch, cellulose ,glycogen

(3) Polysaccharides Polysaccharides

① starch, mainly stored in plant

淀粉颗粒

α-1,4-glycosidic bond

② glycogen, mainly stored in animals

③ cellulose, function as framework of plants

β-1,4-glycosidic bond

Single cellulose molecule

Hydrogen bond

Microfiber Cellulose fiber

Glycolipid, is the compound constituted by saccharide and lipid.Glycoprotein, is the compound constituted by saccharide and protein. Proteoglycans, is the structural elements in connective tissues.

(4) Glycoconjugates Glycoconjugates

They refer to the compounds consisting of saccharide and nonsaccharide, such as protein, lipid etc.Including:

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

starch 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

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 the upper small intestine

(2) Molecule absorbed

Monosaccharide, mainly glucose

1.2 Absorption of Carbohydrates

ADP+Pi

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

Blood circulation

Various tissue cells

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

1.3 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

Other substance

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.

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

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-PGA

NADH+H+

ADPATP

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

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

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

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

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

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

(5) Phosphotrioses interconverse

phosphotriose isomerase

Dihydroxyacetone phosphate

Glyceraldehyde-3-phosphate

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

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

Glyceraldehyde-3-phosphastedehydrogenase

Glyceraldehyde-3-phosphaste

1,3-bisphosphoglycerate

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

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

Substrate-level phosphorylation

Phosphoglycerate kinase

ADP ATP1,3-bisphosphoglycerate

3-phosphoglycerate

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

high-energy compound

Substrate-level phosphorylation

is the production of ATP from ADP by a direct transfer of a high-energy phosphate group from a high-energy transfer compound.

1,3-bisphosphoglycerat

(8) 3-phosphoglycerate→2-phosphoglycerate

3-phosphoglycerate 2-phosphoglycerate

Phosphoglycerate mutase

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

(9) 2-phosphoglycerate →phophoenolpyruvate, PEP

2-phosphoglycerate phophoenolpyruvate

enolase

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

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

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

Phosphoenolpyruvate pyruvate

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

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

制作：吴耀生目录

E1:hexokinase

E2: 6-PFK-1

E3: Pyruvate kinase

lactate

Glycolysis metabolism

NADH+H+

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

1,3-DPG

Pyruvate

DHAP 3-GAPNAD+

NADH+H+

ADP ATP

ADP ATPPEP

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

without the need for oxygen(3) There are three irreversible reaction steps

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

F-1,6-2P

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.

2. Regulation of Glycolysis

Key enzymes

① hexokinase

② 6-phosphofructokinase-1

③ pyruvate kinase

Regulation models

① allosteric regulation

② covalent modification

(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+

H2O [O]

ATP ADP

Cytoplasm

mitochondria

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 CoA.

Pyruvate

Acetyl CoA

NAD+ , HSCoA CO2 , NADH + H+

Pyruvate dehydrogenase complex

The total reaction:

1.2 Oxidation of Pyruvate to acetyl Co A

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

coenzyme

TPPlipoic acid( )HSCoAFAD, NAD+

二氢硫辛酰胺转乙酰酶

5. Yield of NADH+H+

1. Formation of -hydroxyethyl-TPP

2. Yield of acetyl lipoamide

3. Yield of acetyl CoA

4. Formation of lipoamide

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.

1.3 1.3 TTricarboxylic ricarboxylic AAcidcid CCycleycle, , TACTAC

NADH+H+

COCO22

NADH+H+

22GTPGTPGDP+PiGDP+PiFAD

NADH+H+

CoASHCoASH

① ②

①citrate synthase

②aconitase ③isocitrate dehydrogenase

④α-ketoglutarate dehydrogenase complex

⑤succinyl CoA synthetase

⑥succinate dehydrogenase⑦fumarase

⑧malate dehydrogenase

GTP GDP

ATPADP

Nucleoside diphosphate kinase

Summary for TAC

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

② The location of TAC is mitochondria

③ The key points of TAC

For each cycle of TAC ，*One molecule of acetyl CoA is consumed

*Undergo through four times of dehydrogenation, two times of decarboxylation, one time of substrate level phosphorylation

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

Key enyzmes ： 1.citrate synthase2.α-ketoglutarate dehydrogenase complex

3.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

malate malate

Malate dehydroMalate dehydrogenasegenase

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 oxidative phosphorylation.

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

H2OFADH2

energyADP 2ATP

NADH+H+ H2O[O]

energy

ADP 3ATP

Net yield 38 (or 36) ATP

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

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

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

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

Pyruvate

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

GTP ATP

Isocitrate dehydrogenase

Citric acid synthase

α-ketoglutarate dehydrogenase complex

–ATP

ATP –Citric acid Succinyl CoA

– Succinyl CoA NADH

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

Pentose phosphate pathway

First phase

Xylulose-5P C5

Sedoheptulose-7P C7

3-GAP C3

Erythrose-4P C4

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

Secondary phase

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+

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

NADPH+H+

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

glycogen storage and physiological significance

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 yield Glucose-6-phosphate

G G-6-P ATP ADP

hexokinase;glucokinase （ liver ）

Pathway of glycogen synthesis

G-1-P Phosphoglucomutase

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

Glucose-6-phosphate Glucose-1-phosphate

Phosphoglucomutase

* UDPG can be seen as active glucose donor

UDPG pyrophosphorylase

(3) G-1-P turn to UDPG

2Pi+energy

H OHH OH

uridine diphosphate glucose , UDPG

H OHH OH

PPP 尿苷P 尿苷PP uridine

++ UTP uridine P P PP P P

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

UDPG + Gn (primer) Gn+1 + UDP

glycogen synthase

G-G-G-G-G-Gglycogen synthase

G-G-G-G-G-G-GUDPG

G-G-G-G-G-G-G-G-G-G-G-G

(5) The formation of branch of glycogen

分支酶 (branching enzyme)

α-1,6- 糖苷键

α-1,4- 糖苷键

α-1,4 glycosidic bond

α-1,6 glycosidic bond

Glycogen synthesis

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

UTPGlycogen synthase

key Enzymes-Glycogen synthase

Branching enzyme -[amylo-(1-41-6) Transglycosylase]

NotesIt needs primer before the synthesis of Gn

2. Glycogen Degradation ( Glycogenolysis )

* Definition of glycogenolysis

* Cellular site ： cytoplasm

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

(1) Glycogen suffer phosphorolysis

Gn+1 Gn + G-1-Pphosphorylase

phosphorylase transferase α-1,6 glucosidase

Debranching enzyme

hydrolyzing α-1,4 glycosidic bond

(2) The role of debranching enzyme

① transfer glycosyl residues

② hydrolyzing -1,6-glycosidic bond

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

note: 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.

The total process of Glycogenolysis

Gn+1 Gn + G-1-Pphosphorylase

The fates of G-6-P metabolism

G （ to replenish blood sugar ）

G-6-P F-6-P（ into glycolysis ）

Gn （ to synthesize glycogen ）

6-phosphogluconolactone（ into PPP ）

glucuronate（ into glucuronate pathway)

The total chart for glycogenesis and glycogenolysis

UDPG pyrophosphorylase

G-1-P UTP

Gn+1 UDP

G-6-P G

Gn synthase

Phosphoglucomutase

Hexo(gluco)kinase

Phosphorylase

Glucose-6-phosphatase(liver ）

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 regulati

on are rapid regulation models * The enzyme with active or inactive forms can be i

nterconverted mutually by phosphorylation or dephosphorylation

3.1 Phosphorylase (phosphorylated, active )

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, active )

Protein kinase AADP ATP

Protein phosphatase Pi

(phosphorylated, inactive )

Adenyly cyclase （ inactive ）

hormones （ glucagon 、 epinephrine ） + receptor

PKA(inactive)

Phosphorylase b kinase

Gn synthase Gn synthase-P

PKA(active)

Phosphorylase b Phosphorylase a-P

Phosphorylase b kinase-P

Phosphoprotein phosphatase-1

Pi PhosphoproteinPhosphatase-1

Pi Phosphoprotein phosphatase-1

–PhosphoproteinPhosphatase inhibitor-P

PhosphoproteinPhosphatase inhibitor

PKA （ active ）

Adenyly cyclase （ active ）

inactiveactive inactive active

4. The Significance of Glycogenesis and Glycogenolysis

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

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

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

To maintain 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 acid, lactate, and other organic acids.

1.The Basic Process of Gluconeogenesis

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

The main pathway for gluconeogenesis is essentially a reversible process of glycolysis, but there are three energy barriers with irreversible reactions

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 Phosphoenolpyruvate carboxykinase (PEP carboxykinase ) in mitochondria and cytoplasm

Pyruvate

Oxaloacetate

Pyruvate carboxylase ATP + CO2

ADP + Pi

Malate

NADH + H+

Aspartate

Glutamate

α-ketoglutarate

Aspartate Malate

Oxaloacetate

PEP carboxykinase GTP

GDP + CO2

mitochondria

cytoplasm

F-1,6-2P

1,3-DPGA

Pyruvate

DHAP 3-GAP

NADH+H+

ADPATP

1.2 F-1,6-2P turns to F-6-P

F-1,6-2P F-6-P Fructose-1,6-diphosphatase

1.3 G-6-P is hydrolyzed to glucose

G-6-P Glucose glucose-6-phosphatase

Process of Gluconeogenesis

2. The Cori Cycle (Lactate cycle )

Glucose

Pyruvate

Lactate

Lactate Dehydro-genase

NADH+H+

Gluconeo-genesis

MUSCLE

Glucose

Pyruvate

Lactate

Lactate Dehydro-genase

NADH+H+

GlycolysisBlood

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 pile up of lactate 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

ADP ATP

G-6-P G

G-6-Pase

HK ATP ADP

pyruvate

oxaloacetate

Py kinase

Py carboxylase

ADP ATP

CO2+ATP

ADP+Pi GTP

PEP carboxylkinase GDP+Pi

4. The Significance of Gluconeogenesis

(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

gluconeogenesis

Oxidation

CO2 + H2O

Gn synthesis liver (muscle) Gn

PP Pathway Other sugar

Lipid, AA synthesis

Fat, AA

The source and fate 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 glycogenolysis 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 (now is 7.0) mmol/L in clinic.

Renal threshold for glucose

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

The case which glucose presents in urine is called glycosuria

The reasons for glycosuria:

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

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

Summary 1. About carbohydrate introduction

2. Glycolysis 3. Aerobic oxidation of glucose

4. Pentose phosphate pathway

5. Glycogenesis and glycogenolysis 6. Gluconeogenesis

7. Blood sugar and regulation

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.

1. Explain the following concepts :

1.5 Glycogen, Aerobic oxidation

1.4 Pentose Phosphate Pathway

1.3 The Cori Cycle ( lactate cycle )

1.2 Gluconeogenesis, TAC

1.1 Glycolysis, Glycolytic pathway

1.6 substrate level phosphorylation

2 Answer the following questions :

2.3 Which kinds of substances can be turned to glucose through gluconeogenesis pathway?

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

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

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

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

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

2.5 What are the significances of pentose phosphate pathway ?

2.8 Describe the source and fate of blood sugar

2.9 why our body can maintain blood glucose concentration in a normal level

Part Two METABOLISM. Metabolism of Carbohydrate Biological Oxidation Metabolism of Lipids Metabolism...

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