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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
O
OHHHH
OHOH
H OH
H
CH2OH
glucose——hexoaldoses fructose——hexoketoses
(1) MonosaccharideMonosaccharide
O
OHOH
HOH2C
HH
OH H
CH2OH
目 录
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
目 录
α-1,4-glycosidic bond
α-1,6-glycosidic bond
② glycogen, mainly stored in animals
目 录
α-1,4-glycosidic bond
α-1,6-glycosidic bond
③ cellulose, function as framework of plants
目 录
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
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 the upper 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
1.3 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
ATP
Other substance
s
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
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
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
e
(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
制作:吴耀生 目 录
制作:吴耀生 目 录
制作:吴耀生 目 录
E1:hexokinase
E2: 6-PFK-1
E3: Pyruvate kinase
NAD+
lactate
Glycolysis metabolism
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
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
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.
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+
FADH2
H2O [O]
ATP ADP
TAC
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
HSCoA
NAD+
coenzyme
TPPlipoic acid( )HSCoAFAD, NAD+
S
SL
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
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.
1.3 1.3 TTricarboxylic ricarboxylic AAcidcid CCycleycle, , TACTAC
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, 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.
制作:吴耀生 目 录
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
CO2
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
[O]
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
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
Pentose phosphate pathway
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
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+
CO2
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
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
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
PPi
UDPG pyrophosphorylase
(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
++ 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
目 录
α-1,4 glycosidic bond
α-1,6 glycosidic bond
Glycogen synthesis
G G-6-P G-1-P UDP-G + PPi
Gn
Gn+1
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.
制作:吴耀生 目 录
The total process of Glycogenolysis
Gn+1 Gn + G-1-Pphosphorylase
G-6-P
G
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)
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 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
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
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
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 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
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
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
1.2 F-1,6-2P turns to F-6-P
F-1,6-2P F-6-P Fructose-1,6-diphosphatase
Pi
1.3 G-6-P is hydrolyzed to glucose
G-6-P Glucose glucose-6-phosphatase
Pi
制作:吴耀生 目 录目 录
Process of Gluconeogenesis
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
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
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 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