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Chapter 4 Carbohydrate Metabolism
牛永东
生物化学的学习方法 特点一:与数理化不同,尚未进入定量科
学的阶段,还处在定性科学阶段。因此不可能通过公式或定理推出一个准确的结论
特点二: 是没有绝对,几乎所有的结论都可以被一些例外打破(生物多样性)
一般性结论:生物化学的学习应以概念为主 --- 以记忆为主,在记忆的基础上加以理解
【目的与要求】• 掌握糖酵解 glycolysis 、有氧氧化、巴斯德效应 Pastuer
effect 、磷酸戊糖途径 、磷酸戊糖途径、糖异生 gluconeogenesis 、乳酸循环 Cori cycle 等概念……
• 掌握糖酵解、有氧氧化 (TCA cycle) 、磷酸戊糖途径、糖异生、糖原合成 glycogenesis 与分解 glycogenolysis 的细胞定位、过程、关键酶、调节及意义……
• 掌握血糖的来源和去路及其调节……
outline• Introduction• Glycolysis (Anaerobic Degradation)• Aerobic oxidation of glucose• The Pentose Phosphate Pathway• Glycogen Formation and Degradati
on• Gluconeogenesis
Definition of Metabolism• Metabolism (Greek for change) : all the chemical and physical processes that
take place in the body * Synthesis (anabolism): Glucose – Glycogen FA+ Glycerol – TG Amino Acids – Protein Requires Energy
Macromolecules
Small moleculesA
NA
BO
LIS
M
CA
TA
BO
LISM
* Breakdown (catabolism): Glycogen – Glucose TG – Fatty Acids + Glycerol Protein – Amino Acids Energy is released
1. What are 1. What are Carbohydrates?Carbohydrates?
• Carbohydrates are aldehyde or ketone compounds with multiple hydroxyl groups
• Empirical formula = (CH2O)n, literally a “carbon hydrate”
• CHO make up 3% of the body’s organic matter
Functions of Functions of CHOCHO• Energy SourceEnergy Source((66.8 kJ/1g carbohydrate)
• Structural elements
• Component of nucleic acids
• Conversion to lipids and non-essential amino acids
• …….
Categories of Categories of CarbohydratesCarbohydrates
Monosaccharides (Single sugar units): the smallest carbohydrates ,serve as fuel and carbon sources
Disaccharides (formed from 2 monosaccharides joined by a glycoside linkage)
Polysaccharides: many monosaccharide units (starch, cellulose)
Monosaccharides• Glucose (CC66HH1212OO66)
-found in fruits, vegetables, honey
-“blood sugar” -used for energy• Fructose - Found in fruits, honey, corn syru
p -“fruit sugar”• Galactose - Found as part of lactose in milk
Glucose (CC6HH12OO6)
Disaccharides Sucrose = glucose + fructose (brown sugar;25% of sugar inta
ke) Lactose = glucose + galactose (milk sugar; least sweet) Maltose = glucose + glucose (honey) Natural SweetnessNatural Sweetness
MaltoseSucrose
Polysaccharides
starch CH2OH
O
O
OO
O
O
O
O
O
O
O
O
CH2OH
CH2OH CH2OH CH2CH2OH
O
-[1-6] linkage
-[1-4] linkages
Glucose 14
6O H
HH
H
OHOH
H OH
OH
CH2OH
Section 1Section 1DigestionDigestion of
carbohydrates
Starch
Glycogen Salivary
amylase
Pancreatic
amylase
maltose
sucrose
lactose
galactose
stomachBrush
Border
of the
Mucosal
Epithelium
BLOOD
glucosefructose
galactose
glucose
fructose
Monosaccharides
1
2
3
a -
amylase
Mouth
no significant
digestive
enzymes
present
Responsible for
most of
carbohydrate
digestion
limited
breakdown of
starch and
glycogen occurs
to capillaries
Na+ dependent glucose Absorption and transporter,SGLT
Lumen of intestineIntestinal Epithelial cell
Fructose; also glucose,
Glucose Galactose Na+
2K+
Na+
3Na+
ATP
ADP + Pi
= facilitated diffusion
= Na+-dependent co-transport
= Na,K-ATPase
GLUT-5
Brush border
SGLT-1
Fructose
GalactoseGlucose
GLUT-2
GalactoseGlucose
GalactoseGlucose
Na+
Na+
2K+
2K+
2K+
3Na+
3Na+
Family of glucose transporters
Name Tissue location Km CommentsGLUT1 All mammalian tissues 1mmol/L Basal glucose uptakeGLUT2 Liver and pancreatic 15~20mmol/L In the pancreas,plays a role cells in regulation of insulin In the liver, removes excess glucose from the bloodGLUT3 All mammalian tissues 1mmol/L Basal glucose uptakeGLUT4 Muscle and fat cells 5mmol/L Amount in muscle plasma membrane increases with endurance training GLUT5 Small intestine - Primarily a fructose transporter
Not digested: : Dietary Dietary FiberFiber
Water insoluble fibers- Cellulose, hemicellulose , pectins (果胶)……
Water soluble fiber- beans, rice, carrots, fruits……- Obesity, diabetes, cancer……
Recommended intake of fiber20-35 g/day; insoluble:soluble = 3:1
Anaerobic degradation (glycolysis)
glucose
Aerobic oxidation
Glycogen
UDPG
G-1-P
G-6-P 6-phosphogluconate
Fructose 6-p
trioses phosphate non-carbohydrates
pyruvate
acetyl CoAlactate
Tricarboxylic acid cycle
2 2CO+ HO + energy
Gluconeogenesis
Glycogenesis Glycogenolysis
Pentose phosphate pathwayPi
Pi
3. Overview of carbohydrate metabolism
Section 2 Glycolysis (Anaerobic Degradation)
• “Glycolysis” is derived from Greek words glycos (sugar, sweet) and lysis (dissolution)
• The glycolytic pathway (Glucose to pyruvate) was elucidated by 1940, largely through the pioneering contributions of Gustav Embden.so glycolysis is also known as the Embden-Meyerhof pathway
Glycolysis
• Where in cell ?• What are the inputs ?• What are the outcomes ?• Oxygen required ?
Glycolysis (糖酵解)• For glycolysis, the overall goal is to break th
e glucose molecule into smaller, more oxidized pieces
• 11 steps metabolic pathway to convert 6 carbon glucose into 2 molecules of 3 carbon lactate 乳酸and two molecules each of and ATP
• Occurs in cytoplasm• glycolysis has has two two stages: glycolytic pathwa
y (Glucose to pyruvate); Fermentation (发酵) phase (pyruvate to lactate)
• Anaerobic– Does not REQUIRE oxygen– Occurs whether oxygen is available or not
O
CH2OHC1
C2 H
C
C OH
C HHO
C OHH
C OHH
CH2OH
C3
C4
C5
C6
D-glucose
or
OH
D-glucose
breakC3-C4 bond
breakage of C3-C4
bond
glycolytic pathway = breakdown of glucose to yield energy and pyruvate
glycolytic pathway has has two two phases
A. Energy investment phase (Reactions, 1-5) Glucose(6C) is first phophorylated (thus acti
vated) and then cleaved to produce two glyceraldehyde-3-phosphate(3C) intermediates. 2 ATPs are invested. (the preparatory phase)
B. Energy payoff phase (Reactions 6-10) two glyceraldehyde 3-phosphate intermediates
are oxidized, generating to two pyruvate plus four ATP molecules
CH2 O H
HO-C-H
H-C-OH
CHO
H-C-OHH-C-OH
-P-O
O
OH
C=OCH2 OH-P-O
O
OH
glucoseglucose
-P-O
O
OH isomerase
Energy investment phase
Step 3. Phosphofructokinase -1 (PFK-1) (2 ATP utilizati
on)
Step 1. Hexokinase (1 ATP utilization)
Step 2. Phosphoglucose Isomerase (PGI)
H
C H2 OH
HO-C-H
H-C-OH
CHO
H-C-OHH-C-OH
C=OCH2 OH-P-O
O
OH
-P-O
O
OH
HO-C-HC=OCH2O-P-O
O
OH
-P-O
O
OHCH2O
H-C-OHH-C-OH
+H-C-OH
CH2OPO3=
HC=O
Glyceraldehyde 3-PO4
DHAP
CH2OPO3=
C=OCH2OH
dihydroxyaceto
ne phosphate
energy investment phase
4. Aldolase
isomer
ase
dihydroxyacetone phospha
teTPITPI
The isomerization of an aldose to a ketose
Glyceraldehyde 3-P
O4
energy investment phase
5. Triose Phosphate Isomerase (TIM or
TPI )
Glucose
Glucose 6-phosphate
Fructose 6-phosphate
Fructose 1.6-bisphosphate
Dihydroxyacetone phosphate Triose phosphate isome
rase
Aldolase
Phosphofructokinase
Phosphogluco- isomerase
HexokinaseATP
ADP
ATPADP
Glyceraldehyde 3-phosphate
energy investment
phase
Uses 2 ATP
CHO
H-C-OH
CH2OPO3
COO
H-C-OH
CH2OPO3
C
H-C-OH
CH2OPO3
~OPO3
OPO4
NAD+
NADH+ H+
ADP ATP
Glyceraldehyde-3-PO4 dehydrogenase
Phosphoglycerate kinase
(Reactions, 6-10)Energy payoff phase
COO
H-C-OH
CH2OPO3
3-PGA
COO
C=O
CH3
Pyruvate
COO
C~
CH2
OPO3
PEP
COO
H-C-OPO3
CH2OH
2-PGA
Low energyHigh energy
-H2O
ADP ATP
Energy payoff phase
Glyceraldehyde 3-phosphate
NAD+ + Pi
NADH + H+
1,3-Bisphosphoglycerate
Glyceraldehyde 3-phosphate dehydrogenase
Phosphoglycerate kinase ADP
ATP 3-Phosphoglycerate
2-Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
Pyruvate kinase ADPATP
H2OEnolase
Phosphoglyceromutase
energy payoff phase
ATP
generation
Oxidation
ATP generation
Overview of glycolytic pathway
Summary of Energy Relationships for glycolytic
pathway * Input = 2 ATP 1. glucose + ATP glucose-6-P 2. fructose-6-P + ATP fructose 1,6 bisphosphate* Output = 4 ATP + 2 NADH1. 2 glyceraldehyde-3-P + 2 Pi + 2 NAD+ 2 (1,3 bisphosphoglycerate) + 2 NADH2. 2 (1,3 bisphosphoglycerate) + 2 ADP 2 (3-P-glycerate) + 2 ATP3. 2 PEP + 2 ADP 2 pyruvate + 2 ATP
*Net = 2 ATP and 2 NADH
Fate of Pyruvate• Two anerobic pathways: (Low O2 ) - to lactate via lactate dehydrogenase in muscle - to ethanol (fermentation) via ethanol dehydro
genase• Aerobic pathway – through citric acid cycle and
respiration; Enough O2,this pathway yields far more energy
NADH + O2 NAD+ + energy Pyruvate + O2 3CO2 + energy
AnaerobicAnaerobicGlycolysisGlycolysis
PyruvatPyruvateeAlcoholAlcohol
FermentatioFermentationn
Aerobic GlycolysisAerobic Glycolysis
Oxygen availability determines fate of PyrPyr
uvateuvate
The anaerobic fate of Pyruvate ( Reaction 11 of glycolysis )
• Hydrogen at C4 of NADH is transferred to the pyruvate
• uses up all the NADH (reducing equivalents) produced in glycolysis
Energy Yield From GlycolysisEnergy Yield From Glycolysis
• glucose 6 CO2 = -2840 kJ/mol• 2 ATPs produced = 61 kJ/mol glucose• Energy yield = 61/2840 = 2% in all: high investment, low output
Overall process of anaerobic glycolysis in muscle can be represented:
The lactate, the end product, is exported from the muscle cell and carried by the blood to the liver, where it is reconverted to glucose
a. 11 steps ; Location: cytosolb. Original material: glucose (C6H12O6) c. End product: lactate - Twice substrate level phosphorylations - Net of 2 ATP d. Key enzymes: Hexokinase (HK) …….energy investment
phase
Phosphofructokinase 1 (PFK-1) …….energy investment phase
Pyruvate kinase (PK) …….energy payoff phasee. Once dehydrogenation: oxidation Once hydrogenation: reductionf. No oxygen is required
Summary of Glycolysis
The regulation of glycolysisHormone regulationCovalent regulationAllosteric regulation
GlucagonATP
cAMP
ATP ADP
F-6-P F-2,6-BP
PFK-2active
FBP-2inactive
P P
FBP-2 active inactive
PFK-2
Pi
PKA
ATP
ADP Pi
Phosphoprotein Phosphatase
F-1,6-BP
Glucose
ATP
ADP
PFK-1
AMP Citrate
AMP Citrate
-
-
-
Lactate
Adenylate cyclase
Glucose 6-phosphate
glycolysis
3. The significance of glycolysis
• Glycolysis is the emergency energy-yielding pathway, such as play ball, climb mountain.…..• Glycolysis is the major way to produce ATP in some tissues, even though the oxygen supply is sufficient, such as RBC, retina, testis, skin……
Section 3 Aerobic oxidation of glucose
• The process of oxidation completely
from glucose to CO2 and H2O is named
aerobic oxidation
• This process is the major process to provide energy for most tissues
3 phases of Glucose Aerobic oxidation
2. Oxidation from pyruvate to acetyl CoA in mitochondria (3C to 2C) 3. Tricarboxylic acid cycle and oxidative phosphorylation (2C to 1C)
O2O2 O2
Glucose G-6-P
PyruvatePyruvate
Acetyl CoA
TCA cycle
H+ +e
CO2
H2O
cytosol mitochondria
1. Oxidation from glucose to pyruvate in cytosol (6C to 3C)
CoASHCoASH
CH3
CO C
O-
O
CO2CH3
CO S
CoA
NAD+NAD+
Pyruvate DH comPyruvate DH complexplex
2. Oxidation from pyruvate to acetyl CoA (3C to 2C)
Pyruvate+NAD++HSCoA
Acetyl CoA+NADH+H++CO2
NADH
Acetyl-CoA: a common two-carbon unit
E1. pyruvate dehydrogenase (丙酮酸脱氢酶)E2. dihydrolipoyl transacetylase(二氢硫辛酰胺转乙酰酶)
E3. dihydrolipoyl dehydrog
enase
(二氢硫辛酰胺脱氢酶)
Pyruvate dehydrogenase complex
Pyruvate dehydrogenase complex
TPPE1
FADE3
E2
3. Two stages of the 3rd phase of Glucose
Aerobic oxidation• Stage I The acetyl-CoA is completely oxidize
d into CO2, with electrons collected by NAD and FAD via a cyclic pathway (tricarboxylic acid cycle)
• Stage II Electrons of NADH and FADH2 are transferred to O2 via a series carriers, producing H2O and a H+ gradient, which will promote ATP formation ( oxidative phosphorylation )
(NEXT CHAPTER)
Tricarboxylic acid cycle (2C to 1C)• Citric Acid Cycle or Krebs cycle• Occurs in mitochondrial matrix• Is the biochemical hub of the cell, oxidizing car
bon fuels, usually in the form of acetyl CoA, interconversion of carbohydrates, lipids, and some amino acids, as well as serving as a source of precursors for biosynthesis
• For the citric acid cycle, the goal is to use the oxidative power of O2 to derive as much energy as possible from the products of glycolysis
NADH+H+
CO2
C2
NADH+H+
CO2GTP
FADH2
NADH+H+
C6
C4
C4
C5
Tricarboxylic acid cycle
Substrates required: Oxaloacetic Acid GDP 3NAD+ FAD two-carbon units (Acetyl-CoA) Intermediate Reactants: Citric Acid
Output: Oxaloacetic Acid GTP 3 NADH FADH2 2CO2
(4 high-energy electrons)
Each Acetyl-CoA yields 2 CO2, 3 NADH + H+, 1 FADH2, 1 GTP
CO C
CH2
C
O
O-
-O O
CH3
CO S
CoA
Citrate synthaseCitrate synthase
CoASH
Stage I Tricarboxylic acid cycle
Oxaloacetic Acid
++C
CH2
C3
HO C2
CH2
C1
O O-
O
O-
-O O
Citrate4C
2C
6 C
AconitaseAconitase
ciscis-aconitate inter-aconitate intermediatemediate
C
H2C
C
C
CC
O
O-
O
O-
-O
OH
C
CH2
C3
HO C2
CH2
C1
O O-
O
O-
-O O6 C
6 C
Isocitrate DH
O-
NADNADH
a-ketoglutaratea-ketoglutarateIsocitrate
CH2
CH2
C
CC
O O-
-O
OO
CO2
C
CH2
C
H C
CC
O
O
O-
-O
OHO
6 C
5 C
a-ketoglutarate DHa-ketoglutarate DH
NADNAD++, , CoASHCoASH NADNADHHNADNADHH
Succinyl CoASuccinyl CoAa-ketoglutaratea-ketoglutarate
CH2
CH2
C
CC
O O-
-O
OO
CH2
CH2
C
CS
O O-
CoAO
CO2
5 C
4 C
GDP, PGDP, PiiGTPGTP
Succinyl CoASuccinyl CoA
SuccinylCoA synthetaseSuccinylCoA synthetase
CH2
CH2
C
CS
O O-
CoAO
CH2
CH2
C
CO-
O O-
O
CoASH
4C
4C
(FAD)(FAD)
fumaratefumarate
(FADH(FADH22))(FADH(FADH22))CH2
CH2
C
CO-
O O-
O
C
C
C
C
O-
O
O-
O H
H
4C
4C
HH22OO
fumaratefumarate malate
C
C
C
C
O-
O
O-
O H
H
CHO
C
CH2
C
O O-
-O O
H
4C
4C
malate DH
NADNAD++ NADHNADHNADHNADH
malate Oxaloacetic Acid
CHO
C
CH2
C
O O-
-O O
H CO C
CH2
C
O
O-
-O O
4C4
C
Tricarboxylic acid cycle
CH COOH
CH2 COOH
HO
CH2 CO O H
HC C O O H
C H C O O HHO
NAD+
NADH+H+
C O2
CH2 CO O H
C H2
C C O O HO
CH3 C
O
~SCoAO C C O O H
C H2
C O O H
CH2 COOH
C COOH
CH2
HO
COOH
CH2 CO O H
C C O O H
C H CO O H
CoASH
GTPCoASH
GDP+Pi
CH2 COOHCH2 COOH
FAD H2
FAD
HC COO H
CH
HOOC
CH2 CO O H
C H2
CO S C o A~CoASH C O2
NAD+NADH+H+
NAD+NADH+H+ citrate synthasecitrate synthase
isocitrate dehydrogenase
isocitrate dehydrogenase
- ketoglutarate dehydrogenase- ketoglutarate dehydrogenase
Aerobic oxidation of glucose
C6H12O6 + 6O2 + 38 ADP +38 P 6CO2 + 6H2O + 38 ATP
Generation of ATP in aerobic oxidation of glucose
Total per mole of glucose under aerobic conditions: 38 or 36 (32 or 30) ATPs
Reactions Catalyzed by
Methods of ATP production formed moles of ATP
Glyceraldehyde 3-phosphate dehydrogenaseGlycolytic
pathway
Respiratory chain Oxidation of 2 NADH 6 or 4 /5 or 3
Phosphoglycerate kinase Phosphorylation at substrate level 2Pyruvate kinase Phosphorylation at substrate level 2
consumption of ATP by reactions catalyzed by hexokinase and phosphofructokinase- 2
Production ofacetyl CoA
Pyruvate dehydrogenase complex
Respiratory chain Oxidation of 2 NADH
TCA cycle
Isocitrate dehydrogenaseAlpha-ketoglutarateDehydrogenase complex
Succinyl CoA synthetaseSuccinate dehydrogenaseMalate dehydrogenase
Respiratory chain Oxidation of 2 NADH
Respiratory chain Oxidation of 2 NADH
Phosphorylation at substrate level
Respiratory chain Oxidation of 2 FADH2
Respiratory chain Oxidation of 2 NADH
6 or 5
6 or 5
4 or 3
6 or 5
2
6 or 5
3 control points of citric acid cycle :
citrate synthase
isocitrate dehydrogenase
-ketoglutarate dehydrogenase
C2
C 6
C4
C4
C5
Krebs Cycle
pyruvate
Iso C6
Regulation of pyruvate dehydrogenase
Regulation of aerobic oxidation
Regulation of pyruvate dehydrogenase
Inhibited by products,NADH & Acetyl CoA
Also regulated by covalent modification,the kinase & phosphatase also regulated
GTP
Acetyl CoA
Oxaloacetate
CoA
Citrate [1]
cis-Aconitate
Isocitrate
-Ketoglutarate
NAD+
NADH, CO2
[2]
Succinate GDP
[4] Fumarate
FAD
FADH2
[5]
Malate
NAD+
NADH
[6]
CoA, NAD+
[3]
Succinyl CoA NADH, CO2
Allosteric inhibitor
ADPallosteric acti
vator
NADH:allosteric inhibitor
GTPallosteric inhibitor
The Alosteric regulation of citric acid cycle citrate synthase
isocitrate dehydrogenase
- ketoglutarate dehydrogenase
* Pastuer effect• The total amount of glucose consumed by yeast are
about 7 times greater under anaerobic conditions than under aerobic conditions
• This effect is also seen in muscle under anaerobic conditions
• The yield of ATP under anaerobic conditions is 2 per molecule; but under aerobic conditions the yield is 38 ATP per glucose
• Therefore, glucose flux through the pathway is regulated to achieve constant ATP levels or decided by the fate of NADH+H+
Section 4
The Pentose Phosphate
Pathway (PPP)
Pentose phosphate pathway
• The PENTOSE PHOSPHATE pathway ,by carring out oxidation and decarboxylation of the 6-C sugar glucose-6-P, is basically used for the synthesis of NADPH and 5-C sugar ribulose-5-P
• It plays only a minor role (compared to GLYCOLYSIS) in degradation for ATP energy
• Other names: Pentose phosphate Shunt Hexose Monophosphate Shunt
• Two stages:– Oxidative portion (NADPH producing)– Non-oxidative (carbon recycling/unit transfe
rring)• Location: cytosol• Original material: glucose 6-phosphate• End product: NADPH , pentose phosphate• Important in adipose tissue, adrenal cortex, live
r (biosynthesis) 、 Important in red blood cells (antioxidant reasons)
Pentose phosphate pathway
G-6-P dehydrogenase
CHO
C-OH
HO-C
C-OHC-OH
CH2OP
COO-
C-OH
HO-C
C-OHC-OH
CH2OP
C
C-OH
HO-C
CC-OH
CH2OP
O
O
NADP+
NADPH + H+
+ H2O
STAGE I(Oxidation=NADPH producing and formation of pentose phosphate)
Glucose-6-PO46-Phosphoglucono-- lactone
6-Phospho- gluconate
Lactonase
G-6-P dehydrogenase: Rate limiting step, controlled by NADP+ levelsGlucose-6-phosphate Dehydrogenase catalyzes oxidation of the aldehyde (hemiacetal), at C1 of glucose-6-phosphate, to a carboxylic acid, in ester linkage (lactone). NADP+ serves as electron acceptor
COO-
C-OH
HO-C-H
C-OHC-OH
CH2OP
C=OCH2OH
C-OHC-OH
CH2OP
CHO
C-OHC-OH
CH2OP
C-OHCO2
NADP+
NADPH + H+
Ru5P
isomeraseRu5P
epimerase
Ribose-5-PO4
5-p- 木酮糖Xylulose-5-PO4
Ribulose-5-PO4 (Ru5P)
6-Phosphogluconate
6-phosphogluconateDehydrogenase
CH2OH
C-OHC
CH2OP
C=O
HO-
STAGE I
6C
5C
5C
5C
CH2OH
C-OHC
CH2OP
C=O
HO-
CHO
C-OHC-OH
CH2OP
C-OH
C-OHC-OH
CH2OP
C-OHHO-C
C=O
CH2OH
+
C-OH
CH2OP
CHO
酮醇转移酶
Transketolase
7-p- 景天糖Sedoheptulose-7-PO4
Ribose-5-PO4Xyulose-5-PO4
Glyceraldehyde-3-PO4
STAGE II ( Non-oxidative=carbon recycling)
5C
5C
7C
3C
C-OH
CH2OP
CHO
C-OHC-OH
CH2OP
C-OHHO-C
C=O
CH2OH
C-OHC-OH
CH2OP
CHO
C-OHC-OH
CH2OP
HO-CC=O
CH2OH
+
Glyceraldehyde-3-PO4
Fructose-6-PO4
4-p- 赤藓糖Erythrose-4-PO4
Transaldolase醛糖移转酶
Sedoheptulose-7-PO4
STAGE II ( Non-oxidative=carbon recycling)
3C
7C
4C
6C
C-OHC-OH
CH2OP
CHOCH2OH
C-OHC
CH2OP
C=O
HO-+ C-OH
CH2OP
CHO
C-OHC-OH
CH2OP
HO-CC=O
CH2OH
+
Transketolase
Erythrose-4-PO4Xylulose-5-PO4
Glyceraldehyde-3-PO4
Fructose-6-PO4
STAGE II ( Non-oxidative=carbon recycling)
glycolysis
4C
5C
3C
6C
Sedoheptulose 7-P
(7 C)Erythrose 4-P (4C)
Ribose 5-P (5 C)Glyceraldehyde 3-P
(3C)
Fructose 6-P
(6C)
Fructose 6-P
Glyceraldehyde 3-P
GlucoseATP ADP
Glucose 6-P 6-Phosphogluconate
Oxidative stage
Xylulose 5-P ( 5C)
Ribulose 5-P (5C)
CO2NADPH
NADP
NADP NADPH
Non
-oxid
ativ
e
stag
e
Pentose phosphate pathway
C5 + C5 C3 + C7 (Transketola
se)
C3 + C7 C6 + C4 (Transaldola
se)
C5 + C4 C6 + C3 (Transketola
se)
3 C5 2 C6 + C3 (Overall)
+
+ +
+
+
SUMMARY
3CO2
3 G 6-P C5 + C5 + C5 C3 + C6+ C6
3 Glucose-6-PO4 + 6 NADP+ + 3H2O6 NADPH + 6H+ + 3CO2 + 2 Fructose-6-PO4
+ Glyceraldehyde-3-PO4•
Per glucose oxidized, 2 NADPHs are formed
•C7 、 C4 are strictly intermediates
•Glyceraldehyde-3-PO4 is both an intermediate and finalproduct
•Fructose-6-PO4 is never used as an intermediate, return to the glycolytic p
athway
*** The significance of PPP1. Produce ribose 5-phosphate needed for DNA and RNA synthesis2. Generate reducing equivalents NADPH 1) Reducing power for biosynthesis of fatty
acids, cholesterol, folate, and so on 2) Coenzyme of glutathione reductase to k
eep the normal level of reduced glutathione
3) NADPH serves as the coenzyme of mixed function oxidases (mono-oxygenases)
Section 5
Glycogen Biosynthesis and Degradation
Introduction
A constant source of blood glucose is an absolute requirement for life - glucose is the preferred energy source for the brain and for cells with few or no mitochondria, such as mature erythrocytes - glucose is an essential energy source in exercising muscle
1. Glycogen is a highly branched homopolymer of a-glucose (polysaccharide)2. Approx. every 10 residues there is a branch, linked by an a-1,6-glycosidic linkage
What is Glycogen?What is Glycogen?
Reducing
end
CH2OH
O
CH2O
O
CH2OH
O
CH2OH
O
CH2OH
O
CH2OH
O
a-1,4-glycosidic linkage
a-1,6-glycosidic linkage ))
Glycogen Biosynthesis(Glycogenesis)
• Glycogenesis: the process of storing excess glucose as glycogen (In times of plenty the body needs to store fuel)
• occurs in the cell cytoplasm of liver, muscle & kidney, when blood glucose levels are high
• Excess glucose is stored (limited capacity)– liver and muscle are major glycogen storage sites
• liver glycogen used to regulate blood glucose levels– brain cells cannot live for > 5 minutes without gl
ucose• muscle glycogen used to fuel an active muscle
• Glycogenesis involves addition of a-D-glucose residues to the C4 (non-reducing end) of an pre-existing chain
Requirement of formation glycogen
• Glycogenin
• glycogen synthase
• glycogen-branching enzyme
• UDP-glucose pyrophosphorylase
Requirement of Formation glycogen
• Primer– glycogenin acts as the primer to whi
ch the first glucose residue is attached
– glycogenin also catalyzes attachment of additional glucose units to form chains of up to eight units
• Glycogen-branching enzyme
– takes over at this point – chain cannot extend indefinitely
Requirement of Formation glycogen
• Glycogen Synthase– exists in an active (dephosphorylated) and inactive (p
hosphorylated) form– relative amount of each form is regulated by cellular l
evel of cAMP– cAMP is regulated by insulin:glucagon ratio
• High insulin keeps GS in dephosphorylated, active form• High insulin can also stimulate dephosphorylation of GS• High glucagon activates cAMP which activates PK which pho
sphorylates and inactivates GS– Glycogen Synthase reaction is primary target of insuli
n’s stimulatory effect on glycogenesis
glucose G-6-PGK(liver),HK
ATP ADPMg2+
phosphoglucomutase
G-1-P
UTP (uridinetriphosphate) PPi
UDPG (uridinediphosphate glucose)
H2O
2Pi
OCH2OH
PO
O-
O
O-
G-1-P
+ OP-O
O-
O
OP
O-
O
NH
O
ON
O
OHOH
HH
CH2
H
OP
O-
O
UDPG pyro-phosphorylase
OCH2OH
PO
O-
O
NH
O
ON
O
OHOH
HH
CH2
H
OP
O-
O
O
UDPG
GLYCOGEN SYNTHASE
UDP
glycogen¦Á-1,4-glycosidic bond
O
O-UDP
CH2OH
UDPG
+O
CH2OH
O
O O
CH2OH
glycogen primer (n)
UDP
O
O
O
O
O
O
CH2OH CH2OH CH2OH
glycogen (n+1)
GLYCOGEN SYNTHASE
branching enzyme
glycogen¦Á-1,4,¦Á-1,6-glycosidic bond
glycogen primer
UTP
PPi
Glycogenesis
glycogen synthase
oligo 1,6-glucantransferase Debranching
glycogen
synthase
oligo 1,6-glucantransferase Debranching
Glycogenesis
GlycogenolysisGlycogenolysis : glycogen glucose
• In times of need the body needs to mobilize its’ fuel stores
• Hepatic glycogen not sufficient during 12 hr fast• Glycogen degradation• Occurs in cytosol• Signal that glucose is needed is given by hormones
– epinephrine stimulates glycogen breakdown in muscle
– glucagon which stimulates glycogen breakdown in liver in response to low BG
– used to sustain blood glucose level between meals and to provide energy during an emergency/exercise
Glycogenolysis
1,4 glucose 1-phosphate
12 glucose 1-phosphate
1 glucose
phosphorylase a
phosphorylase aglucan transferase
glucosidase
phosphorylase a
Debranching has two enzyme activities in one peptide: oligo -1,4 1,4-glucantransferase and 1,6-glucosidase
Glycogen Phosphorylase Regulation
• Glycogen phosphorylase– exists in a “b” inactive form (dephosphorylat
ed) and an “a” active form (phosphorylated)– phosphorylase kinase converts glycogen phos
phorylase to active form “a” via addition of inorganic phosphate • phosphorylase kinase also exists in an active “a”
and an inactive “b” form– activated by cAMP-dependent protein kinase; it is also acti
vated by calcium ions– PK is activated by glucagon and epinephrine
» via 2nd messenger cAMP
Glycogen Phosphorylase Regulation
• Glycogen phosphorylase “a” (active) is converted to “b” form by phosphoprotein phosphatase– Stimulated by insulin
• Glycogen phosphorylase can also be regulated by allosterically– GP “b” inactive form can be converted to GP
“b” active form by high AMP – GP “b” active form can be converted back to GP
“b” inactive form by high ATP
hormons:glucagon, epinephrine
inactiveadenylate cyclase
ATP
ATP
ATP
ATP
cAMP
inactiveproteinkinase A
active protein kinase A
ADP
ADPADP
phosphorylase b kinase
phosphorylase b kinase
P
Pi
Pi
Pi
H2O
H2O
H2O
phosphorylase b phosphorylase a
P
glycogen synthase(active)
glycogen synthase
P
(inactive)
protein phosphatase-1
inhibitor-1 (inactive)
Pinhibitor-1 (active)ATP
glycogenolysis
glycogenesis
active adenylate cyclase
Regulation of Glycogenesis and Glycogenolysis
The significance of glycogenesis and glycogenolysis- Liver glycogen (as much as 10% of liver wet weight) functions as a glucose reserve for maintaining blood glucose concentration- Muscle glycogen (total 400 gram) serves as a fuel reserve for synthesis of ATP within that tissue
Section 6
Gluconeogenesis
*** Gluconeogenesis• Synthesis of glucose from non-CHO precursors
– Lactate, most amino acids and glycerol ***– Lactate and amino acids (except leucine and
lysine) are converted to either pyruvate or OAA (oxalloacetate)
– Glycerol is converted (phosphorylated) to G3P and then to dihydroxyacetone phosphate
• Occurs primarily in liver, sometimes kidney
Blood Glucose
Ribose 5-PO4Ribose 5-PO4
GlycogenGlycogen
L-lactateL-lactate Pyruvate
PEP
2PGA
3PGA
1,3bisPGA
Gly-3-P
F1,6bisP
OAA
F6P
G6P
DHAP
Glucose
H2O
PO4
Phosphatase
H2OPO4Phosphatase
Kinase
Kinase
Kinase
KinaseGluconeogenesis
Gluconeogenesis• Reversal of glycolysis except at 3 steps
– HK(GK), PFK and PK• 3 Steps need to be bypassed
Hexokinase and Phosphofructokinase are bypassed by glucose 6 phosphatase and fructose 1,6-bisphosphatase
Pyruvate Kinase bypass involves formation of OAA as an intermediate
– OAA in mitochondrial matrix cannot directly cross membrane so is converted to malate
Gluconeogenesis• Bypass of PK reaction continued
– Malate and aspartate can transverse mitochondrial matrix• converted back to OAA in cytoplasm
– OAA is decarboxylated and phosphorylated to PEP by PEP carboxykinase
• Carbon skeletons of many amino acids that enter TCA cycle can thus be used for glucose synthesis (glucogenic amino acids)
Bypasses in Gluconeogenesis-1 (2 reactions)Pyruvate Carboxylase (Gluconeogenesis) catalyzes:
pyruvate + HCO3- + ATP oxaloacetate + ADP + Pi
PEP Carboxykinase (Gluconeogenesis) catalyzes:oxaloacetate + GTP PEP + GDP + CO2
C
C
CH2
O O-
OPO32-
C
C
CH3
O O-
O
ATP ADP + P i C
CH2
C
C
O
O O-
O-
O
HCO3-
GTP GDP
CO2
pyruvate oxaloacetate PEP
Pyruvate Carboxylase PEP Carboxykinase
Fructose 1,6 bi-sphosphatase
glycolysis
ATPADP
Fructose 1,6-2 PO4 Fructose-6-PO4
H2O PO4
Gluconeogenesis
Mg2+
Bypasses in Gluconeogenesis-2
Glucose-6-Phosphatase (Gluconeogenesis) catalyzes: glucose-6-phosphate + H2O glucose + Pi
H O
OH
H
OHH
OH
CH2OH
H
OH
HH O
OH
H
OHH
OH
CH2OPO32-
H
OH
HH2O
1
6
5
4
3 2
+ P i
glucose-6phosphate glucose
Glucose 6 phosphatase
Bypasses in Gluconeogenesis-3
Substrate cycle or futile cycle: nothing is accomplished but the waste of ATP. In substrate cycle, ATP is formed in one direction and then is hydrolyzed in the opposite direction. Substrate cycle produces net hydrolysis of ATP We must remember that the direction of the substrate cycle is strictly controlled by allosteric effectors to meet the needs of the body for energy
Substrate cycle is a pair of opposed irreversible reactions
Glucose Paradox
• Evidence that glucose ingested during a meal is not used to form glycogen directly
• Glucose is first taken up by RBCs in bloodstream and converted to lactate by glycolysis
• Lactate is taken up by liver and converted to G6P by gluconeogenesis
• G6P converted to glycogen
1. To keep blood sugar level stable 2. To replenish liver glycogen3. To clear the products of other tissues’ metab
olites from the blood4. To convert glucogenic amino acids to glucose5. To regulate acid-base balance
H+
phosphoenolpyruvate carboxykinase
induces biosynthesisgluconeogenesis
alpha-ketoglutarate glucose
glutamic acid
glutamine
NH3
NH3
NH4+
H+
NH4+excreted in
urine and pH
raised in blood
Na+ absorbed
urine
The significance of gluconeogenesis
Cori Cycle ( Muscles lack G6-phosphatase ) - used to prevent high blood lactate levels and to fuel muscle activity - l-actate leaves muscle cells - transported via blood to liver - liver converts to glucose - glucose released back into circulation - returned to muscles
F-6-P
F-1,6-BP
phosphofructokinase-1F-1,6-biphosphatase
ATPcitrateADPAMP F-2,6-BPF-1,6-BP
insulin
glucokinasephosphofructokinase-1
pyruvate kinase
glycolysis gluconeogenesis
pyruvate carboxylasephosphoenolpyruvate carboxykinasefructose 1,6-biphosphatase
glucose 6-phosphatase
glucagon Glucocorticoidsepinephrine
Regulation of gluconeogenesis and glycolysis
***** Section VII Blood Sugar and Its Regulation
Blood sugar3.89~6.11m
mol/L
Origin (income)
Fate (outcome)
Dietary
supply Liver
glycogenGluconeoesis
(non-carbohydrate)Other sacchari
des8.89-- 10.00mmol/L
(threshold of kidney)
glycogen
glycogenesis
urine glucose
aerobic oxidationCO2 + H2O + energy
PPPother saccharides
non-carbohydrates(lipids and some amino acids)
glycogenolysis
1
2
2
3
4
55
6
Regulation of high
Blood Sugarinsulin
High blood sugar level (hyperglycemia)
insulin receptor
active transportin muscle and adipose tissuecells (not in liverand brain)
glycolysisand aerobicoxidation
glycogenesisproteinsynthesis
lipogenesislipolysis
gluconeogenesismodulating systemcAMP
Low blood sugar level (hypoglycemia)
glucagon
cAMP
Modulating system
hepatic glycogenolysis
gluconeogenesis lipolysis transport of glucogenic amino acids
glycolysis
hepatic glycogenesis
1 1
3 342
Regulation of Low Blood
Sugar
选择题练习糖代谢
1. 糖类最主要的生理功能是 ( )
A 提供能量
B 细胞膜组分
C 软骨的基质
D 信息传递
E 免疫作用
2. 关于糖类消化吸收的叙述 , 错误的是 ( )
A 食物中的糖主要是淀粉
B 消化的部位主要是小肠
C 部分消化的部位可在口腔
D 胰淀粉酶将淀粉全部水解成葡萄糖
E 异麦芽糖酶可水解 -1,6- 糖苷键
3. 关于糖酵解途径中的关键酶正确的是 ( )
A 磷酸果糖激酶 -1
B 果糖双磷酸酶 -1
C 磷酸甘油酸激酶
D 丙酮酸羧化酶
E 果糖双磷酸酶 -2
4. 1 分子葡萄糖在有氧或无氧条件下经酵解途径氧化产生 ATP 分子数之比为 ( )
A 2
B 4
C 6
D 19
E 36
5. 1 分子乙酰 CoA 经三羧酸循环氧化后的产物是 ( )
A 柠檬酸
B 草酰乙酸
C 2CO2+ 4 分子还原当量
D CO2+H2O
E 草酰乙酸 +CO2
6. 三羧酸循环主要在细胞的哪个部位进行 ?
A 胞液
B 细胞核
C 微粒体
D 线粒体
E 高尔基体
7. 磷酸戊糖途径是在哪个亚细胞部位进行的 ?
A 胞液中
B 线粒体
C 微粒体
D 高尔基体
E 溶酶体
8. 磷酸戊糖途径主要的生理功用 ( )
A 为核酸的生物合成提供核糖
B 为机体提供大量 NADPH+H+
C 生成 6- 磷酸葡萄糖
D 生成 3- 磷酸甘油醛
E 生成 6- 磷酸葡萄糖酸
9. 关于糖原合成的叙述错误的是 ( )
A 葡萄糖的直接供体是 UDPG
B 从 1- 磷酸葡萄糖合成糖原不消耗高能磷酸键
C 新加上的葡萄糖基连于糖原引物非还原端
D 新加上的葡萄糖基以 -1,4 糖苷键连于糖原引物上
E 新加上的葡萄糖基连于糖原引物 C4 上
10. 下例哪种酶不是糖异生的关键酶 ?
A 丙酮酸羧化酶
B 磷酸烯醇式丙酮酸羧基酶
C 磷酸甘油酸激酶
D 果糖双磷酸酶
E 葡萄糖 6- 磷酸酶
11. Which one is the main organ that regulate blood sugar metabolism?
A brain
B kidney
C liver
D pancreas
E adrenal gland
12. The end product of glycolytic pathway in human body is ( )
A CO2 and H2O
B pyruvic acid
C acetone
D lactic acid
E oxalacetic acid
13. Which one can promote synthesis of glucogen, fat and protein simultaneously?
A glycagon
B insulin
C adrenaline
D adrenal cortex hormone
E glucocorticoid
14. Which one is the allosteric inhibitor of 6-phosphofructokinase-1?
A 1,6-diphosphofructose
B 2,6 -diphosphofructose
C AMP
D ADP
E citric acid
15. 关于糖酵解的叙述 , 下列那些是正确的 ?
A 整个过程在胞液中进行
B 糖原的 1 个葡萄糖单位经酵解净生成 2 分子 ATP
C 己糖激酶是关键酶之一
D 是一个可逆过程
E 使 1 分子葡萄糖生成 2 分子乳酸
16. 三羧酸循环中 , 不可逆的反应有 ( )
A 柠檬酸 → 异柠檬酸
B 异柠檬酸 → -酮戊二酸
C -酮戊二酸 → 琥珀酰 CoA
D → 琥珀酸 延胡索酸
E → 苹果酸 草酰乙酸
17. 如果摄入葡萄糖过多 , 在体内的去向是 ( )
A 补充血糖
B 合成糖原储存
C 转变为脂肪
D 转变为唾液酸
E 转变为非必需脂肪酸
18. 胰岛素降血糖的作用是 ( )
A 促进肌肉脂肪等组织摄取葡萄糖
B 激活糖原合成酶促糖原的合成
C 加速糖的氧化分解
D 促进脂肪动员
E 抑制丙酮酸脱氢酶活性
19. The cofactors of pyruvic dehydrogenase complex is ( )
A thioctic acid
B TPP
C CoA
D FAD
E NAD+
20. The high-energy compounds produced by substrate level phosphorylation in glyco-aerobic oxidation are ( )
A ATP
B GTP
C UTP
D CTP
E TTP
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