chapter 4 carbohydrates metabolism
DESCRIPTION
Chapter 4 Carbohydrates Metabolism. The biochemistry and molecular biology department of CMU. § 1 Overview. Carbohydrates in general are polyhydroxy aldehydes or ketones or compounds which yield these on hydrolysis. Biosignificance of Carbohydrates. - PowerPoint PPT PresentationTRANSCRIPT
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Chapter 4
Carbohydrates Metabolism
The biochemistry and molecular biology department of CMU
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§ 1 Overview
• Carbohydrates in general are polyhydroxy aldehydes or ketones or compounds which yield these on hydrolysis.
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Biosignificance of Carbohydrates
• The major source of carbon atoms and energy for living organisms.
• Supplying a huge array of metabolic intermediates for biosynthetic reactions.
• The structural elements in cell coat or connective tissues.
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Glucose transporters (GLUT)
• GLUT1~5
GLUT1: RBC
GLUT4: adipose tissue, muscle
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The metabolism of glucose
• glycolysis• aerobic oxidation• pentose phosphate pathway• glycogen synthesis and
catabolism• gluconeogenesis
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glycogen
Glycogenesis Glycogenolysis
Pentose phosphate pathway
Ribose, NADPH
Glycolysis lactate
H2O+CO2
aerobic oxidation
Digestion absorption
starch
Lactate, amino acids, glycerol
glucose
Gluconeo-
genesis
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§2 Glycolysis
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Glycolysis
• The anaerobic catabolic pathway by
which a molecule of glucose is broken
down into two molecules of lactate.
glucose →2lactic acid (lack of O2)
• All of the enzymes of glycolysis locate
in cytosol.
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1. The procedure of glycolysis
G
pyruvate
lactic acid
glycolytic pathway
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1) Glycolytic pathway :
G → pyruvate
including 10 reactions.
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• Phosphorylated G cannot get out of cell
• Hexokinase , HK (4 isoenzymes) ,
glucokinase, GK in liver ;
• Irreversible .
(1) G phosphorylated into glucose 6-phosphate
OH
OH
H
OHH
OHH
OH
CH2
H
HOOH
OH
H
OHH
OHH
OH
CH2
H
OPATP ADP
Hexokinase
Mg2+
G G-6-P
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hexokinase
glucokinase
occurrence in all tissues only in liver
Km value 0.1mmol/L 10mmol/L
Substrate G, fructose, glucose mannose
Regulation G-6-P Insulin
Comparison of hexokinase and glucokinase
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(2) G-6-P → fructose 6-phosphate
OH
OH
H
OHH
OHH
OH
CH2
H
OP
G-6-P
isomerase OH
CH2OH
H
CH2
OH H
H OH
OOP
F-6-P
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(3) F-6-P → fructose 1,6-bisphosphate
• The second phosphorylation • phosphofructokinase-1, PFK-1
OH
CH2OH
H
CH2
OH H
H OH
OOP
F-1,6-BP
OH
CH2
H
CH2
OH H
H OH
OOP O P
ATP ADP
Mg2+
F-6-P
PFK-1
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(4) F-1,6-BP → 2 Triose phosphates
• Reversible
F-1,6-BP
CH2
C O
C HHO
C OHH
C OHH
CH2
O P
O P
CH2
C O
O P CHO
CHOH
CH2 O PCH2OH
+aldolase
dihydroxyacetone phosphate,
DHAP
glyceraldehyde 3-phosphate,
GAP
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(5) Triose phosphate isomerization
G→2 molecule glyceraldehyde-3-phosphate, consume 2 ATP .
CH2
C O
O P CHO
CHOH
CH2 O PCH2OH
DHAP GAP
phosphotriose isomerase
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(6) Glyceraldehyde 3-phosphate → glycerate 1,3-bisphosphate
CHO
CHOH
CH2 O P
NAD+ NADH+H +Pi
glyceraldehyde 3-phosphate
dehydrogenase,GAPDH
C
CHOH
CH2 O P
O O~ P
glycerate1,3-bisphosphate,
1,3-BPG
glyceraldehyde 3-phosphate
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(7) 1,3-BPG → glycerate 3-phosphate
• Substrate level phosphorylation
COO-
CHOH
CH2 O P
C
CHOH
CH2 O P
O O~ PADP ATP
glycerate 1,3-bisphosphate
glycerate3-phosphate
Phosphoglyceratekinase
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(8) Glycerate 3-phosphate → glycerate 2-phosphate
COO-
CHOH
CH2 O P
COO-
CH
CH2OH
O P
glycerate3-phosphate
glycerate 2-phosphate
Mutase
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(9) Glycerate 2-phosphate → phosphoenol pyruvate
COO-
CH
CH2OH
O P
COO-
C
CH2
O
PEP
~ P + H2O
enolase
glycerate 2-phosphate
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(10) PEP →pyruvate
• Second substrate level phosphorylation• irreversible
COO-
C
CH3
ADP ATPCOO-
C
CH2
O
PEP
~ Ppyruvate kinase
O
Pyruvate
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2) Pyruvate → lactate
COO
C
CH3
NAD+NADH + H+
O
Pyr
COO
CHOH
CH3Lactate dehydrogenase,
LDHLactic acid
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Summary of Glycolysis
ATP ADPMg2+
PFK-1
GAP DHAP
glycerate 1,3-bisphosphate
NADH+H+
glyceraldehyde 3-phosphatedehydrogenase
H3PO4
NADH+H+
NAD+
ADP
ATP glycerate3-phosphate
glycerate 2-phosphate
H2O
PEP
ATP
ADP
pyruvate kinase
lactate
pyruvate
G G-6-P F- 6-P F- 1,6-BP
NAD+
Phosphoglyceratekinase
IsomeraseAldolase
MutaseEnolase
LDH
HK
ATP ADPMg2+
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Total reaction:
C6H12O6 + 2ADP + 2Pi
2CH3CHOHCOOH + 2ATP + 2H2O
Formation of ATP:
The net yield is 2 ~P or 2 molecules of
ATP per glucose.
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2. Regulation of Glycolysis
• Three key enzymes catalyze
irreversible reactions : Hexokinase,
Phosphofructokinase & Pyruvate
Kinase.
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1) PFK-1
The reaction catalyzed by PFK-1 is
usually the rate-limiting step of the
Glycolysis pathway.
This enzyme is regulated by covalent
modification, allosteric regulation.
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bifunctional enzyme
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2) Pyruvate kinase
• Allosteric regulation:
F-1,6-BP acts as allosteric activator ;
ATP and Ala in liver act as allosteric inhibitors;
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• Covalent modification:
phosphorylated by Glucagon
through cAMP and PKA and inhibited.
ATP ADP
PKA
Glucagon
Pyruvate Kinase (active)
Pyruvate Kinase- P (inactive)
cAMP
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3) Hexokinase and glucokinase
• This enzyme is regulated by covalent modification, allosteric regulation and isoenzyme regulation.
• Inhibited by its product G-6-P.
• Insulin induces synthesis of glucokinase.
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3. Significance of glycolysis
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, such as red blood cells, retina, testis, skin, medulla of kidney.
• In glycolysis, 1mol G produces 2mol lactic acid and 2mol ATP.
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§ 3 Aerobic Oxidation of Glucose
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• The process of complete
oxidation of glucose to CO2 and water with liberation of energy as the form of ATP is named aerobic oxidation.
• The main pathway of G oxidation.
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1. Process of aerobic oxidation
G Pyr
cytosol Mitochodria
glycolyticpathway
secondstage
thirdstage
CO2 + H2O+ATPPyr CH3CO~SCoA
firststage
TAC
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1) Oxidative decarboxylation of Pyruvate to Acetyl CoA
• irreversible;• in mitochodria.
COO-
C
CH3
NAD+ NADH + H +
O
pyruvate
CH3CPyruvate
dehydrogenasecomplex
Acetyl CoA
O
~SCoA+ HSCoA + CO2
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Pyruvate dehydrogenase complex:
E1 pyruvate dehydrogenase
Es E2 dihydrolipoyl transacetylase
E3 dihydrolipoyl dehydrogenase
thiamine pyrophosphate, TPP (VB1)
HSCoA (pantothenic acid)
cofactors lipoic Acid
NAD+ (Vpp)
FAD (VB2)
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HSCoA
NAD+
Pyruvate dehydrogenase complex:
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The structure of pyruvate dehydrogenase complex
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S S
CH
H2C
H2C (CH2)4 COOH
SH SH
CH
H2C
H2C (CH2)4 COOH+2H
-2H
lipoic acid dihydrolipoic acid
C
C
NH2HC
NCH2
SC
C
NC
NCH
CH3
CH2CH2H3C O P O
O-
O
P
O
O-
O-
+
TPP
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HSCoA
HS CH2 CH2 NH C CH2
O
CH2 NH C C
O
OH
H
C CH2
CH3
CH3
O P O
OH
O
P
OH
O
O
3'AMP
¦Â-alanine pantoic acid pyrophosphate
pantothenic acid
4'-phosphopantotheine
¦Â-mercapto-ethylamine
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CO2
CoASHNAD+
NADH+H+
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2) Tricarboxylic acid cycle, TCAC
• The cycle comprises the combination of a
molecule of acetyl-CoA with oxaloacetate,
resulting in the formation of a six-carbon
tricarboxylic acid, citrate. There follows a
series of reactions in the course of which
two molecules of CO2 are released and
oxaloacetate is regenerated.
• Also called citrate cycle or Krebs cycle.
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(1) Process of reactions
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Citrate cycle
CO
CH2
COO
COO
CH3CO~SCoA
C
CH2
COO
COO
CH2
HO
COO
C
CH
COO
COO
CH2 COO
CH
CH
COO
COO
CH2 COO
H2O
H2O
HO
CO2
CH2
CH2
COCOO
COOCH2
CH2
COO
CO~ SCoA CO2
NAD+NADH+H+
CH2
CH2
COO
COO GDP+PiGTP
CH
CH2
COO
COO
OOC CH
C COOH
HONAD+
NADH+H+
FAD
FADH2
H2O
acetyl CoA
H2Ooxaloacetate
citrate synthase
citrate
aconitase
cis-aconitate
aconitase
isocitrate
NAD+
NADH+H+
isocitrate dehydrogenase
¦Á-keto-glutarate
¦Á-ketoglutaratedehydrogenase
complex
succinyl-CoA
ADP ATP
CoASH
succinyl CoA syntetase
succinate dehydrogenase
fumarate
succinate
fumarase
malate
malate dehydrogenase
HSCoA
HSCoA
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Summary of Krebs Cycle ①
Reducing equivalents
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② The net reaction of the TCAC:
acetylCoA+3NAD++FAD+GDP+Pi+2H2O
→ 2CO2+3NADH+3H++FADH2+GTP+
HSCoA
③ Irreversible and aerobic reaction
④ The enzymes are located in the
mitochondrial matrix.
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⑤ Anaplerotic reaction of oxaloacetate
pyruvate carboxylase
Biotin
ATP ADP + Pi
+ CO2C
CH3
COOH
OC
C
COOH
COOH
O
H2
NAD+ NADH+H+
malic acid DH+ CO2
malic enzymeC
CH3
COOH
O
NADPH+H+ NADP+
CHOH
C
COOH
COOH
C
C
COOH
COOH
O
H2H2
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(2) Bio-significance of TCAC
① Acts as the final common pathway for
the oxidation of carbohydrates, lipids,
and proteins.
② Serves as the crossroad for the
interconversion among carbohydrates,
lipids, and non-essential amino acids,
and as a source of biosynthetic
intermediates.
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Krebs Cycle is at the hinge of metabolism.
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2. ATP produced in the aerobic oxidation
• acetyl CoA → TCAC : 3 (NADH+H+) + FADH2 + 1GTP → 12 ATP.
• pyruvate →acetyl CoA: NADH+H+ → 3 ATP
• 1 G → 2 pyruvate : 2(NADH+H+) → 6 or 8ATP
1mol G : 36 or 38mol ATP
( 12 + 3 ) ×2 + 6 ( 8 )= 36 ( 38 )
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3. The regulation of aerobic oxidation
• The Key Enzymes of aerobic oxidation
The Key Enzymes of glycolysis
Pyruvate Dehydrogenase Complex
Citrate synthase
Isocitrate dehydrogenase (rate-limiting )
-Ketoglutarate dehydrogenase
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(1) Pyruvate dehydrogenase complex
Pyruvate dehydrogenase(active form)
allosteric inhibitors:
ATP, acetyl CoA,NADH, FA
allosteric activators:AMP, CoA, NAD+,Ca2+
pyruvate dehydrogenase (inactive form)
P
pyruvate dehydrogenase kinase
pyruvate dehydrogenase phosphatase
ATP
ADPH2O
Pi
Ca2+,insulin acetyl CoA,NADH
ADP,NAD+
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(2) Citrate synthase
• Allosteric activator: ADP
• Allosteric inhibitor: NADH, succinyl CoA, citrate, ATP
(3) Isocitrate dehydrogenase
• Allosteric activator: ADP, Ca2+
• Allosteric inhibitor: ATP
(4) -Ketoglutarate dehydrogenase
• Similar with Pyruvate dehydrogenase complex
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Oxidative phosphorylation→TCAC↑
• ATP/ADP↑ inhibit TCAC,
Oxidative phosphorylation ↓
• ATP/ADP↓ , promote TCAC , Oxidative phosphorylation ↑
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4. Pasteur Effect
• Under aerobic conditions, glycolysis is inhibited and this inhibitory effect of oxygen on glycolysis is known as Pasteur effect.
• The key point is NADH : NADH mitochondria
Pyr TCAC CO2 + H2O
Pyr can’t produce to lactate.
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§4 Pentose Phosphate Pathway
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1. The procedure of pentose phosphate pathway/shunt
In cytosol
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1) Oxidative Phase
NADP+NADPH+H+
H2O
CO2
G-6-P
Xylulose 5-P
Ribulose 5-P
Ribose 5-P
G-6-P dehydrogenase
6-Phosphogluconate
6-phosphogluconate dehydrogenase
6-Phosphogluconolactonase
6-phosphogluco-nolactone
Epimerase
Isomerase
NADP+
NADPH+H+
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2) Non-Oxidative PhaseRibose 5-p
Xylulose 5-p
Xylulose 5-p
Fructose 6-p
Glyceraldehyde 3-p
Fructose 6-p
• Transketolase: requires TPP• Transaldolase
Glycolysis
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The net reation:
3G-6-P + 6NADP+ →
2F-6-P + GAP + 6NADPH + H+ + 3CO2
2. Regulation of pentose phosphate pathway
Glucose-6-phosphate Dehydrogenase is the rate-limiting enzyme.
NADPH/NADP+↑, inhibit;
NADPH/NADP+↓, activate.
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3. Significance of pentose Phosphate pathway
1) To supply ribose 5-phosphate for bio-synthesis of nucleic acid;
2) To supply NADPH as H-donor in metabolism;
NADPH is very important “reducing power” for the synthesis of fatty acids and cholesterol, and amino acids, etc.
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NADPH is the coenzyme of glutathione
reductase to keep the normal level of
reduced glutathione;
So, NADPH, glutathione and glutathione reductase together will preserved the integrity of RBC membrane.
2GSH
G-S-S-G NADPH + H+
glutathione reductase
NADP+H2O2
2H2O
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Deficiency of glucose 6-phosphate dehydrogenase results in hemolytic anemia.
favism
NADPH serves as the coenzyme of mixed function oxidases (mono-oxygenases). In liver this enzyme participates in biotransformation.
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§5 Glycogen synthesis and catabolism
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Glycogen is a polymer of glucose residues linked by (1→4) glycosidic bonds, mainly (1→6) glycosidic bonds, at
branch points.
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• The process of glycogenesis
occurs in cytosol of liver and
skeletal muscle mainly.
1. Glycogen synthesis (Glycogenesis)
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• UDPG: G active pattern, G active donor.• In glycogen anabolism, 1 G consumes
2~P. • Glycogen synthase: key E.
GHK or GK
G-6-P
ATP ADP
G-1-PUDPG
pyrophosphorylase
UDPG
UTP PPi Gn UDP
Gn+1glycogensynthase
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O O
OHOH
HH
H
CH2
H
HN
N
O
O
OP
O
O
P
O
O
H O
OH
H
OHH
OH
CH2OH
H
O
H
UDPG
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Branching enzyme
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Phosphorylase: key E;
The end products: 85% of G-1-P and 15% of free G;
There is no the activity of glucose 6-phosphatase (G-6-Pase) in skeletal muscle.
Gn
Pi Gn-1
G-1-P G-6-P G-6-Pase
H2O Pi
GPhosphorylase
2. Glycogen catabolism (glycogenolysis)
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Debranching enzyme:
glucan transferase
-1,6-glucosidase
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Nonreducing ends(1→6) linkage
Glycogen phosphorylase
(1→6) glucosidase activity of debranching enzyme Glucose
Transferase activity of debranching enzyme
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3. Regulation of glycogenesis and
glycogenolysis
1) Allosteric regulation
In liver:
G phosphorylase
glycogenolysis
In muscle:AMP phosphorylase-b
ATPG-6-P
phosphorylase-a
glycogenolysisCa2+
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2) Covalent modification
Glucagonepinephrine
Adenylyl cyclase
cAMP
G proteinreceptor
PKA
glycogenolysis
Phosphorylase
Glycogen synthase
glycogenesisBlood sugar
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glucagon, epinephrine
inactiveadenylate cyclase
activeadenylate cyclase
ATP cAMP
inactivePKA
activePKA
phosphorylase bkinase
phosphorylase bkinase
P
ATP
ADP
H2O
Pi
phosphorylase b
P
P
ATP ADP
Pi
H2OATP ADP
glycogen synthase
glycogen synthase
P
H2OPi protein phosphatase-1
(active) (inactive)
inhibitor-1 (active)
inhibitor-1 (inactive)
phosphorylase a
ATP
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§6 Gluconeogenesis
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• Concept:
The process of transformation of non-carbohydrates to glucose or glycogen is termed as gluconeogenesis.
• Materials: lactate, glycerol, pyruvate and glucogenic amino acid.
• Site: mainly liver, kidney.
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1. Gluconeogenic pathway
• The main pathway for gluconeogenesis
is essentially a reversal of glycolysis,
but there are three energy barriers
obstructing a simple reversal of
glycolysis.
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1) The shunt of carboxylation of Pyr
PEP
ADP
ATP
oxaloacetic acid
Pyr carboxylase
ADP+Pi ATP CO2Biotin
GTP
GDPCO2
PEP carboxykinase
Pyr kinase
COO-
C
CH3
COO-
CH
CH2
O~ P
O
pyruvate
COO-
C
CH2
O
COOH £¨ Mt.£©
£¨ 1/3Mt. 2/3cytosal£©.
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2) F-1, 6-BP →F-6-P
F-6-P F-1,6-BP
ATP ADP
Pi H2O
PFK-1
Fructose-bisphosphatase
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3) G-6-P →G
• 2 lactic acid G consume ATP?
G G-6-P
ATP ADP
Pi H2O
Glucose-6-phosphatase
HK
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gluconeogenesisglucose
G-6-P
glycogen
F-1,6BP
glyceral-dehyde 3-P
glycerol1.3-bisphospho- glycerate
glycerate 3-P
glycerate 2-P
lactate
G-1-P
malic acid
phosphoenol pyruvate
pyruvate
GTP
GDP
CO22/3
malic acid
pyruvate
phosphoenol pyruvate
GTP
GDP
CO21/3
CO2
CYTOSOL MITOCHONDRIA
NAD+ NADH+H+
NAD+
NADH+H+
NAD+
NADH+H+
glutamate
¦Á-ketoglutarate ¦Á-ketoglutarate
glutamate
OAAAspAspOAADHAP
ATP
ADP
ATP
ADP
PKADP
ATP
F-6-P
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2. Regulation of gluconeogenesis
• Substrate cycle:
The interconversion of two substrates
catalyzed by different enzymes for
singly direction reactions is called
“substrate cycle”.
• The substrate cycle produces net
hydrolysis of ATP or GTP.------futile
cycle
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Key enzymes of gluconeogenesis
PEP carboxykinase
Pyr carboxylase
Fructose-bisphosphatase
Glucose-6-phosphatase
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F-1,6-BP
ATP
ADP
Pi
H2O
PFK-1FBPase-1
F-6-P
F-2,6-BP
AMP
glycolysis
gluconeogenesis:
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F-1,6-BP
ATP
ADPF-2,6-BP
PEP
Pyr
acetyl CoA
glucagon
insulinglucagonAla in liverOAA
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3. Significance of gluconeogenesis
(1) Replenishment of Glucose by Gluconeogenesis and Maintaining Normal Blood Sugar Level.
(2) Replenishment of Liver Glycogen.
(3) Regulation of Acid-base Balance.
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First stages(cytosol)
Second stages(Mt.)
Third stages(Mt.)
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Lactic acid (Cori) cycle• Lactate, formed by the oxidation of
glucose in skeletal muscle and by blood, is transported to the liver where it re-forms glucose, which again becomes available via the circulation for oxidation in the tissues. This process is known as the lactic acid cycle or Cori cycle.
• prevent acidosis ; reused lactate
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muscle
glucose
pyruvate
lactate
glucose
blood
pyruvate
lactate
glycolytic pathway
glucose
liver
lactate
NAD+
NADH+H+
NADH+H+
NAD+
gluconeo-genesis
Lactic acid cycle
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§6 Blood Sugar and Its
Regulation
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1. The source and fate of blood sugar
blood sugar3.89¡« 6.11mmol/L
dietary supply
liver glycogen
(gluconeogenesis)
other saccharides
CO2 + H2O + energy
glycogen
other saccharides
non-carbohydrates
>8.89¡«10.00mmol/L(threshold of kidney)
non-carbohydrate
(lipids and some amino acids)
urine glucose
origin (income) fate (outcome)
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Blood sugar level must be maintained within a limited range to ensure the supply of glucose to brain.
The blood glucose concentration is 3.89 ~ 6.11mmol/L normally.
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2. Regulation of blood sugar level
1 ) insulin : for decreasing blood sugar levels.
2 ) glucagon : for increasing blood sugar levels.
3 ) glucocorticoid: for increasing blood sugar levels.
4 ) adrenaline : for increasing blood sugar levels.
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3. Abnormal Blood Sugar Level
• Hyperglycemia: > 7.22 ~ 7.78 mmol/L
• The renal threshold for glucose: 8.89
~ 10.00mmol/L
• Hypoglycemia: < 3.33 ~ 3.89mmol/L
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Pyruvate as a junction point
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