6 shuttles
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Transcript of 6 shuttles
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Shuttles
Balancing the Redox potential between the
cytosol and mitochondria
• Malate - Aspartate Shuttle
• Glycerol-Phosphate-Shuttle
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Shuttles
• For gluconeogenesis: Metabolites must be transported between cytosol and mitochondria. There is no transporter for OAA.
• The redox potential requires balancing between cytosol and mitochondria.
Malate-Aspartate Shuttle for 'transport' of NADH and metabolites.
Glycerol-3-Phosphate Shuttle for 'transport' of NADH
Malate-Aspartate Shuttle
Gluconeogenesis
cytosol Mitochondrion
pyruvate
OAAMalate Malate
OAA
Aspartate
pyruvate
Aspartate
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C–OH|C–OH|C–OH
glycerol
C–OH|C = O|C–OPO3
DHAP
H–C = O|C–OH|C–OPO3
GA3P
C–OH|C–OH|C–OPO3
G3P
ATP
ADP
NADH NAD+
TPI
G3P-DH
Glycerol kinase
Glycerol Metabolism
Can be used in glycerol-phosphate Shuttle
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Pentose Phosphate Pathway (PPP)
orHexose Monophosphate
Shunt
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R5P = ribose-5-phosphateX5P = xylulose-5-phosphate
Glucose
Pyruvate
GlycogenR5P G6P
NADPHglycolysis
G6Pase (li
ver)
nucleotidebiosynthesis
Generates reducing equivalents for reductive biosynthesis and reduction of glutathione.
Energy Production
EnergyStorage
G6P ---> ---> ---> Ribulose-5-Phosphate
2 NADP+ 2 NADPH
Reductive portion
R5P
X5P7
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Important Facts about the PP-Pathway
1. Generates 2 NADPH for every G6P
oxidized. Needed for:
• Reductive biosynthesis
• Reduction of glutathione
2. It produces R5P for nucleotide
synthesis.
3. It produces X5P – an allosteric effector
of carbohydrate metabolism.
4. Pathway is not a dead-end. It generates
metabolites that can feed back into
glycolysis.
5. G6P-DH catalyzes the 1st step:
• Inhibited by high NADPH.
• Induced in liver by high carb diet.8
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Importance of Hexose Monophosphate (HMP)
Shunt in Red Blood Cells
• Role in maintaining viability of red blood cell.
• Provides NADPH to protect against oxidative damage.– NADPH is needed for reduction
of glutathione.– Glutathione can reduce
reactive oxygen species (H2O2, organic peroxides).
– Reducing conditions are necessary for keeping Fe+2 in hemoglobin from being oxidized.
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Glutathione• A tri-peptide
(-glutamyl-cysteinylglycine)• Important for destroying harmful
oxidants.
Glutathione reductase
GSSG2 GSH
NADPH + H+NADP+
Pentose Phosphate Pathway (G6P-DH)
2 GSH + R–O–O–R GSSG + R–OH + H2O
Glutathion peroxidase
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Glutathione in Red Cell
• Helps to maintain sulfhydryl groups of proteins such as hemoglobin. These groups can undergo spontaneous oxidation to disulfides.
2 protein–SH + 1/2 O2 ---> protein–S–S–protein + H2O
GSSG 2 GSH
Glutathione reductase
NADPH NADP+
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Important Facts about the PP-Pathway
1. Generates 2 NADPH for every G6P
oxidized. Needed for:
• Reductive biosynthesis
• Reduction of glutathione
2. It produces R5P for nucleotide
synthesis.
3. It produces X5P – an allosteric effector
of carbohydrate metabolism.
4. Pathway is not a dead-end. It generates
metabolites that can feed back into
glycolysis.
5. G6P-DH catalyzes the 1st step:
• Inhibited by high NADPH.
• Induced in liver by high carb diet.12
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G6P
Ribose-5-P
Ribulose-5-P
2 NADPH
PP2A(phosphoprotein phosphatase 2A)
2 NADP+
Nucleotidesynthesis
F6P + GA3P
Bifunctional Enz ChREBP(transcription factor)
X5P
Role of Metabolites in PPP
+
+ CO2
Intermediates in glycolysis
Allosteric activation
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Remember the BiFunctional Enzyme
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F6P
F-2,6BP
Allosteric activatorPFK-1
Allosteric inhibitorF-1,6BPase
BiF-Enz
kinase Ptase
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Carbohydrates to FatsChREBP = Carbohydrate response
element binding protein• A transcription factor• Highly expressed in liver, kidney, &
adipose tissues.• Inactive state: present in cytosol &
specific ser/th sites are phosphorylated.• Activated by dephosphorylation.
PP2A = Phosphoprotein phosphatase 2A• Function = it dephosphorylates:
– Bifunctional Enzyme– ChREBP
• Activated by Xylulose-5-Phosphate
(X5P)
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ChREBP• When dephosphorylated by PP2A it
translocates to nucleus, gets dephosphorylated
again, binds DNA, and upregulates
transcription of:– pyruvate kinase– acetyl-CoA carboxylase– FA synthase proteins
ChREBP
P P
ChREBP
P
ChREBPChREBP
P
DNA Response Elements mRNA transcripts
PP2Acytosol
nucleus
PP2A
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G6P
NADPH
PP2A
Bifunctional E ChREBP
X5P
Allosteric Effects of X5P in Liver
Activates PFK-2↑[F2,6-BP]
Activates Glycolysis
Effects Transcription:• Pyruvate kinase• Acetyl-CoA carboxylase• FA synthase
+Allosteric activation
Glucose
Promotes Carbs ---> Fats
Which activity?Effect?
Protein Induction
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Glucose
G6P
F1,6-BP
F6P
PEP
pyruvate
acetyl-CoA
OAAcitrate
acetyl-CoA
malonyl-CoA
citrateOAA
malate
malate
X5P
pyruvate
NADH
NAD+
FAs
F2,6-BP+
PP2A
ChREBP
ACC
FAS
NADPH
PK +
+
+BiF-E
NADH
NAD+
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