Shuttles are integral part of basic functioning.If it can help you then GOD.

1. Shuttles
Balancing the Redox
potential between the
cytosol and mitochondria
• Malate - Aspartate Shuttle
• Glycerol-Phosphate-Shuttle
1

2. 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
cytosol
pyruvate
Mitochondrion
pyruvate
Malate
Malate
OAA
OAA
Aspartate
Aspartate
Gluconeogenesis
Malate-Aspartate Shuttle for 'transport' of NADH and
metabolites.
Glycerol-3-Phosphate Shuttle for 'transport' of NADH
2

3. Glycerol Metabolism
H–C = O
|
C–OH
|
C–OPO3
C–OH
|
C–OH
|
C–OH
glycerol
GA3P
ATP
Glycerol kinase
TPI
ADP
C–OH
|
C=O
|
C–OPO3
DHAP
NADH
NAD+
G3P-DH
C–OH
|
C–OH
|
C–OPO3
G3P
Can be used in glycerol-phosphate Shuttle
3

4. 4

5. 5

6. Pentose Phosphate
Pathway (PPP)
or
Hexose Monophosphate
Shunt
6

7. Glucose
nucleotide
biosynthesis
(
se
a
6P
G
l
)
er
iv
G6P
R5P
Glycogen
gly
co
NADPH
Pyruvate
Energy
Storage
lys
is
Energy Production
Generates reducing equivalents for
reductive biosynthesis and reduction
of glutathione.
R5P = ribose-5-phosphate
X5P = xylulose-5-phosphate
2 NADP+
2 NADPH
R5P
G6P ---> ---> ---> Ribulose-5-Phosphate
X5P
Reductive portion
7

8. 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

9. 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.
9

10. Glutathione
• A tri-peptide
(γ-glutamyl-cysteinylglycine)
• Important for destroying harmful
oxidants.
2 GSH + R–O–O–R
GSSG + R–OH + H2O
Glutathion peroxidase
2 GSH
GSSG
Glutathione
reductase
NADP+
NADPH + H+
Pentose Phosphate Pathway (G6P-DH)
10

11. 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+
11

12. 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

13. Role of Metabolites in PPP
2 NADP+
2 NADPH
+ CO2
G6P
Ribulose-5-P
X5P
Ribose-5-P
F6P + GA3P
Intermediates in glycolysis
Allosteric activation
Nucleotide
synthesis
+
PP2A
(phosphoprotein phosphatase 2A)
Bifunctional Enz
ChREBP
(transcription factor)
13

14. Remember the BiFunctional
Enzyme
F6P
kinase
Ptase
BiF-Enz
F-2,6BP
Allosteric activator
PFK-1
Allosteric inhibitor
F-1,6BPase
14

15. Carbohydrates to Fats
ChREBP = 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)
15

16. 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
P
P
P
ChREBP
ChREBP
PP2A
cytosol
nucleus
PP2A
ChREBP
DNA Response Elements
P
ChREBP
mRNA transcripts
16

17. Allosteric Effects of X5P in Liver
Glucose
G6P
NADPH
X5P
Allosteric activation
+
PP2A
Bifunctional E
Which activity?
Effect?
Activates PFK-2
↑[F2,6-BP]
Activates Glycolysis
ChREBP
Effects Transcription:
• Pyruvate kinase
• Acetyl-CoA carboxylase
• FA synthase
Protein Induction
Promotes Carbs ---> Fats
17

18. NADPH
FAs
Glucose
X5P
G6P
F6P
+
BiF-E
FAS
+
PP2A
malonyl-CoA
+
F2,6-BP
F1,6-BP
ACC
acetyl-CoA
NAD+
ChREBP
NADH
OAA
NADH
PEP
PK
NAD+
+
malate
pyruvate
pyruvate
citrate
malate
acetyl-CoA
OAA
citrate
18