6 shuttles

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

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

2. 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 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

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

4. 4

5. 5

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

7. R5P = ribose-5-phosphate
X5P = xylulose-5-phosphate
Glucose
Pyruvate
GlycogenR5P G6P
NADPH
g
l
y
c
o
l
y
s
i
s
G
6 P
a se (liver)
nucleotide
biosynthesis
Generates reducing equivalents for
reductive biosynthesis and reduction
of glutathione.
Energy Production
Energy
Storage
G6P ---> ---> ---> Ribulose-5-Phosphate
2 NADP
+
2 NADPH
Reductive portion
R5P
X5P
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. 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 (H
2
O
2
,
organic peroxides).
–Reducing conditions are
necessary for keeping Fe
+2
in
hemoglobin from being
oxidized.

10. 10
Glutathione
•A tri-peptide
(g-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 + H
2
O
Glutathion peroxidase

11. 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 O
2
---> protein–S–S–protein +
H
2
O
GSSG
2 GSH
Glutathione reductase
NADPH NADP
+

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

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

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

17. 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
17

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