Download Pentose Phosphate Pathway (aka Hexose monophosphate shunt)

Pentose Phosphate Pathway
(aka Hexose monophosphate shunt)
Two main functions of the
Pentose Phosphate Pathway
• Produce NADPH (for fatty acid synthesis,
cholesterol synthesis, detoxification via
CYP450, glutathione activity)
• Produce ribose-5-phosphate for nucleic acid
synthesis
Two phases of the PPP
The net reaction of PPP is:
3 G6P + 6 NADP+ + 3 H2O 
6 NADPH + 6H+ + 3CO2 + 2 F6P + GAP
• Oxidative phase (3G6P  3Ru-5-P)
– Steps 1-3: generation of NADPH equivalents
– Irreversible process
• Non-oxidative phase (3Ru-5-P  2 F6P + GAP)
– Steps 4-8: generation of R5P and/or glycolytic
intermediates
– Reversible process
Step 1
• 3 G6P enters to PPP at one time, this (and succeeding
reactions happen 3 times)
• The enzyme is highly specific for NADP+; the Km for
NAD+ is 1000 greater than for NADP+.
• Allosterically controlled by NADPH/NADP+ ratio
• Inducible enzyme by insulin
• Committed step in PPP
Step 2
Step 3
• A second NADPH is formed
• Oxidative steps are done, a total of 6 NADPH is formed
Steps 4-8
Steps 4 and 5
3 Ru-5-P  2 Xu-5-P + R-5-P (or 3 R-5-P)
• Ru-5-P  Xu-5-P needs an epimerase
• Ru-5-P  R-5-P needs an isomerase
Relative amounts of Xu-5-P and R-5-P depends on the
need of the cell.
Steps 6-8
Recall: Xu-5-P and R5P is generated in the ratio 2:1
Transketolase catalyzes the
transfer of C2 from Xu-5-P to
R-5-P forming S-7-P and GAP.
Requires TPP as cofactor
Goes through a TPP-Xu-5-P
adduct as intermediate
Transaldolase catalyzes the
transfer of C3 from S-7-P to
GAP forming E-4-P and F-6-P.
NO TPP required
A second transketolase
catalyzes the transfer of
C2 from Xu-5-P to E-4-P
forming a second F-6-P
and GAP.
Requires TPP as
cofactor
Goes through a TPP-Xu5-P adduct as
intermediate
Regulation of PPP
• G6PD is the most regulated enzyme: inhibition
by NADPH, expression is dependent on insulin
thus it is only expressed at high glucose
concentration
• Since the non-oxidative pathway is reversible,
the direction is dependent on the need of the
cell for ATP / acetyl CoA (energy / fatty acid
synthesis) vs Ribose-5-P (nucleic acid
synthesis)
CASE 1: Rapidly dividing cells require more ribose 5phosphate than NADPH.
Case 2: The need for NADPH and ribose 5-phosphate is
balanced.
Case 3: More NADPH is needed than ribose 5phosphate; Fatty acid synthesis in adipose cells.
Case 4: The cell needs both NADPH and ATP
NADPH production in RBC
•
•
•
Spontaneous oxidation of Fe2+ in Hb occurs around 1% per
hour, forming superoxides: Hb-Fe2+-O2 -> Hb-Fe3+ + O2-.
O2- and H2O2 may cause hemolysis if not turned reduced to
H2O via glutathione.
Glucose-6-Phosphate dehydrogenase deficiency is a disease
characterized by hemolytic anemia