1. Pentose Phosphate Pathway (aka Hexose monophosphate shunt)

2. 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

3. 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

4. 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

5. Step 2

6. Step 3 A second NADPH is formed
Oxidative steps are done, a total of 6 NADPH is formed

7. Steps 4-8

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.

9. Steps 6-8
Recall: Xu-5-P and R5P is generated in the ratio 2:1

10. 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

11. Transaldolase catalyzes the transfer of C3 from S-7-P to GAP forming E-4-P and F-6-P.
NO TPP required

12. 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-Xu-5-P adduct as intermediate

13. 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)

14. CASE 1: Rapidly dividing cells require more ribose 5- phosphate than NADPH.

15. Case 2: The need for NADPH and ribose 5-phosphate is balanced.

16. Case 3: More NADPH is needed than ribose 5-phosphate; Fatty acid synthesis in adipose cells.

17. Case 4: The cell needs both NADPH and ATP

18. 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