2. Hexose Monophosphate Shunt (HMP Shunt)

3. Learning objectives To explain HMP shunt
To underline the significance of HMP shunt
To compare the features of HMP shunt & glycolysis
To describe the process (reactions) of HMP shunt
To explain the regulation of HMP shunt

4. Hexose Monophosphate Shunt (HMP Shunt)
Also knows as “Pentose Phosphate Pathway (PPP)”
“Pentose Cycle”
“Phosphogluconate Pathway”

5. Occurrence of HMP Shunt
HMP shunt is active in
Liver, lactating mammary glands, thyroid, adipose tissue, leukocytes, RBCs, testes and adrenal cortex
HMP shunt (PPP) is less active in skeletal muscle & non-lactating mammary glands
Site:- Cytosol

6. Biomedical Importance
Alternate pathway for oxidation of Glucose, with no ATP production, but has two major functions;
Provides NADPH, required for reductive syntheses and some other reactions
Provides pentoses, required for Nucleic Acids and Nucleotide synthesis
Deficiency of certain enzymes leads to hemolytic anemia e.g. G6P Dase (G-6-P dehydrogenase )

7. Comparison of HMP Shunt & Glycolysis
S.No.
HMP Shunt
Glycolysis 1
Occurs in specialized tissues
Occurs in all tissues 2
Site is Cytosol 3
Multi-cyclic Process
Not a Multi-cyclic process 4
NADP used as Co-enzyme
NAD used as Co-enzyme

8. Comparison of HMP Shunt & Glycolysis
S.No.
HMP Shunt
Glycolysis 5
ATP required initially 6
ATPs not produced
ATPs produced 7
CO2 is formed during
HMP shunt
No CO2 is formed during glycolysis 8
Pentoses are generated
No pentose is generated 9
Only monophosphate intermediates
Diphosphate intermediates are also involved

9. Overall Reaction 3 Glc – 6 – P 6NADP+ 6NADPH + H+ 3 Glc 3 Pentoses
2 Glc–6–P + 3CO2 + Glyceraldehyde–3–P
6NADP+
6NADPH + H+
3 Glc
3CO2
3 Pentoses
2 Glc + 1 Triose
Or 6 Glc
6CO2
6 Pentoses
5 Glc

10. Phases of HMP Shunt Two Phases 1. Oxidative Phase
Dehydrogenation and decarboxylation of Glucose-6-P to form pentose phosphates (Enzymes – Dehydrogenases)
2. Non-Oxidative Phase
Conversion of pentose phosphates to Glucose-6-P through a series of reactions (Enzymes – Transaldolase and Transketolase)

11. Reactions of HMP Shunt

12. Reactions of HMP Shunt

13. Reactions of HMP Shunt (Contd.)
Enediol
Ribulose-5-P
Reactions of HMP Shunt (Contd.)
TPP
Nucleotides
& Nucleic acids

14. Oxidative stage of Pentose Phosphate Pathway

15. Non-oxidative reactions of PPP

16. Reactions of HMP Shunt (Contd.)

17. Regulation of HMP Shunt
Rate limiting enzyme is G-6-Pdase & the other dehydrogenase
NADPH / NADP ratio
NADPH inhibits both dehydrogenases
Activity of dehydrogenases decreases in
Diabetes mellitus and
Starvation

18. Regulation of HMP Shunt
Insulin (fed state) induces the synthesis of key enzymes (G6Pdase & 6-P-Gluconate-DH)
Activity of these enzymes also increases in lipogenesis (fatty acid & steroid synthesis)
Thyroid hormones also lead to increased activity of the dehydrogenases  increased HMP Shunt

19. Functions of NADPH NADPH is required for Synthesis of fatty acids
Synthesis of Cholesterol (steroids)
Synthesis of Glutamate from -ketoglutarate
Synthesis of Tyrosine from phenylalanine
Synthesis of Gulonic acid from glucuronic acid (Uronic acid pathway)
Synthesis of tetra-hydro-folate(FH4)
Conversion of oxidized glutathione to reduced glutathione (G–S–S–G) (2G – SH)

20. Role of Glutathione
H2O2 increases the rate of oxidation of hemoglobin to methemoglobin and damages the cell membrane  leading to hemolysis
Glutathione degrades (detoxifies) the free radicals and hydroperoxides produced in oxygen rich environments like RBCs

21. Glutathione disulfide
Role of Glutathione
Glutathione
(GSH)
H2O2
2H2O
Glutathione disulfide
(GSSG)
Glutathione Peroxidase
GSSG
NADPH + H+
NADP+
2GSH
Glutathione Reductase

22. G-6-Pdase Deficiency
Oxidant drugs which may cause drug-induced hemolysis in G-6-Pdase deficient subjects include:
Antimalarials (Primaquin & Pamaquin)
Analgesics (Acetyl salicylic acid, Phenacetin)
Sulfonamides
Furadentin & furoxone & many others