HEXOSE MONOPHOSPHATE SHUNT

1. By
DR KHALED SALEH ALGARIRI
International Medicine School – MSU
January 2018

2. Phosphogluconate Pathway
Pentose Cycle
Hexose Monophosphate Pathway or Shunt
Warburg-Dickens-Lipman Pathway
• Definition :This is an alternative pathway to
glycolysis and TCA cycle for the oxidation of
glucose. HMP shunt is more anabolic in nature and
all reactions occur in cytosol.

3. PENTOSE PHOSPHATE PATHWAY
•Three main functions:
• 1) Supply the cell with nicotinamide adenine dinucleotide phosphate
(NADPH ).
• 2) Convert hexoses into pentoses (which are essential components of
• ATP, CoA, NADP+, FAD, RNA, and DNA).
• 3) Enable the complete oxidative degradation of pentoses by
converting them into hexoses and trioses which can then enter the
glycolytic pathway

4. THE ROLES OF NADH AND NADPH IN METABOLISM
There is a fundamental distinction between NADH and NADPH in most
biochemical reactions.
• NADH is oxidized by the electron transport chain to generate ATP.
• In contrast, NADPH functions as an electron donor (i.e., a hydride ion donor)
in biosynthetic reactions.
• Recall that in the oxidation of a substrate, the nicotinamide ring of NADP+
accepts a hydrogen ion and two electrons, which are equivalent to a hydride
ion.
• NADH equivalent 2.5 ATP (TCA Cycle) , NADPH not yield ATP

6. IMPORTANCE
OF NADPH
for reductive synthesis of fatty
acids, steroids, amino acids via
glutamate dehydrogenase &
production of reduced
glutathione in erythrocytes and
other cells.
Production of ribose
residues for
nucleotide and
nucleic acid synthesis
for H2O2
eliminati
on from
body.
As a energy
molecule.

7. THE PERCENTAGE OF GLUCOSE METABOLIZED BY THE PENTOSE
PHOSPHATE PATHWAY VARIES FOR DIFFERENT TISSUES
Since, a main purpose of this pathway is to supply NADPH for
reductive synthesis, it is prominent in tissues that actively carry out
the reductive synthesis of fatty acids and/or steroids from acetyl CoA
• Liver: 5-10% of glucose is metabolized by the pentose phosphate pathway.
• Adipose Tissue: 30 – 50%
• Erythrocytes: 10% (need NADPH to maintain reduced glutathione)
• Thyroid gland, kidney, and brain: 3 – 5%
• Muscle: activity is extremely low

8. LOCATION OF THE PATHWAY
• The enzymes are located in the cytosol.
• The tissues such as liver, adipose tissue, adrenal gland, erythrocytes,
testes & lactating mammary gland, are highly active in HMP shunt.
• Most of these tissues are involved in biosynthesis of fatty acids and
steroids which are dependent on the supply of NADPH.

10. 5 carbon atoms
Regulatory enzyme

11. THE NONOXIDATIVE PHASE OF THE PENTOSE
PATHWAY
• consists of non-oxidative reactions which link the pentose
phosphate pathway with glycolysis.
• This stage allows:
• 1)excess pentoses to be converted to hexoses and trioses which can then enter
glycolysis.
• 2)hexoses to be converted to pentoses, thereby allowing pentose production
without concomitant production of NADPH.
• Two enzymes –transketolase and transaldolase–catalyze a series of three
reactions which convert 3 pentoses into 2 hexoses and 1 triose.
• These reactions involve interconversions of 3, 4, 5, 6, and 7-carbon sugars.
• Transketolase requires the coenzyme thiamine pyrophosphate (TPP), the
transaldolase does not.

14. IMPORTANCE of NADPH
1. NADPH is required for the bio synthesis of fatty acids,
fatty acid, cholestrol and steroids.
2. Free radical Scavenging
• The free radicals (super oxide, hydrogen peroxide) are continuously
produced in all cells.
• These will destroy DNA, proteins, fatty acids & all biomolecules & in turn
cells are destroyed

15. • The free radicals are inactivated by the enzyme systems containing
superoxide dismutase SOD, peroxidase POD & glutathione
reductase.
• Reduced GSH is regenerated with the help of NADPH.

16. 3. Erythrocyte Membrane integrity
• NADPH is required by the RBC to keep the glutathione in the
reduced state.
• In turn, reduced glutathione will detoxify the peroxides & free
radicals formed within the RBC.
• NADPH, glutathione & glutathione reductase together will preserve
the integrity of RBC membrane.

17. 4. Prevention of Met-Hemoglobinemia
NADPH is also required to keep the iron of hemoglobin in the reduced
(ferrous) state & to prevent the accumulation of met-hemoglobin. Met-
hemoglobin cannot carry the oxygen.

18. 5- Detoxification of Drugs
• Most of the drugs and other foreign substances are detoxified by
the liver microsomal P450 enzymes, with the help of NADPH.
6. Lens of Eye:
• Maximum concentration of NADPH is seen in lens of eye.
• NADPH is required for preserving the transparency of lens.

19. 7. Macrophage bactericidal activity
NADPH is required for the production of reactive oxygen species
(ROS) by macrophases to kill bacteria.
8. Availability of Ribose
Ribose & Deoxy – ribose are required for DNA & RNA synthesis.

20. 1- Glucose 6-phosphate Dehydrogenase Deficiency
 Mutations present in some populations causes a deficiency in glucose 6-
phosphate dehydrogenase, with consequent impairment of NADPH
production.
 Detoxification of H2O2 is inhibited, and cellular damage results - lipid
peroxidation leads to erythrocyte membrane breakdown and hemolytic
anemia.
 The deficiency is manifested only when exposed to certain drugs or toxins,
e.g.intake of antimalarial drug like primaquine & ingestion of fava beans(favism)
& sulpha drugs also parecipitate the hemolysis
G-6-PD deficiency results in:
Heamolytic Aneamia
Neonatal Jaundice
Kidney failure
ABNORMALITIES OF HMP SHUNT

21. Glucose 6-Phosphate Dehydrogenase deficiency is a X-linked
recessive hereditary disease which is due to deficiency Of G6PD,which
is require for RBC metabolism

22. • It is an autosomal recessive disorder caused by an
alteration genetic defect in transketolase which
reduces its affinity for TPP (thiamine deficiency)
•Symptoms are:
• Mental disorders
• Severe memory loss
• Partial paralysis
2-WERNICKE-KORSAKOFF SYNDROME

23. Results in:
•Liver cirrhosis
•Male infertility
3-DEFICIENCY OF TRANSALDOSE

24. REGULATION OF HMP SHUNT
 The entry of glucose 6-phosphate (Rate-limiting step) into the pentose
phosphate pathway is controlled by the cellular concentration of NADPH
 NADPH is a strong inhibitor of glucose 6-phosphatedehydrogenase (G6PD) .
NADPH is used in various pathways, inhibition is relieved & the enzyme is
accelerated to produce more NADPH.

25.  The synthesis of glucose 6-phosphate dehydrogenase is induced by
the increased insulin/glucagon ratio after a high carbohydrate meal.
In contrast, the enzymes decrease in diabetes mellitus.
REGULATION OF HMP SHUNT ,, cont