HMP
Shunt
Darwish
• HMP pathway or HMP shunt is also called as
pentose phosphate pathway or phosphogluconate
pathway.
• This is an alternative pathway to glycolysis and
TCA cycle for the oxidation of glucose.
• HMP shunt is more anabolic in nature.
• It is concerned with the biosynthesis of NADPH &
pentoses.
• About 10% of glucose entering in this
pathway/day.
• The liver & RBC metabolise about 30% of glucose
by this pathway.
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.
HMP shunt-unique multifunctional
pathway
• It starts with glucose 6-phosphate.
• No ATP is directly utilized or produced in HMP
shunt
• It is multifunctional pathway, several
interconvertible substances produced, which
are proceed in different directions in the
metabolic reactions
Mg++ Glucose 6 phosphate
Glucose
Glycolysis
Pentose phophate
ATP ADP pathway
Glycogenesis
Hexokinase
Two phases
Oxidative
phase
Non
oxidative
phase
Reactions of the pathway
• Reactions of the pathway:
• Divided into Two phases oxidative & non – oxidative.
• Oxidative phase
• Step:1
• Glucose 6- phosphate is oxidised by NADP-
dependent Glucose 6- phosphate dehydrogenase
(G6PD), 6- phosphogluconolactone is formed.
• NADPH is formed in this reaction and this is a rate limiting
step.
• Step:2
• 6-phosphogluconolactone is hydrolysed by glucono lactone
hydrolase to form 6-phosphogluconate.
• Step : 3
• The next reaction involving the synthesis of NADPH and is
catalysed by 6 – phosphogluconate dehydrogenase to
produce 3 keto 6 – phosphogluconate which then undergoes
decarboxylation to give ribulose 5 – phosphate.
Non-Oxidative Phase
• Step: 4
• The ribulose -5-phosphate is then isomerized to
ribose -5-phosphate or epimerised to xylulose -5-
phosphate
• Step: 5 Transketolase reaction
• Transketolase is a thiamine pyrophosphate (TPP)
dependent enzyme.
Ribose 5
phosphate
Step 4
Isomerase
Ribulose 5
phosphate
Epimerase
Xilulose 5
phosphate
• It transfers two-carbon unit from xylulose 5-
phosphate to ribose 5-phosphate to form a 7-
carbon sugar, sedoheptulose 7-phosphate and
glyceraldehyde 3 – phosphate.
Step 5
Ribose 5 Glyceraldehyde 3
phosphate Phosphate
TPP
Transketolase
Xylulose 5 phosphate
Sedoheptulose 7
phosphate
• Step: 6 Transaldolase reaction
• Transaldolase brings about the transfer of a 3 –
carbon fragment from sedoheptulose 7-phosphate
to glyceraldehyde 3-phosphate to give fructose 6-
phosphate & 4 – carbon erythrose 4 – phosphate.
Step 6
Glyceraldehyde 3 Erythrose 4
Phosphate Phosphate
Transaldolase
Sedoheptulose 7
phosphate Fructose 6 phosphate
• Step: 7 Second transketolase Reaction
• In another transketolase reaction a 2 – carbon
unit is transferred from xylulose 5 – phosphate to
erythrose 4 – phosphate to form fructose 6 –
phosphate & glyceraldehyde 3 – phosphate.
• Fructose 6 – phosphate & glyceraldehyde 3 –
phosphate are further metabolized by glycolysis &
TCA cycle.
Step 7
Erythrose 4 Glyceraldehyde 3
Phosphate Phosphate
TPP
Transketolase
Xylulose 5 phosphate
Fructose 6
phosphate
HMP-Shunt pathway
Glucose 6-phosphate
NADP+
Gl
Mg +2 ucos
dehydrogenase
e
NADPH + H+
6P-
6-phosphoglucanolactone
Glucanolactone
hydrolase
6-
phosphogluconate
Phosphogluconate
NADP+Mg+2 dehydrogenase
CO2, NADPH + H+
Ribulose 5-phosphate
Ribulose 5-phosphate
Xylulose 5-phosphate
Fructose Xylulose 5-phosphate Ribose 5-phosphate
6-
Phosphate
Transketolase, TPP
Transketolase, TPP
Sedoheptolose 7-
phosphate Glyceraldehyde
Glyceraldehyde 3-
phosphate 3-
phosphate
Erythrose 4-
Phosphate Transaldolase
Fructose
6-
Fructose 6-
Phosphate
Significance of HMP
Shunt
• HMP shunt is unique in generating two important products-
pentoses and NADPH
• Importance of pentoses:
In HMP shunt, hexoses are converted into pentoses, the
most important being ribose 5 – phosphate.
• This pentose or its derivatives are useful for the synthesis of
nucleic acids (DNA & RNA)
• Many nucleotides such as ATP, NAD+, FAD & CoA
Importance of NADPH
• NADPH is required for the bio synthesis of fatty
acids and steroids.
• NADPH is used in the synthesis of certain
amino acids involving the enzyme glutamate
dehydrogenase.
• 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.
• The free radicals are inactivated by the enzyme
systems containing SOD, POD &
glutathione reductase.
• Reduced GSH is regenerated with the help of
NADH.
• Erythrocyte Membrane intigrity
• 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 intigrity of RBC
membrane.
• 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.
• Detoxification of Drugs
• Most of the drugs and other foreign substances are
detoxified by the liver microsomal P450 enzymes,
with the help of NADPH.
• Lens of Eye:
• Maximum concentration of NADPH is seen in lens
of eye.
• NADPH is required for preserving the
transparency of lens.
• Macrophage bactericidal activity:
NADPH is required for the production of reactive
oxygen species (ROS) by macrophases to kill
bacteria.
• Availability of Ribose:
Ribose & Deoxy – ribose are required for DNA
& RNA synthesis.
• Ribose is also necessary for nucleotide co –
enzymes.
• Reversal of non – oxidative phase is present in all
tissues, by which ribose could be made available.
• What about ATP
ATP is neither utilized nor produced by the
HMP shunt.
• Cells do not use the shunt pathway for energy
production.
Regulation of HMP
Shunt
The entry of glucose 6-phosphate into the pentose
phosphate pathway is controlled by the cellular
concentration of NADPH
NADPH is a strong inhibitor of glucose 6-phosphate
dehydrogenase (G6PD)
NADPH is used in various pathways, inhibition is
relieved & the enzyme is accelerated to produce
more NADPH
The synthesis of glucose 6-phosphate
dehydrogenase is induced by the increased
insulin/glucagon ratio after a high carbohydrate
meal.
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
• It is an inherited sex – linked trait.
• It is more severe in RBC.
• Decreased activity of G6PD impairs the synthesis of
NADPH in RBC.
• This results in the accumulation of met hemoglobin
& peroxides in erythrocytes leading to hemolysis.
• 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
Some patients developed severe symptoms
• Jaundice, decrease in Hb, destruction of RBCs.
• In deficiency of G6PD, Hb can no longer be maintained in the
reduced form.
• Hb molecules then cross-link with one another to form
aggregates called Heinz bodies on membranes.
• Membranes damaged by the Heinz bodies & ROS
become
deformed & the cell undergos LYSIS Hemolytic
anemia
G6PD deficiency & malaria
• G6PD deficiency is associated with resistance to malaria
(caused by plasmodium infection)
• The parasite requires reduced glutathione for its survival,
which will not be available in adequate amounts in
deficiency of G6PD.
• Met – hemoglobinemia
• G6PD deficient persons will show increased Met –
hemoglobin in circulation, even though cyanosis may not
be manifested.
Thiamine Deficiency
• The transketolase activity is measured in RBCs is an
index of the thiamine status of an individual.
• The occurrence & manifestation of Wernickes
korsakoffs syndrome (encephalopathy) which is seen in
alcoholics & those with thiamine deficiency is due to a
genetic defect in the enzyme transketolase.
• The symptoms include mental disorder, loss of memory &
partial paralysis.
References
• Textbook of Biochemistry – U Satyanarayana
• Textbook of Biochemistry – DM Vasudevan
