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Hexose Monophosphate Pathway
Also called the pentose phosphate pathway, or phosphogluconate pathway
 It consists of two irreversible oxidative reactions, followed by a series of
reversible sugar-phosphate interconversions
 No ATP is directly consumed or produced in the cycle.
 Carbon 1 of glucose 6-phosphate is released as CO2, and two NADPH are
produced for each glucose 6-phosphate entering the oxidative part of the
pathway.
 The rate and direction of the reactions at any given time are determined
by the supply of and demand for intermediates in the cycle.
 The HMP occurs in the cytosol of the cell.
 The pathway provides a major portion of the cell's NADPH, which functions
as a biochemical reductant.
The HMP also produces ribose-phosphate, required for biosynthesis of
nucleotides,
Hexose Monophosphate Pathway
Oxidative Reactions
The oxidative portion of the HMP leads to the formation of ribulose 5phosphate, CO2, and two molecules of NADPH for each molecule of
glucose 6-phosphate oxidized.
A. Dehydrogenation of glucose 6-phosphate
B. Hydrolysis of 6-phosphogluconolactone and formation of ribulose 5phosphate.
Reductive
anabolic pathway
H+
NADPH
NADPH
NADP+
NADP+
G6PO4
1
6-Phospho
gluconate 2
Ribulose-5-PO4
Oxidative Reaction Irreversible
Xylulose5
phosphate
Oxidative Reactions
 Glucose-6-phosphate Dehydrogenase catalyzes oxidation of
the aldehyde at C1 of glucose-6-phosphate, to a carboxylic acid
in ester linkage (lactone).
 NADP+ serves as electron acceptor.
 Lactone is hydrolyzed resulting in ring opening. The product is
6-phosphogluconate.
Oxidative Reactions
 Phosphogluconate Dehydrogenase catalyzes oxidative decarboxylation
of 6-phosphogluconate, to yield the 5-C ketose ribulose-5-phosphate.
NADP+ again serves as oxidant (electron acceptor).
Regulation: Glucose-6-phosphate Dehydrogenase is the committed step
of the Pentose Phosphate Pathway. This enzyme is regulated by availability
of the substrate NADP+. As NADPH is utilized in reductive synthetic
pathways, the increasing concentration of NADP+ stimulates the Pentose
Phosphate Pathway, to replenish NADPH.
Structure of NADPH
Hexose Monophosphate Pathway
Nonoxidative reaction
Nucleic acid
biosynthesis
Ribose-5-PO4
Sedoheptulose
–7-PO4
Erythrose-4PO4
Fructose-6PO4
Ribulose-5PO4
Xylulose-5phosphate
Glyceraldehyde
-3-PO4
Xylulose-5PO4
Glyceraldehydes
-3-PO4
Fructose-6PO4
Glycolic pathway
Transketolase (transfer 2-C unit) and Transaldolase (transfer 3-C
unit)
Nonoxidative reactions
Formation of ribose 5phosphate from
intermediates of glycolysis
Under conditions where the
demand for pentoses for
incorporation into nucleotides
and nucleic acids is greater
than the need for NADPH,
the nonoxidative reactions
can provide the biosynthesis
of ribose 5-phosphate from
fructose 6-phosphate in the
absence of the oxidative
steps.
Reductive biosynthesis: Uses of NADPH
The electrons in NADPH are destined for use in reductive biosynthesis
rather than for transfer to oxygen as in the case with NADH.
NADPH that can be used as source of electrons in biosynthesis of fatty
acids and steroids.
Reduction of hydrogen peroxide:
• Hydrogen peroxide and other reactive oxygen intermediates are
highly reactive and can cause serious damages, eact with double bonds
in fatty acid moieties of membrane lipids, making membranes leaky.
•The cell has several protective mechanisms that serve
to minimize the toxic potential f these compounds.
enzymes that catalyze antioxidant reactions:
Reduced glutathione can chemically detoxify hydrogen
peroxide. Regeneration of glutathione reductase from
the oxidizes form utilizes NADPH as source of
electrons.
Structure of NADPH
The cell has several protective mechanisms that serve to minimize the toxic
potential f these compounds.
I) Enzymes that catalyze antioxidant reactions:
Glutathione is a tripeptide that includes cysteine.
Its functional group is the cysteine thiol.
Glutathione has a role in degradation of hydroperoxides that arise spontaneously
in the oxygen-rich environment within red blood cells.
Reduced glutathione can chemically detoxify hydrogen peroxide . this
reaction catalyzed by glutathione peroxidase forms oxidized glutathione.
The cell regenerate reduced glutathione in a reaction catalyzed by electrons thus
NADPH indirectly provides electrons for the reduction of hydrogen peroxide.
Reduced glutathione can chemically detoxify hydrogen peroxide .
This reaction is catalyzed by glutathione peroxidase.
The cell regenerate reduced glutathione in a reaction catalyzed by
Glutathione Reductase
NADPH indirectly provides electrons for the reduction of hydrogen
peroxide.
GSH + ROOH
GSSG + NADPH + H+
GSSG + ROH + H2O 2
2 GSH + NADP+
II) Antioxidant chemicals:
A number of intracellular reducing agents, such as ascorbate, vitamin E and  carotene are able to reduce and thus detoxify oxygen intermediates in cells
III) Cytochrome p-450 system:
NADPH is critical for the liver microsomal cytochrome P-450 monooxygenase
system.
This is the major pathway for hydroxylation of aromatic and aliphatic compounds,
such as steroids, alcohols and many drugs.
These oxidations also serve to detoxify drugs and foreign compounds by
converting them into soluble forms more readily excreted through the kidney
IV) Phagocytosis by white blood cells:
Neutrophils and monocytes have oxygen-dependent
and oxygen-independent mechanisms for killing
bacteria.
The oxygen-dependent mechanism include the
myeloperoxidase (MPO) system and another system
that involves the generation of oxygen –derived
free radicals.
 Oxygen-independent systems utilize pH changes
in the phagolysosomes and lysosomal enzymes to
destroy pathogens.
After phagocytosis has occurred, NADPH oxidase,
converts molecular oxygen into superoxide. (the
respiratory burst). Next superoxide is converted into
hydrogen peroxide by superoxide dismutase (SOD). In
the presence of MPO, peroxide plus chloride ions are
converted into hypochlorous acid that kills the
bacteria.
Glucose 6 phosphate dehydrogenase deficiency:
Glucose 6 phosphate dehydrogenase(G6PD) deficiency is an inherited disease (Xlinked disorder) characterized by hemolytic anemia caused by the inability to
detoxify oxidizing agents.
 G6PD deficiency is the most common disease producing enzyme abnormality in
humans.
The life span of many individuals with G6PD deficiency is shortened as a result of
complications arising from chronic hemolysis.
 It is most common in the Mediterranean, the Middle East, South East Asia and
West Africa. It is rare among Caucasians
Role of G6PD in red blood cells:
 Diminished G6PD activity impairs the ability to form NADPH that is essential in
the detoxification of free radicals and peroxides formed within the cell.
All cells of the affected individual have enzyme deficiency. But it is most sever in
erythrocytes where the HMP provides the only means of generating NADPH.
 Other tissues have other NADPH sources as NADP+ - dependent malate
Precipitating factors in G6PD deficiency:
Some factors precipitate the hemolytic anemia in G6PD deficiency patents:
1. Oxidant drugs: like antibiotics e.g; sulfamethoxazole, Antimalarials e.g;
premaquine
2. Favism: The hemolytic effect of ingesting fava beans is observed in patients with
favism (G6PD deficiency).
3. Infection: The inflammatory response to infection results in the generation of
free radicals in macrophages, which can diffuse into the red blood cells and cause
oxidative damage.
4. Neonatal jaundice:
Individuals with G6PD
deficiency may
experience neonatal
jaundice, which may
result from impaired
hepatic catabolism or
increased production of
bilirubin.
The end