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Hexose MonoPhosphate (HMP) shunt pathway
It is also known as "pentose phosphate pathway-PPP" because the
reactions involve formation of pentose phosphates. It
occurs in the cytosol
of the cell.
Instead of glucose going through the glycolytic pathway, it is
shunted through this pathway; so it is known as the shunt pathway. Since
the first carbon atom of glucose is liberated as CO2, it is called the direct
oxidative pathway of glucose metabolism. About 10% of glucose
molecules per day are entering in this pathway. The major purpose of this
pathway is generation of NADPH and pentose phosphates.
No ATP is
directly consumed or produced in this pathway.
Overview of the Shunt Pathway
The HMP shunt pathway
consists of two
phases; oxidative and non-
oxidative.
During the oxidative phase, glucose-6-phosphate is oxidized with
the generation of 2 molecules of NADPH, and one molecule of
pentose phosphate, with the liberation of one molecule of CO
2
.
- Overall equation of 1st phase is:
Glucose 6-phosphate+2 NADP
+
+H
2
O
ribose 5-phosphate+CO
2
+2NADPH +2 H
+
2
During the non-oxidative phase, the pentose phosphate is converted
to intermediates of glycolysis.
Regulation of HMP Shunt Pathway
The first reaction of HMP Shunt catalyzed by NADP+ dependent
Glucose-6-phosphate dehydrogenase (GPD).This is the rate-limiting step,
Regulation is affected by this enzyme. The pathway is mainly regulated
by the level of NADP+. GPD is inhibited by NADPH. The oxidative
phase is therefore controlled by the level of NADP+ and non-oxidative
phase by the requirement of pentoses. Insulin will induce GPD
and therefore will increase the overall pathway.
Use and Importance of HMP Shunt Pathway
The hexose monophosphate pathway is used for production of NADPH
from NADP. The NADPH is required for biosynthetic reactions
that
require reducing power such as fatty acid synthesis, cholesterol synthesis,
drug reduction, and as a cofactor for some non-synthetic enzymatic
reactions. In addition, HMP is used for the production of ribose for
nucleotide and nucleic acid synthesis. The hexose monophosphate
pathway also allows the entry of some carbohydrates into the glycolytic
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pathway, and therefore acts as a connection route between different
pathways. NADPH plays two critical roles in red blood cells, both of
these roles are related to the oxygen-transport function of the red blood
cell. The first role is related to glutathione: erythrocytes require NADPH
to maintain their levels of reduced glutathione. Oxygen is toxic without
reduced glutathione (Peroxides that spontaneously formed from
molecular oxygen would oxidize the lipid components of the red blood
cell membranes, oxidized membranes are significantly less flexible than
normal membranes, and result in damage to the red blood cells when the
cells attempt to transit capillaries. In addition, peroxides tend to damage
hemoglobin, resulting in precipitation of the protein. Insoluble aggregates
of hemoglobin have severely impaired oxygen carrying capacity. Two
enzymes are required to deal with the peroxides. First; Glutathione
peroxidase uses reduced glutathione to convert the peroxide to an alcohol.
Second Glutathione reductase uses NADPH to regenerate the reduced
glutathione).
The second role of NADPH in red blood cells is related to hemoglobin
(Oxygen tends to oxidize the hemoglobin iron from Fe +2 to the more
stable Fe +3 state resulting in methemoglobin. This is a problem: the Fe
+3 state of heme iron binds oxygen very poorly which disturb RBCs
function. NADPH is used to supply reducing equivalents to
methemoglobin reductase, the enzyme that returns the hemoglobin to the
Fe +2oxidation state.
Clinical Significance of Shunt Pathway
G6PD Deficiency
Glucose 6-phosphate dehydrogenase (G6PD) deficiency is an inherited
X-linked disease characterized by hemolytic anemia caused by the
inability to detoxify oxidizing agents. The deficiency is manifested only
when exposed to certain drugs or toxins. In G6PD deficient cells, the
level of NADPH is low; hence further production of peroxides will lead
to cell lysis
.
In some forms of G6PD deficiency, persons are particularly
susceptible to the hemolytic effect of the fava bean, this condition called
(favism).