3. Overview
The pentose phosphate
pathway is also called Hexose
Monophosphate Shunt or
Phosphogluconate Pathway.
It is an alternate route for the
oxidation of glucose without
direct consumption or
generation of ATP.
It takes place entirely in the
cytoplasm.
4. The pentose pathway is a shunt.
The pathway begins with the glycolytic
intermediate glucose 6-P.
It reconnects with glycolysis because two of the
end products of the pentose pathway are
glyceraldehyde 3-P and fructose 6-P; two
intermediates further down in the glycolytic
pathway.
It is for this reason that the pentose pathway is
often referred to as a shunt.
8. What does the pentose
phosphate pathway achieve?
The pathway yields reducing potential in the form
of NADPH to be used in anabolic reactions
requiring electrons.
The pathway yields ribose 5-phosphate.
Nucleotide biosynthesis leading to:
DNA
RNA
Various cofactors (CoA, FAD, SAM, NAD+/NADP+).
9. Importance of pentose phosphate pathway :
Generation of NADPH
- mainly used for reductive synthesis
of fatty acids, cholesterol and
steroid hormones.
- hydroxylation reaction in
metabolism of phenylalanine and
tryptophan.
- production of reduced glutathione
in erythrocytes and other cells.
Production of ribose residues
- used for nucleotide, nucleic acid ,
and coenzyme biosynthesis
Serves as an entry into Glycolysis for
both 5‐carbon & 6‐carbon sugars.
11. The PPP is divided into two phases
Oxidative non-reversible phase
-generates NAPDH
-Glucose 6-p undergoes dehydrogenation and
decarboxylation to give a pentose, ribulose
5-p, which is converted to its isomer, D-
ribose 5-p.
-Overall equation of 1st phase:
Glucose 6-p + 2 NADP++ H2O ribose 5-p +
CO2 + 2 NADPH + 2 H+
Non-oxidative reversible phase
-ribose 5‐P is converted back to Glucose 6-p by
a series of reactions involving especially two
enzymes
1. Transketolase :Transfer of the 2‐C fragment
2. Transaldolase :Transfer of the 3‐C fragment
13. Importance of PPP in RBC
When erythrocytes are exposed to
chemicals that generate high levels of
superoxide radicals, GSH (Reduced
Glutathione) is required to reduce
these damaging compounds
Glutathione Peroxidase catalyzes
degradation of organic hydroperoxides
by reduction, as two glutathione
molecules are oxidized to a disulfide
GSSG
The PPP is responsible for
maintaining high levels of NADPH in
red blood cells for use as a reductant
in the glutathione reductase reaction.
14. Regulation of the pentose phosphate
pathway
Glucose-6-P dehydrogenase
(Rate Limiting Reaction) is
controlled by:
Allosteric Regulation
-Feedback inhibited by
NADPH
Inducible enzyme
-The synthesis of glucose 6-
phosphate dehydrogenase is
induced by the increased
insulin/glucagon ratio after a
high carbohydrate meal.
18. NADPH + H+ is formed
from two separate
reactions.
The glucose 6-phosphate
DH (G6PD) reaction is the
rate limiting step and is
essentially irreversible.
There is a medical story
for this enzyme.
Cells have a greater need
for NADPH than ribose 5-
phosphate.
25. Reduced
glutathione (GSH)
Glutathione is a
tripeptide composed of
glutamate, cystein,
glycine.
Reduced glutathione
(GSH) maintains the
normal reduced state
of the cell.
26. Glutathione Functions -1
It serves as a reductant.
Conjugates to drugs making them water
soluble.
Involved in amino acid transport across cell
membranes.
Cofactor in some enzymatic reactions.
rearrangement of protein disulfide bonds.
27. Glutathione Functions -2
The sulfhydryl of GSH(glutathione) is used to
reduce peroxides (ROS) formed during oxygen
transport.
Reactive oxygen species (ROS) damage
macromolecules (DNA, RNA, and protein) and
ultimately lead to cell death.
The resulting oxidized form of GSH is two
molecules linked by a disulfide bridge (GSSG-
glutathione disulfide)).
28. So, what happens if glucose 6-phosphate DH is
defective?
Insufficient production of NADPH.
Which translates into insufficient glutathione.
Is this a medical problem?
YES
29. Glutathione and Erythrocytes -1
GSH is extremely important particularly in the
highly oxidizing environment of the red blood cell.
Mature RBCs have no mitochondria and are
totally dependent on NADPH from the pentose
phosphate pathway to regenerate GSH from
GSSG via glutathione reductase.
In fact, as much as 10% of glucose consumption,
by erythrocytes, is mediated by the pentose
pathway.
30. Glutathione and Erythrocytes -2
The reduced form of glutathione serves as a
sulfhydryl buffer.
It maintains cysteine residues in hemoglobin and
other proteins in a reduced state.
GSH is essential for normal RBC structure and
keeping hemoglobin in Fe++ state.
31. Glutathione and Erythrocytes -3
Reduced glutathione also detoxifies peroxides.
2GSH + ROOH GSSG + H2O + ROH
Cells with low levels of GSH are susceptible
hemolysis.
Individuals with reduced GSH are subject to
hemolysis.
This is often clinically seen as black urine under
certain conditions.
32. Conditions for hemolytic anemia
related G6PD deficiency.
The ingestion of oxidative agents that generate
peroxides or reactive oxygen species (ROS).
Antimalarials - pamaquine
purine glycoside from fava beans.
Individules with G6PD deficiency can not produce
sufficient GSH to cope with the ROS.
Proteins become cross linked leading to Heinz
body formation and cell lysis.
33.
34. Glucose 6-phosphate DH
deficiency and nonspherocytic
hemolytic anemia.
Over 300 genetic variants of the G6PD protein
are known.
Thus, there is a remarkable variation in the
clinical spectrum.
G6PD deficiency is an inheritable X-linked
recessive disorder.
Approximately 10-14% of the male African
American population is affected.
It is also seen in Caucasians from the
Mediterranean Basin.
35.
People with the disorder are not normally anemic and
display no evidence of the disease until the red cells
are exposed to an oxidant or stress.
Drugs that can precipitate this reaction:
antimalarial agents
sulfonamides (antibiotic)
aspirin
nonsteroidal antiinflammatory drugs (NSAIDs)
nitrofurantoin
quinidine
quinine
exposure to certain chemicals - mothballs
36. FAVISM
Individuals with G6PD deficiency must not eat
Fava beans.
Pythagoras
Erythrocytes lyse=dark or black urine.
Interesting
The growth Plasmodium falciparum (malaria
parasite) fails in G6PD deficient individuals.
37. Glucose-6-phosphate dehydrogenase
deficiency causes hemolytic anemia
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.
Most G6PD‐deficient individuals are asymptomatic ‐ only in
combination with certain environmental factors (sulfa
antibiotics, herbicides, antimalarials, *divicine) do clinical
manifestations occur.
*toxic ingredient of fava beans
