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Pentosephosphate

The Pentose Phosphate Pathway, also known as the pentose shunt, occurs in the cytosol and begins with glucose 6-phosphate, reconnecting with glycolysis to produce NADPH and ribose 5-phosphate for nucleotide biosynthesis. It has two phases, with the glucose 6-phosphate dehydrogenase reaction being the rate-limiting step, and is crucial for rapidly dividing cells and maintaining glutathione levels in erythrocytes. Deficiencies in this pathway can lead to conditions like hemolytic anemia, particularly in individuals with G6PD deficiency.

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0% found this document useful (0 votes)
14 views43 pages

Pentosephosphate

The Pentose Phosphate Pathway, also known as the pentose shunt, occurs in the cytosol and begins with glucose 6-phosphate, reconnecting with glycolysis to produce NADPH and ribose 5-phosphate for nucleotide biosynthesis. It has two phases, with the glucose 6-phosphate dehydrogenase reaction being the rate-limiting step, and is crucial for rapidly dividing cells and maintaining glutathione levels in erythrocytes. Deficiencies in this pathway can lead to conditions like hemolytic anemia, particularly in individuals with G6PD deficiency.

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Seema Hedaoo
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Lecture # 7

Pentose Phosphate Pathway


Pentose Phosphate Pathway

Also known as:


• Pentose shunt
• Hexose monophosphate shunt
• Phosphogluconate pathway

• It occurs in the cytosol.


One fate of G6P is
the pentose
pathway.
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.
Moderate glucose flux

Glycolysis
only
Large glucose flux

Pentose
Phosphate
Glycolysis Pathway
It’s a shunt
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+).
NADPH is a
phosphorylated
form of NADH.

In general, with
some exceptions,
NADH is used to
drive the
phosphorylation of
ADP to ATP. NADPH
is used where
reducing potential
is required for
synthetic
The pentose
pathway can
be divided
into two
phases.

Non-oxidative
interconversion of
sugars
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.
Regulatory enzyme

5 carbon atoms
Regulatory enzyme

The enzyme is highly specific for


NADP+; the Km for NAD+ is 1000 greater
than for NADP+.
Don’t panic, you need not know
all the reactions in detail;
stay tuned.
The nonoxidative phase of the
pentose pathway
This entails extensive carbon atom
rearrangement.

Transketolase requires
the coenzyme thiamine
pyrophosphate (TPP),
the transaldolase does
not.
• Transketolase (TPP) and
transaldolase are the link back
to glycolysis.
• Glyceraldehyde 3-phosphate
• Fructose 6-phosphate
• Net result:
3C5  2C6 + C3
Ingested
ribose can
enter the
glycolytic
pathway
through the
pentose
pathway.
Regulation of the Pentose
Pathway
• Glucose 6-phosphate DH is the
regulatory enzyme.
• NADPH is a potent competitive
inhibitor of the enzyme.
• Usually the ratio NADPH/NADP+ is
high so the enzyme is inhibited.
• But, with increased demand for
NADPH, the ratio decreases and
enzyme activity is stimulated.
• The reactions of the non-
oxidative portion of the pentose
pathway are readily reversible.

• The concentrations of the


products and reactants can shift
depending on the metabolic needs
of a particular cell or tissue.
Rapidly dividing cells require more
ribose 5- phosphate than NADPH.
The need for NADPH and ribose 5-phosphate
is balanced.
More NADPH is needed than ribose 5-
phosphate; Fatty acid synthesis in
adipose cells.
The cell needs both NADPH and ATP
Glutathione and NADPH

• What is glutathione?
• Why is it important?
• How is it related to NADPH?
Glutathione is a
tripeptide
composed of
glutamate,
cystein, glycine.

Reduced
glutathione (GSH)
maintains the
normal reduced
state of the
cell. Reduced
glutathione
(GSH)
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.
Glutathione Functions -2

• The sulfhydryl of GSH 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).
The enzyme
glutathione
reductase uses
NADPH as a
cofactor to
reduce GSSG back
to two moles of
GSH. Thus, the
pentose pathway
is linked to the
supply of
adequate amounts
of GSH.
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
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.
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.
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.
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.
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.
• 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
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.

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