2. Hexose Monophosphate
Pentose Phosphate Pathway
Glycolysis, TCA, and oxidative phosphorylation are
primarily concerned with the generation of ATP.
The PPP meets the need of all organisms for a source of
NADPH to use in reductive biosynthesis.
The reducing power is NADPH.
There is a fundamental distinction
NADH
NADPH
The direction of HMP depends on the supply and demand for
intermediates in the cycle…
5. Two Major Functions
1. NADPH
2. Ribose
Overall reaction:
3G-6-P + 6NADP+ 3CO2 + 2G-6-P + Glyceraldehyde-3P + 6NADPH + 6H+
It occurs in the cytosol because NADP+ is used as a hydrogen
acceptor.
There are two sequential reactions.
1. Oxidative
2. Nonoxidative
6.
7.
8.
9.
10. Oxidative and Nonoxidative Reactions
In oxidative, G-6-P undergoes dehydrogenation and
decarboxylation to give a pentose ribulose-5-P.
In nonoxidative, ribulose 5-P is converted back to
G-6-P by a series of reactions involving two
enzymes
1. Transketolase
2. Transaldolase
Dehydrogenation of G-6-P is the major biological
control of the HMP.
G-6-PD is strongly inhibited by NADPH.
26. Ribose-5-P + Xylulose-5-P Transketolase, TPP Sedoheptulane-7-P +
Glyceraldehyde-3-P
2C unit----- transferred by transketolase
This 2-C moiety is bound to TPP first then transferred.
Two products of transketolase then enter another reaction known
as transaldolation.
3C unit---- transferred by transaldolase
Sedoheptulase-7-P + Glyceraldehyde-3-P Transaldolase F-G-P +
Erythrope-4-P
27. Another transketolase reaction:
‒ X-5-P + E-4-P Transketolase G-3-P + F-6-P
‒ X-5-P serves as a donor of “active glycoaldehyde”.
Therefore, at the end of PPP:
‒ NADPH
‒ Ribose-5-P
‒ Glyce 3-P and Fructose-6-P Gly
The differences between glycolytic pathway and PPP are:
‒ NADPH
‒ CO2
‒ ATP
‒ Ribose-5-P for nucleotide synthesis
28. The PPP is much more active in adipose tissue than in
muscle.
It is important in tissues such as adipose, liver, mammary gland, and
adrenal cortex (NADPH depended synthesis of steroids).
Transketolase that is defective in TPP binding can cause
a neuropsychiatric disorder.
• Wernicke-Korsakoff Syndrome
‒ Lack of TPP in susceptible people
‒ Paralysis of eye movements
‒ Abnormal gait
‒ Decreased mental function
‒ Severely impaired memory
‒ Transketolase from patients with the Wernicke-Korsakoff
syndrome binds thiamine PP ten times less than does the
enzyme from normal persons
29. The flow of Glc-6-P depends
on the need for NADPH, ribose 5-P, and ATP
Mode 1
• Much more ribose 5-P is needed than NADPH
• It is seen in rapidly dividing cells
• The stoichiometry of mode 1 is:
5 Glc 6-P + ATP 6 ribose 5-P + ADP + H+
Mode 2
• The needs for NADPH = ribose 5-P are balanced.
• Formation of 2 NADPH and 1 Ribose 5-P
• The stoichiometry of mode 2 is:
Glc6-P + 2NADP+ + H2O ribose 5-P + 2NADPH + 2H+ CO2
30.
31.
32.
33. Continue on modes
Mode 3
• Much more NADPH than ribose 5-P is required. For example
adipose tissue requires a high level of NADPH for the synthesis of
fatty acids.
– Glc6-P is completely oxidized to CO2
– 3 reactions are active
• Oxidative phase forms 2 NADPH and 1 Ribose 5-P
• Ribose 5-P F-6-P and Glyceraldehyde 3-P
• Glc6-P is made from F-6-P and Glyceraldehyde 3-P
The sum of the mode 3 reaction is:
• (The stoichiometry of mode 3) is:
Glc6-P + 12NADP+ + 7H2O 6CO2 + 12 NADPH + 12H++ Pi
Therefore Glc6-P can be completely oxidized to CO2 with the
generation of NADPH
34.
35. Continue on modes
Mode 4
– Both NADPH and ATP are required.
– Ribose 5-P pyruvate, F-6-P and glyceraldehyde 3-P
– These enter glycolytic pathway
The stoichiometry of mode 4 is:
3 Glc6-P + 6 NAD+ + 5 Pi + 8 ADP
5 pyruvate + 3CO2 + 6 NADPH + 5 NADH + 8 ATP + 2 H2O + 8 H+
– Pyruvate can be oxidized more!
36.
37.
38. G-6-P dehydrogenase deficiency
G-6-P dehydrogenase deficiency causes a drug induced
hemolytic anemia.
An antimalarial drug primaquine was introduced in 1926.
Some patients developed severe symptoms like:
• Jaundice
• Hb decrease
• Massive destruction of red blood cells
• Death
In 1956, the basis of drug induced hemolytic anemia was
elucidated
The primary defect is a deficiency in G-6-P dehydrogenase
in red blood cells.
39. Role of NADPH in RBCs
GSSG GSH by glutathione reductase, which requires
NADPH.
GSH keeps Cys residues in hemoglobin and other RBC
proteins in the reduced state.
Normally, the ratio of the GSH/GSSG 500 in RBCs
Electrons are transferred by NADPH to FAD first on the
reductase, then to a S-S bridge between 2 Cys residues in the
enzyme subunit, and finally to GSSG.
GSH + ROOH GSSG + H2O + ROH
Cells with low GSH are more susceptible to hemolysis
because ROOH eliminated by GSH preoxidase by using
GSH as a reducing agent.
42. Cells with low GSH
Cells with low GSH are more susceptible to hemolysis
when fava beans are eaten.
In some regions where malaria is endemic (the middle
east) fava beans are a staple food.
They are known to contain two beta glycosieds
– Vicine
– Convicine
They oxidize GSH!
Individuals who eat fresh fava beans are protected to a
certain extent from malaria.
A condition known as favism results when some Glc 6-P
deficient individuals develop a severe hemolytic anemia
after ingestion of fava beans.
43.
44. More about Glc 6-P dehydrogenase deficiency
In the absence of G-6-P dehydrogenase, 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 cell membranes.
Membranes damaged by the Heinz bodies and ROS
(reactive Oxygen Species) become deformed and the cell
undergos LYSIS Hemolytic anemia!
45. The light micrograph shows
RBC obtained from a person
deficient in Glc 6-P
dehydrogenase. The dark
dots represent Hb aggregates.
RBCs in such people lyse if
there is oxidative stress
(an increase in ROS)
46. Adeficiency of Glc 6-P dehydrogenase confers an
evolutionary advantage in some circumstances
11% of African-Americans have this deficiency.
This suggest that this deficiency may indeed be useful under certain
environmental conditions.
In fact, deficiency of Glc 6-P dehydrogenase protects against
malaria! How??
– In order for the parasites (Plasmodium Falciparum) to survive, GSH is
needed and products of PPP are also needed for optimal growth!!!
– Thus, Glc 6-P dehydrogenase deficiency is a mechanism of protection
against malaria, which accounts for its high frequency in malaria-
infested regions of the world.
WE SEE HERE ONCE AGAIN THE INTERPLAY OF
HEREDITY AND ENVIRONMENT IN THE PRODUCTION
OF DISEASE!