The document summarizes key aspects of the pentose phosphate pathway (PPP). It describes the two main functions of the PPP as generating NADPH and producing ribose-5-phosphate. It also outlines the oxidative and nonoxidative branches of the PPP and explains how the pathway can operate in different modes depending on the cell's needs for NADPH, ribose-5-phosphate, or ATP. The document also discusses glucose-6-phosphate dehydrogenase deficiency and its implications.

1. Berg • Tymoczko • Stryer
Biochemistry
Sixth Edition
Chapter 20:
The Calvin Cycle and the Pentose
Phosphate Pathway
Copyright © 2007 by W. H. Freeman and Company

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…

3. Structure of
nicotinamide
derived e carriers
• In NAD+, R = H
• In NADP+, R = PO3-

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

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.

11. Oxidative Branch

17. Non-oxidative Branch

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

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

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!

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.

40. Glutathione reductase

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.

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!