1.
PENTOSE PHOSPHATE PATHWAY
Pentose Phosphate Pathway: Oxidative & Non-oxidative Phases
OUTLINE
I) INTRODUCTION
II) PENTOSE PHOSPHATE PATHWAY
III) SIGNIFICANCE OF THE PRODUCTS OF PPP
IV) APPENDIX
V) REVIEW QUESTIONS
I) INTRODUCTION
Importance of Pentose Phosphate Pathway (PPP)
o Important in synthesis reactions
 Neurotransmitters
 Lipids (cholesterol)
 Nucleotides
o Free radical reactions
(A) REVIEW OF GLYCOLYSIS
Glucose undergoes glycolysis depending on the body’s
needs
Location: cytosol
GLUT-2
o Transports glucose into the liver cell (Figure 1)
Last edited: 8/10/2021
Medical Editor: Jona Frondoso
Isomerization of DHAP
DHAP is isomerized to the more stable glyceraldehyde-3phosphate (G3P) by triose phosphate isomerase
((Figure 2)
FYI:
At this point of the glycolytic pathway, we are now dealing
with two molecules of glyceraldehyde 3-phosphate
(G3P).
Therefore, each succeeding step will result to two
molecules of the intermediate or product
Oxidation of G3P
Oxidation of glyceraldehyde-3-phosphate to 1,3bisphosphoglycerate (1,3-BPG) by glyceraldehyde 3phosphate dehydrogenase (Figure 2)
o Oxidizing agent is 2 NAD+ which is reduced to 2
NADH [Nelson & Cox, 2017]
Coupled with the addition of phosphate group to G3P
forming 1,3-bisphosphoglycerate (1,3-BPG)
Synthesis of 3-PG producing ATP
Conversion
of
1,3-bisphosphoglycerate
to
3phosphoglycerate (3-PG) with the production of ATP
(Figure 2)
Catalyzed by phosphoglycerate kinase
Shift of the phosphate group from C3 to C2
Figure 1. Transport of glucose into the liver cell via GLUT-2
transporter.
Phosphorylation of Glucose
Addition of phosphate group from ATP to glucose (Figure
2)
Catalyzed by glucokinase
Products are glucose-6-phosphate (G6P) and ADP
Isomerization of Glucose-6-phosphate
Isomerization of glucose 6-phosphate (G6P) to fructose6-phosphate (F6P) (Figure 2)
Catalyzed by phosphoglucoisomerase
Phosphorylation of Fructose-6-phosphate
Addition of phosphate group from ATP to fructose-6phosphate (F6P) (Figure 2)
Catalyzed by phosphofructokinase-1 (PFK)
Products are fructose-1,6-bisphosphate (F-1,6BP) and
ADP
Cleavage of Fructose-1,6-bisphosphate
• Aldolase cleaves fructose 1,6-bisphosphate (F1,6-BP) to
dihydroxyacetone phosphate (DHAP) and glyceraldehyde
3-phosphate (G3P) (Figure 2)
PENTOSE PHOSPHATE PATHWAY
Shift of phosphate group from carbon 3 to carbon 2 of
phosphoglycerate by phosphoglycerate mutase (Figure
2)
Produces 2-phosphoglycerate (2PG)
Dehydration of 2-PG
Dehydration of 2-phosphoglycerate (2PG) by enolase
(Figure 2)
Results in the formation of phosphoenolpyruvate (PEP)
Formation of pyruvate producing ATP
Conversion of PEP to pyruvate catalyzed by pyruvate
kinase (Figure 2)
Also produces 2 ATP
FYI:
ATP from Substrate-Level Phosphorylation (Figure 2)
Energy Investment Phase = -2 ATP
-1 ATP from Step 1 (Phosphorylation of glucose)
-1 ATP from Step 3 (Phosphorylation F6P)
Energy Generation Phase = +4 ATP
+2 ATP from Step 7 (Synthesis of 3-PG)
+2 ATP from Step 10 (Formation of pyruvate)
Net ATP Yield
– 2 ATP + 4 ATP = 2 ATP
METABOLISM: Note #1.
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Formation of 6-Phosphogluconate
Addition of water (H2O) to 6-phosphogluconolactone
producing a proton (H+) and 6-phosphogluconate (Figure
5)
o 6-phosphogluconate - 6-carbon molecule
Catalyzed by lactONase
o Lactase – converts lactose to glucose and galactose
Figure 5. Formation of 6-phosphogluconate from 6phosphogluconolactone.
Formation of Ribulose-5-phosphate
Oxidation of 6-phosphogluconate forming ribulose-5phosphate (Figure 6)
o Oxidizing agent is NADP+ forming NADPH
o Ribulose-5-phosphate: 5-carbon molecule
Coupled with the decarboxylation of 6-phosphogluconate
producing carbon dioxide (CO2)
Catalyzed by 6-phosphogluconate
o Not as important as G6P dehydrogenase
Figure 2. Overview of the glycolytic pathway and the number of
ATP generated in each step,
II) PENTOSE PHOSPHATE PATHWAY
Pentose Phosphate Pathway (PPP) and the glycolytic
pathway are so intertwined.
Figure 6. Formation of ribulose-5-phosphate from 6phosphogluconate.
Remember:
NADPH Products
(A) OXIDATIVE PHASE
1st molecule of NADPH
o Oxidation of glucose-6-phosphate
Consists of four steps
Significance
2nd molecule of NADPH
o Formation of ribulose-5-phosphate
To make NADPH
To make ribose-5-phosphate
Oxidation of Glucose-6-phosphate
Oxidation of glucose-6-phosphate (G6P)
phosphogluconolactone (Figure 3)
o G6P - 6-carbon molecule
o Phosphogluconolactone - 6-carbon molecule
to
6-
Oxidizing agent is NADP+, which picks up hydride ions
(Figure 4), forming NADPH
Catalyzed by glucose-6-phosphate dehydrogenase
Formation of Ribose-5-phosphate and Xyulose-5phosphate
Ribulose-5-phosphate have two fates.
Formation of two different molecules depending on the
enzyme
o Isomerase → Ribose-5-phosphate
o Epimerase → Xyulose-5-phosphate
Formation of ribose-5-phosphate
Figure 3. Oxidation of glucose-6-phosphate to 6phosphogluconolactone.
Remember:
Hydride has two electrons instead of just 1 electron
Figure 4. Chemical structure of hydride
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METABOLISM: Note #1.
Isomerization of ribulose-5-phosphate
phosphate (Figure 7)
o Ribulose-5-phosphate – a ketone
o Ribose-5-phosphate – an aldehyde
to
ribose-5-
Catalyzed by isomerase
Formation of xyulose-5-phosphate
Epimerization of ribulose-5-phosphate to xyulose-5phosphate (Figure 7)
Catalyzed by epimerase
PENTOSE PHOSPHATE PATHWAY
Fusion of Ribose-5-phosphate and Xyulose-5phosphate
Catalyzed by transketolase
o Thiamine pyrophosphate (TPP) - coenzyme of
transketolase
Figure 7. Formation of ribose-5-phosphate and xyulose-5phosphate from ribulose-5-phosphate.
Remember:
Isomers vs Epimers
Isomers
o Same chemical formula but differs in the
arrangement of their atoms [Nelson & Cox, 2017]
Epimers
o A diastereomer which differs in chirality in one
carbon only
o Ribulose-5-phosphate and xyulose-5-phosphate are
epimers
o They are identical except for their stereochemistry in
C3
C
Ribulose-5Xyulose-5number
phosphate
phosphate
3
R
R
4
S
R
5
S
R
R = rotates clockwise; S = rotates counterclockwise
(B) NON-OXIDATIVE PHASE
Carbon-shuffling reactions
Consist of 3 reversible steps (Figure 8)
Significance
Can make ribose-5-phosphate without making
NADPH via glycolytic intermediates
 Glyceraldehyde-3-phosphate to make ribose-5phosphate
 Glyceraldehyde-3-phosphate
and
fructose-6phosphate to form erythrose-4-phosphate and
xyulose-5-phosphate
 Erythrose-4-phosphate and fructose-6-phosphate
to make glyceraldehyde-3-phosphate and
sedoheptulose-7-phosphate
 Glyceraldehyde-3-phosphate and sedoheptulose7-phosphate to form ribose-5-phosphate and
xyulose-5-phosphate
Can make ribose-5-phosphate to glycolytic
intermediates
Transketolase catalyzes the transfer of a 2-carbon
fragment from ribose-5-phosphate to xyulose-5-phosphate
(Figure 8)
o To remember, keep in mind that the chemical structure
of ketone is a carbonyl group in between two carbons,
so transketolase transfers two carbons.
Products are:
o Glyceraldehyde-3-phosphate – 3-carbon molecule
o Seduheptulose-7-phosphate – 7-carbon molecule
Fates of Glyceraldehyde-3-phosphate
Can be fed up into the glycolytic pathway
o Depends on body’s needs
Can fuse with Sedoheptulose-7-phosphate
Fusion
of
Glyceraldehyde-3-phosphate
Sedoheptulose-7-phosphate
and
Catalyzed by transaldolase
Transaldolase catalyzes the transfer of a 3-carbon
fragment
from
sedoheptulose-7-phosphate
to
glyceraldehyde-3-phosphate (Figure 8)
Products are:
o Fructose-6-phosphate – 6-carbon molecule
 Can be fed up into the glycolytic pathway
 Depends on the body’s needs
o Erythrose-4-phosphate – 4-carbon molecule
Fates of Fructose-6-phosphate
Can be fed up into the glycolytic pathway
o Depends on body’s needs
Remember:
5C+ 5C = 3C + 7C = 6C + 4C
Ribose-5- phosphate + Xyulose-5-phosphate →
Glyceraldehyde-3-phosphate
+
Sedoheptulose-7phosphate → Fructose-6-phosphate + Erythrose-4phosphate
To remember this reaction, keep in mind that the number
of carbons in the reactants is equal to the number carbons
in the products, which are both 10 (a coincidence in PPP.
Fusion of Erythrose-4-phosphate and Xyulose-5phosphate
Free ribulose-5-phosphate can be acted on with an
epimerase enzyme forming xyulose-5-phosphate (Figure
8)
Xyulose-5-phosphate reacts with erythrose-4-phosphate
catalyzed by another transketolase enzyme
o TPP – coenzyme of transketolase
Figure 8. Non-oxidative phase of the pentose phosphate
pathway.
PENTOSE PHOSPHATE PATHWAY
Transketolase transfers 2-carbon fragment from xyulose5-phosphate to erythrose-4-phosphate (Figure 8)
Products are:
o Glyceraldehyde-3-phosphate
 Can be fed up into the glycolytic pathway
depending on the body’s needs
o Fructose-6-phosphate
 Can also be fed up into the glycolytic pathway
depending on the body’s needs
METABOLISM: Note #1.
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 Deficiency in specific enzymes that generate
NADPH → appearance of Heinz bodies
(indicative of hemolytic anemia)
III) SIGNIFICANCE OF THE PRODUCTS OF PPP
The two main products of PPP are
o NADPH
o Ribose-5-phosphate
(B) RIBOSE-5-PHOSPHATE
(A) NADPH
A good reducing agent for any type of biosynthetic
reactions
Used in
o Fatty acid synthesis
 Specifically, in reduction steps
o Cholesterol metabolism
 To convert HMG-CoA to mevalonate
o Nucleotide metabolism
o Neurotransmitter synthesis
o Free radical reactions
 Aids antioxidants
Important in biosynthesis of
o Nucleotides
 DNA
 RNA
o ATP
o Electron shuttles
 NAD+
 FAD+
o Coenzyme A
IV) APPENDIX
Figure 9. Overview of the pentose phosphate pathway (PPP) and the importance of NADPH and ribose-5-phosphate.
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METABOLISM: Note #1.
PENTOSE PHOSPHATE PATHWAY
V) REVIEW QUESTIONS
Which of the following statements is correct about the
oxidative phase of the PPP?
a) Begins with the oxidation of glucose-1-phosphate to
6-phosphogluconolactone
b) The phase of the PPP which produces NADH and
ribose-5-phosphate.
c) Isomerase converts ribulose-5-phosphate to ribose5-phosphate
d) Xyulose-5-phosphate and ribulose-5-phosphate are
enantiomers.
2) Which of the following statements is correct about
the non-oxidative phase of the PPP?
a) All steps are reversible except to the last step
b) Allows synthesis of ribose-5-phosphate without
making NADPH via glycolytic intermediates
c) Transketolase catalyzes the transfer of a 2-carbon
from xyulose-5-phosphate to ribose-5-phosphate
d) The coenzyme of transaldolase is thiamine
pyrophosphate
3) The first transketolase reaction forms which
intermediate?
a) Sedoheptulose-7-phosphate
b) Fructose-6-phosphate
c) Erythrose-4-phosphate
d) Xyulose-5-phosphate
4) What is the significance of NADPH?
a) To convert HMG-CoA to mevalonate
b) To aid in free radical reactions
c) For neurotransmitter synthesis
d) All of the choices are correct.
5) Which steps involves the production of NADPH?
a) Formation of ribulose-5-phosphate
b) Oxidation of glucose-6-phosphate
c) Formation of 6-phosphogluconate
d) Two of the choices are correct.
CHECK YOUR ANSWERS
VI) REFERENCES
Nelson, D., & Cox, M. (2017). Lehninger Principles of
Biochemistry (7th ed.). New York: W.H Freeman and Company.
PENTOSE PHOSPHATE PATHWAY
METABOLISM: Note #1.
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