The Pentose Phosphate Shunt
(AKA: Pentose Phosphate Pathway, PPP)
Uses Glucose 6P to produce 3, 4, 5, 6 and 7
carbon sugars.
In the process of doing this it reduces NAD+ to
NADPH which is needed for reductive
biosynthesis.
NADPH is needed for synthesis of fatty acids
Fatty acids are a highly reduced energy store
Palmitate is the primary fatty acid, made to 16Cs by the
serial addition of 2Cs from Acetyl-S-CoA
Acetyl-S-CoA
Just attaching Acetyls
together would yield
this, which is NOT found
This is palmitate the
primary product of the
following reaction
Fatty acid synthesis and NADPH
continued
8Acetyl-CoA +7ATP +7H+ + H20 + 14 NADPH a
8 CoA + 7Pi +7ADP +Palmitate + 14 NADP+
So Palmitate and all other reduced fatty acids require
the oxidation of NADPH to NADP+.
Oxidation is the opposite of reduction. If something
is reduced then something else must be oxidized.
NADP+ is reduced to NADPH in the pentose
phosphate pathway
In NADP+
(oxidized)
In NADPH
(reduced)
This phosphate
is not present
in NAD+ or NADH
NADPH
NH2
derived
from niacin
(vitamin B3)
Dietary Deficiency of Niacin - Pellegra
Disease characterized by the “three
Ds” - dematitis, diarrhea, and
dementia.
“Pellegra” - Italian for “rough skin”.
Mental hospitals in the southern
states filled up every late
winter/early spring with patients
with pellegra. In 1930 there were
about 200,000 cases of pellegra in
the US.
A man with an
early stage of
pellagra known as
“pellagra gloves”.
Pellegra or “corn disease” was
originally thought to be an
infectious disease or result from
eating contaminated corn.
80% of niacin in corn is bound
to a substance making it
unavailable.
Native Americans did not get
pellegra because they treated
their corn with alkali (lime or
wood ashes) to make hominy
before grinding it.
Dr. Joseph Goldberger
- realized pellagra was
due to a dietary
deficiency and was
not an infectious
disease.
Figure 22.22 The
pentose phosphate
pathway.
The Oxidative Steps of the Pentose
Phosphate Pathway
1. Glucose-6-P Dehydrogenase
Irreversible 1st step - highly regulated!
2. Gluconolactonase
The uncatalyzed reaction happens too
3. 6-Phosphogluconate Dehydrogenase
An oxidative decarboxylation (in that order)
The Oxidative Steps of the Pentose
Phosphate Pathway
Figure 22.23 The glucose-6-phosphate dehydrogenase reaction is
the committed step in the pentose phosphate pathway.
Figure 22.24 The Gluconolactonase Reaction
Figure 22.24 The gluconolactonase reaction. The
uncatalyzed reaction also occurs.
The Oxidative Steps of the Pentose
Phosphate Pathway
Figure 22.25 The 6-phosphogluconate dehydrogenase
reaction. The initial NADP+-dependent dehydrogenation yields
a β-keto acid, 3-keto-6-phosphogluconate, which is very
susceptible to decarboxyation (the second step). The resulting
product, D-ribulose-5-P, is the substrate for the nonoxidative
reactions of the pentose phosphate pathway.
Figure 22.22 The
pentose phosphate
pathway.
The Nonoxidative Steps of the Pentose
Phosphate Pathway
Five steps, but only 4 types of reaction...
Phosphopentose isomerase
converts ketose to aldose
Phosphopentose epimerase
epimerizes at C-3
Transketolase ( a TPP-dependent reaction)
transfer of two-carbon units
Transaldolase (uses a Schiff base mechanism)
transfers a three-carbon unit
Figure 22.22 The
pentose phosphate
pathway.
The Nonoxidative Steps of the Pentose
Phosphate Pathway
Figure 22.26 The phosphopentose isomerase reaction
converts a ketose to an aldose. The reaction involves an
enediol intermediate.
Figure 22.22 The
pentose phosphate
pathway.
The Nonoxidative Steps of the Pentose
Phosphate Pathway
Figure 22.27 The phosphopentose epimerase reaction
interconverts ribulose-5-P and xylulose-5-phosphate. The
mechanism involves an enediol intermediate and occurs with
inversion at C-3.
Figure 22.22 The
pentose phosphate
pathway.
The Nonoxidative Steps of the Pentose
Phosphate Pathway
Figure 22.28 The transketolase reaction of step 6 in the
pentose phosphate pathway. This is a two-carbon transfer
reaction that requires thiamine pyrophosphate as a
coenzyme. TPP chemistry was discussed in Chapter 19
(see the pyruvate dehydrogenase reaction).
Figure 22.22 The
pentose phosphate
pathway.
The Nonoxidative Steps of the Pentose
Phosphate Pathway
Figure 22.31 The transaldolase reaction. In this reaction,
a 3-carbon unit is transferred, first to an active site
lysine, and then to the acceptor molecule.
Figure 22.22 The
pentose phosphate
pathway.
The Nonoxidative Steps of the Pentose
Phosphate Pathway
Figure 22.29 The transketolase reaction of step 8 in the
pentose phosphate pathway. This is another two-carbon
transfer, and it also requires TPP as a coenzyme.
Utilization of Glucose-6-P Depends on the
Cell’s Need for ATP, NADPH, and Rib-5-P
Glucose can be a substrate either for glycolysis or for the
pentose phosphate pathway
The choice depends on the relative needs of the cell for
biosynthesis and for energy from metabolism
ATP can be made if G-6-P is sent to glycolysis
Or, if NADPH or ribose-5-P are needed for biosynthesis,
G-6-P can be directed to the pentose phosphate pathway
Depending on these relative needs, the reactions of
glycolysis and the pentose phosphate pathway can be
combined in four principal ways
Four Ways to Combine the Reactions of Glycolysis
and Pentose Phosphate
1) Both Ribose-5-P and NADPH are needed by the cell
In this case, the first four reactions of the pentose
phosphate pathway predominate
NADPH is produced and ribose-5-P is the principal
product of carbon metabolism
2) More Ribose-5-P than NADPH is needed by the cell
Synthesis of ribose-5-P can be accomplished without
making NADPH, by bypassing the oxidative
reactions of the pentose phosphate pathway
Four Ways to Combine the Reactions of
Glycolysis and Pentose Phosphate
Case 1: Both ribose-5-P and NADPH are needed
Figure 22.33 When biosynthetic demands dictate, the first
four reactions of the pentose phosphate pathway
predominate and the principal products are ribose-5-P and
NADPH.
Four Ways to Combine the Reactions of Glycolysis
and Pentose Phosphate
3) More NADPH than ribose-5-P is needed by the cell
This can be accomplished if ribose-5-P produced in the
pentose phosphate pathway is recycled to produce
glycolytic intermediates
4) Both NADPH and ATP are needed by the cell, but
ribose-5-P is not
This can be done by recycling ribose-5-P, as in case 3
above, if fructose-6-P and glyceraldehyde-3-P made
in this way proceed through glycolysis to produce
ATP and pyruvate, and pyruvate continues through
the TCA cycle to make more ATP
Xylulose-5-Phosphate is a Metabolic Regulator
In addition to its role in the pentose phosphate
pathway, xylulose-5-P is also a signaling
molecule
When blood glucose rises, glycolysis and the pentose
phosphate pathways are activated in the liver
The latter pathway makes xylulose-5-P, which
stimulates protein phosphatase 2A (PP2A)
PP2A dephosphorylates PFK-2/F-2,6-Bpase and also
carbohydrate-responsive element-binding
protein (ChREBP)
Glycolysis and lipid biosynthesis are both activated
as a result
Xylulose-5-Phosphate is a Metabolic Regulator
Activation of PP2A triggers dephosphorylation of PFK-2/F2,6BPase, which raises F-2,6-BP levels, activating glycolysis and
inhibiting gluconeogenesis.
Figure 22.34
Dephosphorylation of ChREBP
elevates expression of genes for
lipogenesis.
Aldose Reductase and Diabetic Cataract
Formation
The complications of diabetes include a high
propensity for cataract formation in later life
Hyperglycemia is the cause, but why?
Evidence points to the polyol pathway, in which
glucose and other simple sugars are reduced in
NADPH-dependent reactions
Glucose is reduced by aldose reductase to sorbitol,
which accumulates in lens fiber cells, increasing
pressure and eventually rupturing the cells
Aldose reductase inhibitors such as tolrestat and
epalrestat suppress cataract formation
Aldose Reductase and Diabetic Cataract
Formation
Glucose is reduced by aldose reductase to sorbitol, which
accumulates in lens fiber cells, increasing pressure and
eventually rupturing the cells
Aldose reductase inhibitors such as tolrestat and epalrestat
suppress cataract formation
Glucose 6-Phosphate Dehydrogenase Deficiency
- affects more than 400 million people in the world.
- most common enzyme abnormality (enzymopathy) in people.
- the disease results in acute hemolytic anemia.
-red blood cells are particularly affected because they lack mitochondria.
-NADPH is important for maintaining adequate levels of reduced
glutathione (GSH) in the cell.
- The GSH is critical for destroying hydrogen peroxide and maintaining the
cysteine residues in hemoglobin and other rbc proteins in the reduced
state as well as the iron in hemoglobin in the ferrous state.
Glucose 6-Phosphate Dehydrogenase Deficiency (cont’d)
More than 400 variants of G6PD deficiency .
Most of the mutations are single-base changes that result in an amino acid
substitution.
The G6PD gene is on the X chromosome so males are primarily affected.
Most female carriers (heterozygotes) are asymptomatic.
G-6-PD deficiency affects all races. The highest prevalence is among
persons of African, Asian, or Mediterranean descent.
Severity varies significantly between racial groups because of different
variants of the enzyme.
Glucose 6-Phosphate Dehydrogenase Deficiency (cont’d)
About 11% of African-American males are affected by
the so-called A-type.
In Africa, female carriers of the mutation were found to
have an increased resistance to malaria.
People originating in the Mediterranean region may
have another, more serious variant, called the Mediterranean
type.
People are usually asymptomatic but certain drugs
can trigger a severe episode of hemolytic anemia within hours
of exposure.
Drugs that can bring on an acute reaction include:
•
•
•
•
•
•
•
•
antimalarial agents
sulfonamides (antibiotic)
aspirin
nonsteroidal anti-inflammatory drugs
nitrofurantoin
quinidine
quinine
others
Bacterial and viral infections can also trigger episodes.