The pentose phosphate pathway generates reducing equivalents in the form of NADPH and produces ribose-5-phosphate. It functions primarily in anabolic biosynthesis reactions that require NADPH, such as fatty acid and nucleic acid synthesis. Cells with high levels of these biosynthetic pathways, such as liver, adipose, and lactating mammary gland cells, have high levels of pentose phosphate pathway enzymes. The pathway oxidizes glucose through a series of reactions that ultimately produce ribulose-5-phosphate, which can be converted back into glucose-6-phosphate or other three and six carbon intermediates.

1. PENTOSE PHOSPHATE
PATHWAY

2. Introduction
The pentose phosphate pathway is primarily an anabolic pathway
that utilizes the 6 carbons of glucose to generate 5 carbon sugars
and reducing equivalents. However, this pathway does oxidize
glucose and under certain conditions can completely oxidize
glucose to CO2
and water. The primary functions of this pathway
are:
• To generate reducing equivalents, in the form of
NADPH, for reductive biosynthesis reactions within cells.
•To provide the cell with ribose-5-phosphate (R5P) for
the synthesis of the nucleotides and nucleic acids.
• Although not a significant function of the PPP, it can
operate to metabolize dietary pentose sugars derived
from the digestion of nucleic acids as well as to
rearrange the carbon skeletons of dietary carbohydrates

3. Enzymes that function primarily in the reductive direction utilize
the NADP+
/NADPH cofactor pair as co-factors as opposed to
oxidative enzymes that utilize the NAD+
/NADH cofactor pair. The
reactions of fatty acid biosynthesis and steroid biosynthesis
utilize large amounts of NADPH. As a consequence, cells of the
liver, adipose tissue, adrenal cortex, testis and
lactating mammary gland have high levels of the PPP
enzymes. In fact 30% of the oxidation of glucose in the liver
occurs via the PPP. Additionally, erythrocytes utilize the
reactions of the PPP to generate large amounts of NADPH used
in the reduction of glutathione (see below). The conversion of
ribonucleotides to deoxyribonucleotides (through the action of
ribonucleotide reductase) requires NADPH as the electron
source, therefore, any rapidly proliferating cell needs large
quantities of NADPH.

4. Linear (oxidative) portion of the Pentose Phosphate
Pathway
The Pentose Phosphate Pathway (also called Phosphogluconate
Pathway, or Hexose Monophosphate Shunt) is depicted with
structures. The linear portion of the pathway carries out oxidation and
decarboxylation of glucose-6-phosphate, producing the 5-C sugar
ribulose-5-phosphate.
Enzymes that function primarily in the reductive direction utilize the NADP+
/NADPH
cofactor pair as co-factors as opposed to oxidative enzymes that utilize the
NAD+
/NADH cofactor pair. The reactions of fatty acid biosynthesis and steroid
biosynthesis utilize large amounts of NADPH. As a consequence, cells of the liver,
adipose tissue, adrenal cortex, testis and lactating mammary gland have high
levels of the PPP enzymes. In fact 30% of the oxidation of glucose in the liver occurs
via the PPP. Additionally, erythrocytes utilize the reactions of the PPP to generate
large amounts of NADPH used in the reduction of glutathione (see below). The
conversion of ribonucleotides to deoxyribonucleotides (through the action of
ribonucleotide reductase) requires NADPH as the electron source, therefore, any
rapidly proliferating cell needs large quantities of NADPH.

7. Glucose-6-phosphate Dehydrogenase catalyzes oxidation of
the aldehyde (hemiacetal), at C1 of glucose-6-phosphate, to a
carboxylic acid in ester linkage (lactone). NADP+
serves as
electron acceptor.
6-Phosphogluconolactonase catalyzes hydrolysis of the ester
linkage (lactone) resulting in ring opening. The product is 6-
phosphogluconate. Although ring opening occurs in the absence of
a catalyst, 6-Phosphogluconolactonase speeds up the reaction,

8. Phosphogluconate
Dehydrogenase catalyzes
oxidative decarboxylation of
6-phosphogluconate, to yield the
5-C ketose ribulose-5-
phosphate.
The hydroxyl at C3 (C2 of the
product) is oxidized to a ketone.
This promotes loss of the
carboxyl at C1 as CO2. NADP+
again serves as oxidant (electron
acceptor).
Reduction of NADP+
(as with NAD+
)
involves transfer of 2e-
plus 1H+
to the
nicotinamide moiety.

9. Regulation:
Glucose-6-phosphate Dehydrogenase is the
committed step of the Pentose Phosphate Pathway.
This enzyme is regulated by availability of the substrate
NADP+
. As NADPH is utilized in reductive synthetic
pathways, the increasing concentration of NADP+
stimulates the Pentose Phosphate Pathway, to replenish
NADPH.
The remainder of the Pentoseproduct ribose-5-phosphate,
or to the 3-C glyceraldehyde-3-phosphate and the 6-C
fructose-6-phosphate Phosphate Pathway accomplishes
conversion of the 5-C ribulose-5-phosphate to the 5-C

10. Additional enzymes include Ribulose-5-phosphate Epimerase, Ribulose-5-
phosphate Isomerase, Transketolase, and Transaldolase.
Epimerase interconverts the stereoisomers ribulose-5-phosphate and xylulose-5-
phosphate.
Isomerase converts the ketose ribulose-5-phosphate to the aldose ribose-5-
phosphate.
Both reactions involve deprotonation to form an endiolate intermediate,
followed by specific reprotonation to yield the product.

11. Transketolase and Transaldolase catalyze transfer of
2-C and 3-C molecular fragments respectively, in each case
from a ketose donor to an aldose acceptor. However the
traditional enzyme names are used here.
ransketolase transfers a 2-C fragment from xylulose-5-phosphate to either
ibose-5-phosphate or erythrose-4-phosphate.
ransketolase utilizes as prosthetic group thiamine pyrophosphate (TPP), a derivative of
tamin B1. H+
readily dissociates from the C between N and S in the thiazolium ring

12. Transaldolase catalyzes transfer of a 3-C
dihydroxyacetone moiety, from sedoheptulose-7-
phosphate to glyceraldehyde-3-phosphate. The e-amino
group of an active site lysine residue reacts with the
carbonyl C of sedoheptulose-7-phosphate to form a
protonated Schiff base intermediate.
Aldol cleavage results in release of erythrose-4-
phosphate. The Schiff base stabilizes the carbanion on
C3.
Completion of the reaction occurs by reversal, as the
carbanion attacks instead the aldehyde carbon of the 3-
carbon aldose glyceraldehyde-3-phosphate to yield the 6-
carbon fructose-6-phosphate

14. C5 + C5 =C3 + C7 (Transketolase)
C3 + C7 = C6 + C4
(Transaldolase)
C5 + C4 = C6 + C3
(Transketolase)
____________________________
___________
3 C5 =2C6 + C3 (Overall)
Glucose-6-phosphate may be
regenerated from either the 3-C
product glyceraldehyde-3-
phosphate or the 6-C product
fructose-6-phosphate, via
enzymes of Gluconeogenesis

16. Glutathione is a tripeptide that includes a glutamate residue linked by an
isopeptide bond involving the side-chain carbonyl group. Its functional group is a
cysteine thiol.
One role of glutathione is degradation of hydroperoxides that arise
spontaneously in the oxygen-rich environment within red blood cells.
Hydroperoxides can react with double bonds in fatty acid moieties of membrane
lipids, making membranes leaky.
Glutathione Peroxidase catalyzes degradation of organic hydroperoxides by
reduction, as two glutathione molecules are oxidized to a disulfide. In the reaction
summary below, glutathione is represented as GSH.
2 GSH + ROOH à GSSG + ROH + H2O
Glutathione Peroxidase contains the trace element selenium as a functional
group. The enzyme's primary structure includes an analog of cysteine,
selenocysteine, with Se replacing S.
Regeneration of reduced glutathione requires NADPH, produced within
erythrocytes in the Pentose Phosphate Pathway. Glutathione Reductase
catalyzes:
GSSG + NADPH + H+
à 2 GSH + NADP+
Genetic deficiency of Glucose-6-phosphate Dehydrogenase can lead to a hemolytic
anemia, because of an inadequate supply of NADPH within red blood cells. The
effect of a partial deficiency of Glucose-6-phosphate Dehydrogenase activity is
exacerbated by substances that lead to increased production of peroxides (e.g., the