Transcript Pentose Phosphate Shunt

Ferchmin 2015
1) Pentose phosphate pathway or shunt (PPP).
2) Oxidative and isomerization parts.
3) Regulation
4) Metabolic roles of PPP
5) Reduction of glutathione.
In glycolysis there was no net
oxidation/reduction only
“reshuffling” of the redox state
of the carbons
PENTOSE PHOSPHATE SHUNT or
HEXOSE MONOPHOSPHATE PATHWAY
This pathway consists of two parts:
1) Glucose-6-P undergoes two oxidations by NADP+, the second is
an oxidative decarboxylation that forms a pentose-P.
2) The P-pentoses that are formed during the first part are
transformed into glucose-6-P.
GPDH deficiency is relatively common
in persons with roots from regions
with endemic malaria.
In glycolysis followed by TCA (Kreb’s) cycle the first Cs
to be converted to CO2 are # 3 and 4. In PPP is C #1.
Glucose-6-Phosphate Dehydrogenase Deficiency
Glucose-6-phosphate dehydrogenase deficiency is an inherited condition caused by a defect or defects in
the gene that codes for the enzyme, glucose-6-phosphate dehydrogenase (G6PD). It can cause hemolytic
anemia, varying in severity from life-long anemia, to rare bouts of anemia to total unawareness of the
condition. The episodes of hemolytic anemia can be triggered by common medicines, oxidants, infection, or
by eating fava beans.
G6PD deficiency is the most common enzyme deficiency in the world, with about 400 million people
living with it. It is most prevalent in people of African, Mediterranean, and Asian ancestry. The incidence
in different populations varies from zero in South American Indians to less than 0.1% of Northern
Europeans to about 50% of Kurdish males. In the United States, it is most common among African
American males; about 11 to 14% are G6PD-deficient. G6PD deficiency is a sex-linked recessive trait.
Thus, males have only one copy of the G6PD gene, but females have two copies. Recessive genes are
masked in the presence of a gene that encodes normal G6PD. Accordingly, females with one copy of the
gene for G6PD deficiency are usually normal, while males with one copy have the trait.
G6PD is present in all human cells but is particularly important to red blood cells. It is required to make
NADPH in red blood cells and maintain the RBC reduced. It is also required to make glutathione.
Glutathione and NADPH both help protect red blood cells against oxidative damage. Thus, when G6PD
is defective, and the demand for NADPH is too high oxidative damage to red blood cells readily occurs
causing hemolysis and hemolytic anemia.
As of 1998, there are almost 100 different known forms of G6PD enzyme molecules encoded by
defective G6PD genes, yet not one of them is completely inactive. Suggesting that the activity of G6PD
is indispensable for supporting life. Many G6PD defective enzymes are deficient in their stability rather
than their initial ability to function. Since red blood cells lack nuclei, they, unlike other cells, cannot
synthesize new enzyme molecules to replace defective ones. Hence, we expect young red blood cells to
have new, functional G6PD and older cells to have non-functioning G6PD. This explains why episodes
of hemolytic anemia are frequently self-limiting; new red blood cells are generated with enzymes able to
afford protection from oxidation.
2) Nonoxidative steps of pentose phosphate shunt
transketolase
requires thiamine
pyrophosphate
(vitamin B1)
Positive
regulator of
lipid
synthesis
transketolase
requires thiamine
pyrophosphate
(vitamin B1)
Do you? If you don’t study this. The NBE
boys want you to know the sequences: 1)
vitamin, 2) coenzyme, 3) enzyme involved,
4) name of disease caused by vitamin
deficiency and symptoms.
GSSG is oxidized
and GSH reduced
glutathione. This
will be discussed
in the next page
Glutathione synthesis is not ribosomal and glutathione is not directly encoded in DNA.
Notice the unusual bonds between cysteine and glutamate.
What is wrong with this bond?
Link between hexose monophosphate pathway and reduction of peroxides
Proposed mechanism of glutathione peroxidase
Glutathione peroxidase has selenocysteine a rare amino acid that contains selenium. The story
of selenocysteine incorporation into proteins is unusual.
There are many antioxidants that neutralize the oxygen reactive species (ROS). Among them
are: vitamins C and E and recently the tomato red pigment, lycopene. Lycopene, became
notorious for reportedly preventing prostate cancer and retinal macula degeneration.