Glucose 6-phosphate dehydrogenase deficiency. HMIM224. Objectives of the Lecture. 1- Understanding the main functional concepts for pentose phosphate pathway (also called hexose monophosphate pathway). 2- Identify the main general uses of NADPH for normal cellular
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Pentose Phosphate Pathway (PPP) or Hexose Monophosphate Pathway (HMP)
for each one molecule
First enzyme in
Pentose phosphate pathway (or hexose monophosphate pathway)
occurs in the cytosol of many cells of the body including RBCs.
1- Role in fatty acid synthesis (reductive agent)
2- Role in antioxidant mechanisms (part of glutathione system)
3- Role in oxygen-dependent phagocytosis by WBCs
4- Role in synthesis of nitric oxide (NO)
Hydrogen peroxide (H2O2) is one member of the family of reactive oxygen species (ROS).
Reactive oxygen species (ROS) are formed from partial reduction of molecular O2i.e.
adding electrons to oxygen leading to the formation of superoxide, hydrogen peroxide
and hydroxyl radical.
ROSare formed continuously from aerobic metabolism of drugs and environmental toxins
ordiminished antioxidants. All these lead to oxidative stress.
ROScause damage to DNA, protein and unsaturated lipids of the cells including cell
They are implicated in cancer, chronic inflammatory disease and aging.
The cell has different protective mechanisms that serve to minimize the toxic potential of
ROS (antioxidant effect) as follows:
A) Enzymes that catalyze antioxidant reactions:
i-Catalase & superoxide dismutase enzymes
catalyze the conversion of the toxic ROS to harmless products.
ii- Glutathione reductase
reduces oxidized glutathione to reduced glutathione
B) Antioxidant chemicals:
Vitamins E, C and b-carotene (precursor of vitamin A) reduce ROS .
Reduced Glutathione (G-SH) reduces hydrogen peroxide (H2O2) into
oxidized glutathione (G-S-S-G) and water. The reaction is catalyzed
by glutathione peroxidase
Oxidized glutathione is reduced to reduced glutathione by
glutathione reductase using NADPH as a source of reducing
inability to detoxify oxidized agents.
The highest prevalence in the Middle East, tropical Africa & Asia.
Males have one X chromosome
So, they will be diseased if they have the affected gene (xY)
Femaleshave 2 X chromosomes
may be homozygous or heterozygous
Homozygous: are diseased (xx)
Heterozygous: are not diseased BUT: carriers (Xx)
& can transfer the disease to their sons
( Xx )
Daughters are normal
Sons are affected
Punnet Square for X-linked Recessive Inheritance
Reduction of amounts of NADPH in RBCs in G6PD deficiency causes decrease
in reduction of oxidized glutathione to reduced glutathione.
Role of reduced glutathione in RBCs:
1- Reduced glutathione gets rid of ROS including hydrogen peroxide.
2- Reduced Glutathione helps to keep sulfhydryl groups of hemoglobin
protein in the reduced state.
Reduction of production of reduced glutathione results in:
1- A decrease in detoxication of peroixides. This causes damage to RBCs
membrane and hemolysis (ending in hemolytic anemia).
2- Hemoglobin protein is denatured forming insoluble masses (Heinz
bodies). Heinz bodies attach to red cell membranes.
Membrane proteins are also oxidized.
Accordingly, red cells become rigid and removed from the circulation
by macrophages in the spleen and liver ending in anemia
Decreased amounts of reduced glutathionedue to decreased production of NADPH
Deficiency of G6PD occurs in all cells of affected individual.
It is severe in RBCsbecause the only pathway to form NADPH in RBCs is
pentose phosphate pathway (using G6PD).
Antibiotics : e.g. sulfamethoxazole
Antimalarias: e.g. primaquine
Antipyretics : e.g. acetanilid
The hemolytic effect of ingesting of fava beans is not observed in all
individuals with G6PD deficiency but all patients with favism have G6PD
enzyme's active site and hence, do not affect enzyme activity.
altered catalytic activity,
an alteration of binding affinityfor NADP+ or Glucose 6-phosphate.
residual enzyme activity in the patient’s red cells.
G6PD Variants can be classified into :
Class III (G6PD Group A-) :
A moderate form of the disease
RBCs contain unstable G6PD enzyme, but normal activity in younger RBCs and
Accordingly, only older RBCs are hemolysed in a hemolytic episode.
Class II mutations (G6PD Mediterranean):
G6PD enzyme shows normal stability but, very low activity in all RBCs.
Class I mutations:
It is often associated with chronic non spherocytic anaemia
(occurs even in absence of oxidative stress).
G6PD Deficiency Hemolytic Anemia