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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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slide2

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
    • metabolism with special focus on its rule for antioxidant mechanisms.
    • 3- Describing the genetic & biochemical basis of glucose 6 phosphate
    • dehydrogenase deficiency (G6PD deficiency) with identifying its clinical
    • implication in causing hemolytic anemia.
  • 4- Recognizing the precipitating factors for G6PD deficiency anemia
  • 5- Recalling classes of G6PD deficiency anemia ( as indicated by variants of G6P
  • dehydrogenase enzyme)
  • 6- Discussing the biochemical & clinical rationale for lines of diagnosis of G6PD
  • deficiency anemia.
slide3

Pentose Phosphate Pathway (PPP) or Hexose Monophosphate Pathway (HMP)

  • Pentose Phosphate Pathway (PPP)
  • or Hexose monophosphate pathway (HMP):
  • - is an alternative oxidative pathway for glucose rather glycolysis
  • - results in noATP production (not like glycolysis)
  • - is the major pathway for NADPH production
  • - produces ribose-5-phosphate for nucleotide synthesis (required
  • for DNA, RNA & others)
pentose phosphate pathway ppp or hexose monophosphate pathway hmp as a source for nadph
Pentose Phosphate Pathway (PPP) or Hexose Monophosphate Pathway (HMP)as a source for NADPH

2 NADPH

are produced

for each one molecule

of glucose

Glucose

Glucose 6-phsphate

Dehydrogenase

First enzyme in

the pathway

Pentose phosphate pathway (or hexose monophosphate pathway)

occurs in the cytosol of many cells of the body including RBCs.

slide6

Pentose Phosphate Pathway (PPP)

Glucose-6-phosphate dehydrogenase

slide7

Uses of NADPH in normal cellular metabolism

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)

slide8

Role of NADPH in antioxidant mechanisms

Introduction

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

membranes..

They are implicated in cancer, chronic inflammatory disease and aging.

role of nadph in antioxidant mechanisms cont
Role of NADPH in antioxidant mechanisms (cont.)

Introduction (cont.):

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 .

role of nadph in antioxidant mechanisms cont1
Role of NADPH in antioxidant mechanisms (cont.)

Introduction(cont.):

Reduced Glutathione:

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

equivalents.

slide12

Reduced glutathione

Oxidized glutathione

slide13

Glucose 6-phosphate dehydrogenase deficiency

(G6PD deficiency)

Definition

  • It is an inherited disease characterized by hemolytic anemia caused by

inability to detoxify oxidized agents.

  • G6PD deficiency is the most common disease producing enzyme anomalies in humans, affecting more than 200 million individuals worldwide.

The highest prevalence in the Middle East, tropical Africa & Asia.

  • G6PD Deficiency is caused by 400 different mutations in gene coding for G6PD, only few of them causes the clinical symptoms of the disease.
mode of inheritance of g6pd deficiency
Mode of inheritance of G6PD Deficiency
  • It is X- linked recessivegenetic disorder (gene is carried on X-chromosome).
  • The gene is present on the X chromosome
  • The inheritance follows specific pattern:

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

slide15

Normal

Heterozygous (carrier)

Mother

( Xx )

Normal

Father

(XY)

50% of

Daughters are normal

carriers

50% of

Sons are affected

Punnet Square for X-linked Recessive Inheritance

decreased amounts of reduced glutathione due to decreased production of nadph
Decreased amounts of reduced glutathionedue to decreased production of NADPH

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.

decreased amounts of reduced glutathione due to decreased production of nadph1
Decreased amounts of reduced glutathionedue to decreased production of NADPH

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

slide19

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).

precipitating factors in g6pd deficiency
Precipitating factors in G6PD deficiency:
  • Individuals who have inherited one of the many G6PD mutations do not show

clinical manifestation.

  • Some of patients with G6PD develop hemolytic anemia if they are exposed or ingest any of the followings oxidizing agents:

1-Oxidant drugs:

Antibiotics : e.g. sulfamethoxazole

Antimalarias: e.g. primaquine

Antipyretics : e.g. acetanilid

2- Favism:

The hemolytic effect of ingesting of fava beans is not observed in all

individuals with G6PD deficiency but all patients with favism have G6PD

deficiency

g6pd variants
G6PD Variants
  • Most G6PD variantsare caused by point mutationsin the G6PD gene.
  • Some of these point mutations do not disturb the structure of the

enzyme's active site and hence, do not affect enzyme activity.

  • Other point mutations may lead to production of mutant enzymes with one or more of the following:

altered catalytic activity,

decrease stability

an alteration of binding affinityfor NADP+ or Glucose 6-phosphate.

  • The severity of diseases usually correlates with the amount of

residual enzyme activity in the patient’s red cells.

g6pd variants1
G6PD Variants

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

reticulocytes.

Accordingly, only older RBCs are hemolysed in a hemolytic episode.

Class II mutations (G6PD Mediterranean):

More severe

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 variants2
G6PD Variants
  • Both G6PD Mediterranean and G6PD A- represent mutant enzymes that differ from the normal variants by a single amino acid. This change is due to DNA changes in the form of point mutations or missense mutations.
  • Frame shift mutations or large deletions have not been identified indicating that the complete absence of G6PD is lethal.
  • Mutation causing non spherocytic hemolytic anemia are clustered near the carboxyl end of the enzyme, whereas mutations causing milder forms of the disease tend to be located at the amino end of the enzyme.
slide24

Diagnosis of

G6PD Deficiency Hemolytic Anemia

  • Diagnosis of hemolytic anemia
  • CBC and reticulocytic count
  • Screening:
  • Qualitative assessment of G6PD enzymatic activity
  • (UV-based test)
  • Confirmatory test:
  • Quantitative measurement of G6PD enzymatic activity
  • Molecular test:
  • Detection of G6PD gene mutation
reference
Reference
  • Lippincott’s Illustrated Biochemistry
  • Essential Hematology(Hoffbrand, Pettit & Moss)