Pentose phosphate pathway and NADPH

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					UNIT II:
Intermediary Metabolism

   Pentose phosphate pathway
          and NADPH
Figure 13.1. Hexose monophosphate pathway shown as a component of the
metabolic map
• The pentose phosphate pathway (a.k.a, hexose
  monophosphate shunt, or 6-phosphogluconate pathway)
  occurs in cytosol of the cell
• It consists of two, irreversible oxidative reactions, followed by
  a series of reversible sugar-phosphate interconversions.
• No ATP is directly consumed or produced in the cycle.
  Carbon one of G-6-P is released as CO2, & 2 NADPH are
  produced for each G-6-P molecule entering the oxidative
  part of the pathway.
• The rate & direction of the reversible reactions of the
  pathway are determined by the supply of & demand for
  intermediates of the cycle.
• The pathway provides a major portion of the body’s NADPH,
  which functions as a biochemical reductant.
• It also produces ribose-5-P required for biosynthesis of
  nucleotides, & provides a mechanism for metabolic use of
  five-carbon sugars obtained from diet or degradation of
  structural CHOs in the body.
II. Irreversible oxidative reactions

-   The oxidative portion of pentose phosphate
    pathway consists of 3 reactions that lead to
    formation of ribulose 5-P, CO2, & 2 molecules
    of NADPH for each molecule of G-6-P
-   This portion of the pathway is particularly
    important in the liver & lactating mammary
    glands, which are active in the biosynthesis of
    fatty acids, in adrenal cortex, which is active in
    the NADPH-dependent synthesis of steroids, &
    in RBCs, which require NADPH to keep
    glutathione reduced
A. Dehyerogenation of glucose-6-phosphate
- Glucose 6-phosphate dehydrogenase (G6PD) catalyzes
   an irreversible oxidation of G-6-P to 6-
   phosphogluconolactone in a reaction that is specific for
   NADP+ as its coenz.
- The pentose phosphate pathway is regulated primarily at
   the G6PD reaction. NADPH is a potent competitive
   inhibitor of the enz, &, under metabolic conditions, the
   ratio of NADPH/NADP+ is sufficiently high to
   substantially inhibit enz activity.
- However, with increased demand for NADPH, the ratio
   of NADPH/NADP+ decreases & flux through the cycle
   increases in response to the enhanced activity of G6PD.
- Insulin enhances G6PD gene expression, & flux through
   the pathway increases in the well-fed state
B. Formation of ribulose-5-phosphate
- 6-phosphogluconolactone is hydrolyzed by 6-
phosphogluconolactone hydrolase. The reaction is
irreversible & not rate-limiting.
- The subsequent oxidative decarboxylation of 6-
phosphogluconate is catalyzed by 6-phosphogluconate
dehydrogenase. This irreversible reaction produces a
pentose sugar-phosphate (ribulose 5-P), CO2 (from C-1 of
glucose), & a 2nd molecule of NADPH.
Figure 13.2. Reactions of the hexose monophosphate pathway. Enzymes numbered
above are 1) glucose 6-phosphate dehydrogenase and 6-phosphogluconolactone
hydrolase, 2) 6-phosphogluconate dehydrogenase, 3) ribose 5-phosphate isomerase,
4) phosphopentose epimerase, 5) and 7) transketolase (coenzyme: thiamine
pyrophosphate), and 6) transaldolase.
III. Reversible nonoxidative reactions
- The nonoxidative reactions of pentose
   phosphate pathway occur in all cell types
   synthesizing nucleotides & nucleic acids.
- These reactions catalyze the interconversion of
   3-, 4-, 5-, 6-, & 7-carbon sugars. These
   reversible reactions permit ribulose-5-P
   (produced by oxidative portion of pathway) to be
   converted either to ribose 5-P (needed for
   nucleotide synthesis) or to intermediates of
   glycolysis, F-6-P & glyceraldehyde 3-P.
- E.g., many cells that carry out reductive
  biosynthetic reactions have a greater need for
  NADPH than for ribose-5-P. In this case,
  transketolase (which transfers 2-C units) &
  transaldolase (which transfers 3-C units) convert
  ribulose 5-P produced as an end-product of the
  oxidative reactions to glyceraldehyde 3-P & F-6-
  P, which are intermediates of glycolysis.
- In contrast, under conditions in which the
  demand for ribose for incorporation into
  nucleotides & nucleic acids is greater than the
  need for NADPH, the nonoxidative reactions can
  provide the biosynthesis of ribose-5-P from
  glyceraldehyde 3-P & F-6-P in the absence of
  the oxidative steps
Figure 13.3. Formation of ribose 5-phosphate from intermediates of glycolysis.
IV. Uses of NADPH
- The coenz NADP+ differs from NAD+ only by
  the presence of a P-group (-PO4=) on one of the
  ribose units.
- This seemingly small change in structure allows
  NADP+ to interact with NADP+-specific enz’s
  that have unique roles in the cell. E.g., the
  steady-state ratio of NADP+/NADPH in the
  cytosol of hepatocytes is ~ 0.1, which favors the
  use of NADPH in reductive biosynthetic
- This contrasts with the high ratio of NAD+/NADH
  (~ 1000 in the cytosol of hepatocytes), which
  favors an oxidative role of NAD+.
Figure 13.4. Structure of NADPH.
A. Reductive biosynthesis
- NADPH can be thought of as a high-
  energy molecule, much in the same way
  as NADH. However, the e’s of NADPH are
  destined for use in reductive biosynthesis,
  rather than for transfer to oxygen as is the
  case with NADH.
 - Thus, in the metabolic transformations of
  the pentose phosphate pathway, part of
  the energy of G-6-P is conserved in
  NADPH, a molecule that can be used in
  reactions requiring a high electron-
  potential e-donor.
B. Reduction of hydrogen peroxide
- Hydrogen peroxide is one of a family of reactive oxygen
   species that are formed from the partial reduction of
   molecular oxygen.
- These cpds are formed continuously as by-products of
   aerobic metabolism, through reactions with drugs &
   environmental toxins, or when level of antioxidants is
   diminished, all creating the condition “oxidative stress”.
- The highly reactive oxygen intermediates can cause
   serious chemical damage to DNA, proteins, &
   unsaturated lipids, and can lead to cell death.
- These reactive oxygen species have been implicated in
   a number of pathologic processes including reperfusion
   injury, cancer, inflammatory disease, and aging.
- The cell has several protective mechanisms that
   minimize the toxic potential of these cpds.
1. Enzymes that catalyze antioxidant reactions:
- A tripeptide-thiol (γ-glutamylcysteinylglycine) present in
   most cells, can chemically detoxify hydrogen peroxide
- This reaction, catalyzed by the selenium-requiring
   glutathione peroxidase, forms oxidized glutathione, which
   no longer has protective property
- The cell regenerates reduced glutathione in a reaction
   catalyzed by glutathione reductase, using NADPH as a
   source of reducing electrons
- Thus, NADPH indirectly provides e’s for the reduction of
   hydrogen peroxide
- Additional enz’s, such as superoxide dismutase &
   catalase, catalyze the conversion of other toxic oxygen
   intermediates to harmless products
- As a group, these enz’s serve as a defense system to
   guard against the toxic effects of reactive oxygen species
Figure 13.5
A. Formation of reactive intermediates from molecular oxygen. B. Actions of
antioxidant enzymes. G-SH = reduced
glutathione; G-S-S-G = oxidized glutathione.
Figure 13.6. A. Structure of glutathione (G-SH). [Note:
Glutamate is linked to cysteine through a γ-carboxyl, rather
than an α-carboxyl.] B. Glutathione-mediated reduction of
hydrogen peroxide by NADPH.
- RBCs are totally dependent on the pentose phosphate
   pathway for their supply of NADPH because, unlike other
   cell types, RBCs do not have an alternate source for this
   essential coenz.
- If G6PD is compromised in some way, NADPH levels will
   fall, & oxidized glutathione can’t be reduced
- As a result, hydrogen peroxide will accumulate,
   threatening memb stability & causing RBC lysis
2. Antioxidant chemicals
- A number of intracellular reducing agents such as ascorbate, vitamin
   E, & β-carotene, are able to reduce &, thus, detoxify oxygen
   intermediates in the lab.
- Consumption of foods rich in these antioxidant cpds has been
   correlated with a reduced risk for certain types of cancers, as well as
   decreased frequency of certain other chronic health problems
- Thus, it is tempting to speculate that the effects of these cpds are, in
   part, an expression of their ability to quench the toxic effect of
   oxygen intermediates
- However, clinical trials with antioxidants as dietary supplements
   have failed to show clear beneficial effects.
- In the case of dietary supplementation with β-carotene, the rate of
   lung cancer in smokers increased rather than decreased.
- Thus, the health-promoting effects of dietary fruits & vegetables
   probably reflects a complex interaction among many naturally
   occurring cpds, which has not been duplicated by consumption of
   isolated antioxidant cpds
C. Cytochrome P450 monooxygenase system
- Monooxygenases (mixed function oxidases) incorporate
  one atom from molecular oxygen into a substrate
  (creating a hydroxyl group), with the other atom being
  reduced to water
- In the cytochrome P450 monooxygenase system,
  NADPH provides the reducing equivalents required by
  this series of reactions
- This system performs different functions in two separate
  locations in cells. The overall reaction catalyzed by Cyt-
  P450 enz is:
    R-H + O2 + NADPH + H+ → R-OH + H2O + NADP+
  Where R may be a steroid, drug, or other chemical
Note: Cyt-P450s (CYPs) are actually a superfamily
  comprised of 100s of genes, coding for related, heme-
  containing enz’s that participate in a broad variety of
Figure 13.7
Cytochrome P450
monooxygenase cycle.
1. Mitochondrial system:
- The function of the mitoch Cyt-P450 monooxygenase
   system is to participate in the hydroxylation of steroids, a
   process that makes these hydrophobic cpds more water
- E.g., in the steroid hormone-producing tissues, e.g.,
   placenta, ovaries, testes, & adrenal cortex, it is used to
   hydroxylate intermediates in the conversion of
   cholesterol to steroid hormones
- The liver uses this system in bile acid synthesis, & the
   kidney uses it to hydroxylate vitamin 25-
   hydroxycholecalciferol (vitamin D) to its biologically
   active 1,25-hydroxylated form
2. Microsomal system:
- An extremely important function of the microsomal Cyt-P450
   monooxygenase system found associated with memb’s of
   sER (particularly in liver) is the detoxification foreign cpds
- Xenobiotics include numerous drugs & such varied
   pollutants as petroleum products, carcinogens, & pesticides
- The Cyt-P450 monooxygenase system can be used to
   hydroxylate these toxins, again using NADPH as source of
   reducing equivalents
- The purpose of these modifications is 2-fold. 1st, it may itself
   activate or inactivate a drug or 2nd, make a toxic cpd more
   soluble, thus facilitating its excretion in the urine or feces.
- Frequently, however, the new hydroxyl group will serve as a
   site for conjugation with a polar cpd, such as glucuronic
   acid, which will significantly increase the cpd’s solubility
D. Phagocytosis by white blood cells
- Phagocytosis is the ingestion by receptor-mediated
  endocytosis of m/o’s, foreign particles, & cellular debris
  by cells such as neutrophils & macrophages
- It is an important body defense mechanism, particularly
  in bacterial infections.
- Neutrophils & monocytes are armed with both oxygen-
  independent & oxygen-dependent mechanisms for killing
- The oxygen-dependent mechanisms include the
  myeloperoxidase (MPO) system & a system that
  generates oxygen-derived free radicals
- Oxygen-independent systems use pH changes in
  phagolysosomes & lysosomal enz’s to destroy
• Overall, the MPO system is the most potent of the
  bactericidal mechanisms.
• An invading bacterium is recognized by the immune
  system & attacked by antibodies that bind it to a receptor
  on a phagocytic cell
• After internalization of the m/o has occurred, NADPH
  oxidase, located in the leukocyte CM, converts molecular
  oxygen from the surrounding tissue into superoxide
• The rapid consumption of molecular oxygen that
  accompanies formation of superoxide is referred to as
  the respiratory burst
- NADPH oxidase is a complex enz, with subunits
  containing a cytochrome & a flavin coenz group
- Genetic deficiencies in this enz cause chronic
  granulomatosis, a disease characterized by severe,
  persistent, chronic pyogenic infections
- Next, superoxide is spontaneously converted into
  hydrogen peroxide. Any superoxide that escapes the
  phagolysosome is converted to hydrogen peroxide by
  superoxide dismutase (SOD).
- This product is then neutralized by catalase or
  glutathione peroxidase
- In the presence of MPO, a lysosomal enz present within
  the phagolysosome, peroxide plus chloride ions are
  converted into hypochorous acid (HOCl, the major
  component of household bleach), which kills the
- Excess peroxide is either neutralized by catalase or by
  glutathione peroxidase
Figure 13.8
Phagocytosis and the oxygen
dependent pathway of microbial
killing. IgG = the antibody
immunoglobulin G.
E. Synthesis of nitric oxide
- Nitric oxide (NO) is recognized as a mediator in a broad
   array of biologic systems
- NO is the endothelium-derived relaxing factor, which
   causes vasodilation by relaxing vascular smooth muscle.
- NO also acts as a neurotransmitter, prevents platelet
   aggregation, & plays an essential role in macrophage
- NO has a very short half-life in tissues (3-10 seconds)
   because it reacts with oxygen & superoxide, & then is
   converted into nitrates & nitrites.
- NO is a free radical gas that is confused with nitrous oxide
   (N2O), the “laughing gas” that is used as an anesthetic &
   is chemically stable
1. Synthesis of NO:
- Arg, O2, & NADPH are substrates for cytosolic NO synthase.
- Flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD),
    heme, & tetrahydropterin are coenz’s for the enz, & NO & citrulline
    are products of the reaction
- Three NO synthases have been identified. Two are constitutive
    (synthesized at a constant rate regardless of physiologic demand),
    Ca2+-calmodulin-dependent enzymes. They are found primarily in
    endothelium (eNOS), & neural tissue (nNOS), & constantly produce
    low levels of NO
- An inducible, Ca2+-independent enz. (iNOS) can be expressed in
    many cells, including hepatocytes, macrophages, monocytes, &
- The specific inducers for NO synthase vary with cell type, & include
    tumor necrosis factor-α, bacterial endotoxins, & inflammatory
    cytokines. These cpds have been shown to promote synthesis of
    iNOS, which can result in large amounts of NO being produced over
    hours or even days.
Figure 13.9
Synthesis and some of the
actions of nitric oxide.
2. Action of NO on vascular endothelium:
- NO is an important mediator in the control of vascular smooth
   muscle tone
- NO is synthesized by eNOS in endothelial cells & diffuses to
   vascular smooth muscle, where it activates the cytosolic form of
   guanylate cyclase
Note: this reaction is analogous to the formation of cAMP by adenylate
   cyclase, except that this guanylate cyclase is not membrane-
- The resultant rise in cGMP causes muscle relaxation through
   activation of protein kinase G, which phospho. myosin light-chain
   kinase & renders it inactive, thereby decreasing smooth muscle
Note: vasodilator nitrates, such as nitroglycerin & nitroprusside, are
   metabolized to nitric oxide, which causes relaxation of vascular
   smooth muscle &, therefore, lowers blood pressure. Thus, NO can
   be envisioned as an endogenous nitrovasodilator
3. Role of NO in mediating macrophage bactericidal
- In macrophages, iNOS activity is normally low, but
   synthesis of the enz is significantly stimulated by
   bacterial LPS & γ-IFN release in response to infection.
- Activated macrophages form superoxide radicals that
   combine with NO to form intermediates that decompose,
   forming the highly bactericidal OH•- radical
Note: NO production in macrophages is also effective
   against viral, fungal, helmintic, & protozoan infections
4. Other functions of NO:
- NO is a potent inhibitor of platelet aggregation (by
   activating cGMP pathway). It is characterized as a
   neurotransmitter in the brain
V. Glucose 6-P dehydrogenase deficiency
- G6PD deficiency is an inherited disease characterized
  by hemolytic anemia caused by the inability to detoxify
  oxidizing agent
- G6PD deficiency is the most common disease-producing
  enz abnormality in humans, affecting > 200 million
  individuals worldwide.
- This deficiency has the highest prevalence in the Middle
  East, tropical Africa & Asia, & parts of the Mediterranean
- G6PD deficiency is X-linked, & is in fact, a family of
  deficiencies caused by > 400 different mutations in the
  gene coding for G6PD. Only some of these mutations
  cause clinical symptoms
• The lifespan of many individuals with G6PD deficiency is
  somewhat shortened as a result of complications arising
  from chronic hemolysis
• This slightly negative effect of G6PD deficiency has been
  balanced in evolution by an advantage in survival, an
  increased resistance to falciparum malaria shown by
  female carrier of the mutation
Note: sickle cell trait & β-thalassemia minor also confer
A. Role of G6PD in RBCs
- Diminished G6PD activity impairs the ability of the cell to
   form NADPH that is essential for the maintenance of
   reduced glutathione pool. This results in decrease in the
   cellular detoxification of free radicals & peroxides formed
   within cell
- Glutathione also helps maintain the reduced states of
   sulfhydryl groups in proteins, including Hb. Oxidation of
   those sulfhydryl groups leads to formation of denatured
   proteins that form insoluble masses (called Heinz
   bodies) that attach to the red cell memb’s.
- Additional oxidation of memb proteins causes the red
   cells to be rigid & non-deformable, & they are removed
   from the circulation by macrophages in spleen & liver
Figure 13.10. Pathways of G-6-P mtabolism in the erythrocyte
Figure 13.11
Heinz bodies in erythrocytes of patient with G6PD deficiency.
- Although G6PD deficiency occurs in all cells of the
  affected individual, it is most severe in erythrocytes,
  where the pentose phosphate pathway provides the only
  means of generating NADPH
- Other tissues have alternative sources for NADPH
  production (e.g., NADP+-dependent malate
  dehydrogenase) that keep glutathione reduced
- The erythrocyte has no nucleus or ribosomes & can’t
  renew its supply of the enz. Thus, RBCs are particularly
  vulnerable to enz variants with diminished stability
B. Precipitating factors in G6PD deficiency
-   Most individuals who have inherited one of the many
    G6PD mutations do not show clinical manifestations.
    However, some patients with G6PD deficiency develop
    hemolytic anemia if they are treated with an oxidant
    drug, ingest fava beans, or contract a severe infection
1. Oxidant drugs: commonly used drugs that produce
    hemolytic anemia in patients with G6PD deficiency are
    best remembered from the mnemonic AAA =
    Antibiotics (e.g., sulfa, methoxazole &
    chloramphenicol), Antimalarials (e.g., primaquine but
    not quinine), and Antipyretics (e.g., acetanilid but not
2.   Favism: some forms of G6PD deficiency, e.g., the
     Mediterranean variant, are particularly susceptible to
     the hemolytic effect of the fava bean, a dietary staple
     in Mediterranean region. Favism, the hemolytic effect
     of ingesting fava beans, is not observed in all
     individuals with G6PD deficiency, but all patients with
     favism have G6PD deficiency
3.   Infection: infection is the most common precipitating
     factor of hemolysis in G6PD deficiency. The
     inflammatory response to infection results in the
     generation of free radicals in macrophages, which can
     diffuse into the RBCs & cause oxidative damage
4.   Neonatal jaundice: babies with G6PD deficiency may
     experience neonatal jaundice appearing 1-4 days after
     birth. The jaundice, which may be severe, results from
     impaired hepatic catabolism of heme or increased
     production of bilirubin
C. Properties of the variant enzymes
- Almost all G6PD variants are caused by point mutations
  in the G6PD gene.
- Some mutations do not disrupt the structure of the enz’s
  active site &, hence, do not affect enzymic activity
- However, many mutant enz’s show altered kinetic
  properties. E.g., variant enz’s may show decreased
  catalytic activity, decreased stability, or an alteration of
  binding affinity for NADP+, NADPH, or G-6-P
- Severity of disease usually correlates with amount of
  residual enz activity in patients’ RBCs. E.g., variants can
  be classified as:
Figure 13.12
Classification of G6PD deficiency variants.
• G6PD A- is the prototype of the moderate (class III) form
  of disease. The RBCs contain an unstable, but kinetically
  normal G6PD, with most of the enz activity present in the
  reticulocytes & younger erythrocytes
• The oldest cells, therefore, have the lowest level of enz
  activity, & are preferentially removed in a hemolytic
• G6PD Mediterranean is the prototype of a more severe
  (class II) deficiency in which the enz shows normal
  stability but scarcely detectable activity in all RBCs.
• Class I mutations are often associated with chronic non-
  spherocytic anemia, which occurs even in absence of
  oxidative stress
Figure 13.13
Decline of erythrocyte G6PD
activity with cell
age for the three most
commonly encountered
forms of the enzyme.
D. Molecular biology of G6PD
- Cloning of G6PD gene & the sequencing of its cDNA
  have permitted identification of mutations that cause
  G6PD deficiency
- More than 300 different mutations or mutation
  combinations have been identified in this gene, a finding
  that explains the numerous biochemical variants
- Most of these DNA changes are missense, point
  mutations. Both G6PD A- & G6PD Mediterranean
  represent mutant enz’s that differ from the respective
  normal variants by a single aa
- Large deletions or frameshifts mutations have not been
  identified, suggesting that complete absence of G6PD
  activity is probably lethal
5 yr old boy presents to the emergency room:
febrile, pale, tachycardic, tachypneic and minimally responsive

AM: good health
PM: abdominal pain, headache, fever
by late evening: tachypneic and incoherent

Lab tests: massive nonimmune intravasuclar hemolysis and

The patient is of Greek ethnicity.

Mother notes that although there is no family history of
hemolysis, she has some European cousins with a ‘blood

She later recalls that her son had been eating fava beans in
the garden while she worked in the yard

• The pentose phosphate pathway consists of 2 irreversible oxidative
  reactions followed by a series of reversible sugar-phosphate
• No ATP is directly consumed or produced in the cycle
• The oxidative portion is particularly important in liver & mammary
  glands, which are active in biosynthesis of fatty acids, in adrenal
  cortex, which is active in NADPH-dependent synthesis of steroids, &
  in erythrocytes, which require NADPH to keep glutathione reduced
• G-6-P is irreversibly converted to ribulose-5-P, & 2 NADPH are
• The regulated step is G6PD, which is strongly inhibited by NADPH
• Reversible nonoxidative reactions interconvert sugars. This part of
  pathway is the source of ribose 5-P required for nt & nucleic acid
• Because reactions are reversible, they can be entered from F-6-P &
  GA 3P (glycolytic intermediates) if ribose is needed & G6PD is
• NADPH is a source of reducing equivalents in reductive
  biosynthesis, such as production of fatty acids &
  steroids. It is also required for reduction of hydrogen
  peroxide, providing the reducing equivalents required by
  glutathione (GSH).
• GSH is used by glutathione peroxidase to reduce
  peroxide to water. The oxidized glutathione is reduced
  by glutathione reductase, using NADPH as the source of
• NADPH provides reducing equivalents for cyt-P450
  monooxygenase system, which is used in hydroxylation
  of steroids to produce steroid hormones, bile acid
  synthesis by liver, & activation of vitamin D. the system
  also detoxify foreign cpds, e.g., drugs & varied
  pollutants, including carcinogens, pesticides, &
  petroleum products
• NADPH provides reducing equivalents for phagocytes in
  the process of eliminating invading m/o’s
• NADPH oxidase uses molecular oxygen & NADPH e’s to
  produce superoxide radicals, which, in turn, can be
  converted to peroxide, hypochlorous acid, & hydroxyl
  radicals. Myeloperoxidase is an important enz in this
• A genetic defect in NADPH oxidase causes chronic
  granulomatosis, a disease characterized by severe,
  persistent, chronic pyogenic infections
• NADPH is required for synthesis of nitric oxide (NO), an
  important molecule that causes vasodilation by relaxing
  vascular smooth muscle, acts as a kind of
  neurotransmitter, prevents platelet aggregation, & helps
  mediate macrophage bactericidal activity
• G6PD deficiency is a genetic disease characterized by hemolytic
  anemia. It impairs ability of cell to form NADPH that is essential for
  maintenance of reduced glutathione pool.
• Cells most affected are RBCs because they do not have additional
  sources of NADPH
• Free radicals & peroxides formed within the cells can’t be
  neutralized, causing denaturation of protein (e.g., Hb, forming Heinz
  bodies) & memb proteins. Cells become rigid, & they are removed
  by reticuloendothelial system of spleen & liver
• Hemolytic anemia can be caused by production of free radicals &
  peroxides following the taking of oxidant drugs, ingestion of fava
  beans, or severe infections
• Babies with G6PD deficiency may experience neonatal jaundice
  appearing 1-4 days after birth
• Degree of severity of anemia depends on location of mutation in
  G6PD gene. Class I mutations are the most severe (e.g., G6PD
  Mediterranean). They are often associated with chronic non-
  spherocytic anemia. Class III mutations (e.g., G6PD A-) cause a
  more moderate form of the disease

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