PENTOSE PATHWAY

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BIOC 460 - DR. TISCHLER LECTURE 26
PENTOSE PATHWAY ANTIOXIDANTS
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OBJECTIVES
1. For the pentose phosphate pathway a.
describe the oxidative and non-oxidative branches
b. describe how the oxidative branch is
regulated c. distinguish between the 3 modes in
terms of the roles of the potential endproducts
of each mode. 2. Describe the consequences of
thiamine deficiency 3. In relation to
antioxidant function in the body a. list the
major active (reactive) oxygen species, identify
the antioxidant which reduces that
species. b. describe the metabolism of
glutathione c. identify the enzymes that remove
peroxides and superoxide radicals from a
cell and name their cofactor. d. describe the
relationships between the components of the
antioxidant cascade including the reactions
involved. e. discuss why a defect of
glucose-6-phosphate dehydrogenase in the
red blood cell might lead to loss of membrane
integrity.
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PHYSIOLOGICAL PREMISE Do you have a partial
enzyme deficiency about which you are unaware?
There are circumstances where an individual may
have such a partial deficiency but be unaware of
the fact until a physiological event shifts the
balance of metabolic processes. For example,
individuals with malaria are given a drug called
primaquine. When the body metabolizes primaquine
it increases the demand for production of NADPH
in most cells. A major source of NADPH is the
glucose-6-phosphate dehydrogenase (G6PDH)
reaction in the pentose phosphate pathway. In the
red blood cell, this pathway is essential for
removing peroxides, which can oxidize lipids in
the plasma membrane causing the cell to become
more fragile. Stressing the system with
primaquine in an individual with a partial
deficiency of G6PDH will lead to red cell
destruction and hence the individual becomes
anemic.
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Functions of Pentose Phosphate Pathway

• NADPH for biosynthetic pathways (e.g., synthesis
  of fatty acids and cholesterol)
• 2) NADPH for maintaining glutathione in its
  reduced state (see discussion of glutathione
  later)
• 3) Pentose sugar for synthesis of nucleic acids

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glycolytic intermediates
Figure 1. The pentose phosphate pathway
containing an oxidative and a non-oxidative
branch
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Nucleic acids
Ribulose 5-P
Ribose 5-P
Xylulose 5-P
Glyceraldehyde 3-P
Transketolase
Transketolase
Non-oxidative Branch
Sedoheptulose 7-P
Glyceraldehyde 3-P
Transaldolase
Fructose 6-P
Erythrose 4-P
Fructose 6-P
Ribose-5-P is the sugar required for the
synthesis of nucleic acids
Figure 2. Using the non-oxidative branch of the
pentose pathway to produce ribose-5-phosphate for
the nucleic acid pathways (Mode 1).
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NADPH
NADP
6-Phosphogluconate
Glucose 6-P
NADP
NADPH
CO2
Ribulose 5-P
Ribose 5-P
Nucleic acids
Figure 3. Using the oxidative branch of the
pentose pathway to produce NADPH for biosynthetic
reactions and ribose-5-phosphate for producing
nucleic acids (Mode 2).
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NADPH
NADP
Glucose 6-P (3)
6-Phosphogluconate
NADP
Oxidative Branch
NADPH
CO2
Ribulose 5-P (3)
Glyceraldehyde 3-P (1)
Ribose 5-P (1)
Xylulose 5-P (2)
Non- oxidative Branch
back to glucose-6-P or to glycolysis
Sedoheptulose 7-P (1)
Glyceraldehyde 3-P (1)
Erythrose 4-P (1)
Fructose 6-P (1)
Fructose 6-P (1)
back to glucose-6-P or to glycolysis
Figure 4. Using the oxidative branch to produce
NADPH for biosynthesis and returning ribulose-5-P
to glycolytic intermediates (mode 3)
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NUTRITIONAL PREMISE THIAMINE (VITAMIN B1)

• used by transketolase, PDH, ?KgDH
• deficiency affects nucleic acid synthesis/energy
  metabolism
• Wernicke-Korsakoff syndrome observed in
  alcoholics due to poor diet
• thiamine deficiency in individuals on high CHO
  diet
• (e.g., rice) causes beriberi
• patients tire easily
• cardiac decompensation
• energy depletion on high CHO diet

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Brain atrophy due to Wernickes
encephalopathy Slide to be shown in class
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Table 1. Reactive Oxygen Species and
Antioxidants that Reduce Them
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O2
Figure 5. Pathways for the formation of reactive
oxygen species
? lipid radical
? Singlet oxygen
? Haber-Weiss reaction ? Fenton reaction
? Peroxyl radical
? lipid peroxyl radical
? Superoxide radical anion
? Superoxide dismutase
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Figure 6. Reactions of glutathione reduction
and oxidation
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SUMMARY OF ANTI-OXIDANT ENZYMES
Glutathione peroxidase 2 GSH H2O2 ? GSSG 2
H2O Uses selenium as a cofactor
Catalase 2 H2O2 ? H2O O2
Lipid Peroxidase removes LOOH
Superoxide dismutase 2 O2-? 2H ? H2O2 O2
Mitochondrial - Mn2 cofactor Cytoplasmic
Cu2-Zn2 cofactors mutations associated with
familial amyotrophic lateral sclerosis (FALS)
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NUTRITIONAL CORRELATE SELENIUM

• selenocysteine in glutathione peroxidase
• intake may be related to lower cancer mortality
• cancer patients have lower plasma Se levels
• risk may be higher in those with low Se intake
• AZCC study reduced incidence of prostate,
  colon, lung cancers
• toxicity (gt 1 mg/day) results in hair loss, GI
  upset, nerve damage

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Figure 7. Antioxidant cascade Reduced
forms/reduction Oxidized forms/oxidation
rxn 5
rxn 6
rxn 9
rxn 4
rxn 7
rxn 1
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Medical Scenario If the antioxidant protective
system in the red blood cell becomes defective,
hemolytic anemia occurs that is red blood cells
undergo hemolysis and their concentration in the
blood decreases. Such is the case if glucose
6-phosphate dehydrogenase is defective in the
pentose phosphate pathway. In individuals whose
glucose 6-phosphate dehydrogenase is defective,
there is insufficient NADPH produced in red blood
cells to maintain the ratio of reduced
glutathione to oxidized glutathione at its normal
value of well over 100. Hence, peroxides destroy
the red cell membrane because of the limited
protective mechanism in these cells.