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BIOC 460 - DR. TISCHLER
LECTURE 30
PENTOSE PATHWAY
&
ANTIOXIDANTS
OBJECTIVES
1. Pentose-phosphate pathway:
a) oxidative and non-oxidative branches
b) cofactor with each branch
c) how oxidative branch is regulated
d) three modes of the pentose phosphate pathway in
terms of roles of the potential endproducts of each
mode.
2.
Antioxidant functions:
a) major active oxygen species; rank according to
relative reactivity
b) enzymes that remove peroxides and superoxide
radicals from a cell and name their cofactor.
c) why a defect of glucose-6-phosphate
dehydrogenase in the red blood cell might lead to
loss of membrane integrity.
d) relationships between components of antioxidant
cascade including the reactions involved
Functions of Pentose Phosphate Pathway
1) 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
Glucose-6-P-DH
NADP NADPH
Glucose 6-P
6-Phosphogluconate
NADP
6-Pgluconate DH
NADPH
glycolytic
Ribulose 5-P CO2
intermediates
Glyceraldehyde 3-P
Xylulose 5-P
Transketolase
Glyceraldehyde 3-P
Erythrose 4-P
Nucleic
acids
Ribose 5-P
TPP
Transketolase
Sedoheptulose-7-P
Transaldolase
Fructose 6-P
Oxidative
Branch
Fructose 6-P
Figure 1. The pentose phosphate pathway
containing an oxidative and a non-oxidative branch
Nonoxidative
Branch
Glyceraldehyde 3-P
Fructose 6-P
Transketolase
Ribulose 5-P
Nucleic acids
Ribose 5-P
Xylulose 5-P
Transketolase
Glyceraldehyde 3-P
Erythrose 4-P
Sedoheptulose 7-P
Transaldolase
Fructose 6-P
Nonoxidative
Branch
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).
NADP
Glucose 6-P
NADPH
6-Phosphogluconate
NADP
Ribulose 5-P
CO
Oxidative
Branch
NADPH
2
Ribose 5-P
Nucleic
acids
Figure 3. Using the oxidative branch of the pentose pathway
to produce NADPH for biosynthetic reactions and ribose-5phosphate for producing nucleic acids (Mode 2).
NADPH
NADP
6-Phosphogluconate
NADP
Glucose 6-P
(3)
Ribulose 5-P (3)
NADPH
CO2
Oxidative
Branch
Glyceraldehyde 3-P (1)
Xylulose 5-P (2)
back to
glucose-6-P
or to glycolysis
Glyceraldehyde 3-P
(1)
Ribose 5-P (1)
Sedoheptulose 7-P
(1)
Erythrose 4-P (1)
Fructose 6-P (1)
Nonoxidative
Branch
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)
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
Carl Wernicke
Sergei Korsakoff
Patient with
beriberi
Table 1. ACTIVE OXYGEN SPECIES
Reactivity
AO Species
Least
singlet oxygen
superoxide radical anion (O2-)
Moderate
hydrogen peroxide (HOOH)
lipid peroxyl radical (LOO)
Most
hydroxyl radical (OH)
H2O2
2 GSH
glutathione
peroxidase
glutathione
reductase
NADP+
2 H2 O
GSSG
NADPH + H+
pentose pathway
Figure 5. Reactions of glutathione reduction and oxidation
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)
lipid peroxyl radical
LOO
LOOH
Vit Ered
VIT Eox
VIT Cox
Glutathionered
(GSH)
Vit Cred
+ROOH
NADP+
Glucose-6-P
Figure 6. Antioxidant cascade
Reduced forms/reduction
Oxidized forms/oxidation
hydroxyl radical (OH)
superoxide radical (O2-)
reduced
products
Glutathioneox
(GSSG)
H 2 O2
2H2O
NADPH + H+
Pentose phosphate pathway
Ribulose-5-P