CHEM 445 / BIOL 445
Biochemistry II

J. D. Cronk
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15. header

Lecture 15. Glutathione and glucose 6-phosphate dehydrogenase deficiency

Friday 23 February 2007

Modes of the pentose phosphate pathway. Glutathione - a cellular redox buffer. Effects of glucose 6-phosphate dehydrogenase deficiency. ROS - Reactive Oxygen Species.

Reading: BTS6, Ch.20, p.583-589.

  
15. Summary

Lecture 15 Summary

Modes of the PPP: (Discussed on pp.583-585 of Ref.1.)

Fates of NADPH produced by the oxidative branch of the pentose phosphate pathway. Effects of glucose 6-phosphate dehydrogenase deficiency. Relationship to oxidative stress. Favism, or Why Pythagoras wouldn't eat falafel.

Glutathione - a cellular redox buffer

Glutathione (g-Glu-Cys-Gly) is an iso-tripeptide. Its reduced form - the sulfhydryl form shown in the figure below - undergoes oxidation to form a disulfide-linked pair of glutathione molecules. The equation for this reaction is 2GSH = GSSG + 2e- + 2H+., where GSH represents reduced glutathione, and GSSG is oxidized glutathione.
Structural formula for glutathione  

A sufficient pool of reduced glutathione is necessary to help cells cope with oxidative stress. For example, GSH reacts with peroxides, which might otherwise lead to oxidative damage. When glutathione is oxidized, the reducing power of NADPH is used to regenerate GSH. The enzyme that catalyzes the reaction is glutathione reductase [EC 1.8.1.7], a flavin-containing protein.

Oxidative stress, discussed further below, has a significant impact on cellular survivability and is a major factor in theories of aging. Erythrocytes (red blood cells) in particular experience oxidative stress due to their periodic high oxygen content. Reduced glutathione is normally kept at a relatively high concentration vs. the oxidized form. The reduced glutathione is a substrate in glutathione peroxidase enzymes [EC 1.11.1.9 and EC 1.11.1.12] that catalyze reduction of hydrogen peroxide or organic peroxides to water or alcohols, respectively. Glutathione peroxidase is unusual in being a selenium-containing enzyme. Selenium, from industrial sources, is normally considered a toxin, but it is necessary in small amounts. Even more intriguingly, a selenocysteine residue is incorporated in glutathione peroxidase via the alternate translation of its mRNA at a UGA stop codon. The signal for this "recoding" resides on another part of the mRNA for glutathione peroxidase, in its 3'- untranslated region (3'-UTR, downstream from the open reading frame) and is not fully efficient.

Effects of glucose 6-phosphate dehydrogenase deficiency

Because of the role of the oxidative branch of the pentose phosphate pathway, disruption of enzymes in this pathway compromise cellular resistance to oxidative stress. Genetic defects in glucose 6-phosphate dehydrogenase [G6PDH, EC 1.1.1.49] leads to sensitivity of affected cells to oxidative stress. This is especially acute in erythrocytes (red blood cells) since these cells lack mitochondria, and the G6PDH reaction is their only source of NADPH. In humans and a number of other species, the gene for this enzyme is located on the X chromosome and shows considerable polymorphism. Lack of G6PDH activity results in hemolytic anemia. Reduced levels of G6PDH activity often shows up as drug-induced hemolytic anemia and favism. The relatively high frequency of genetic variants of G6PDH among populations where malaria is endemic is thought to be linked to resistance to Plasmodium falciparum arising from low levels of reduced glutathione (GSH) and other products of the pentose phosphate pathway.

ROS Primer

The chemical meaning of "oxidative stress" is primarily tied to the generation of reactive oxygen species (ROS). See Lecture 5 for a description of ROS.

Study questions

  • Describe the different "modes" of the PPP and the circumstances under which each predominates.
  • Explain the importance of NADPH in protecting cells from oxidative stress
  • Explain the persistence of G6PDH deficiency in populations exposed to malaria.

Page updated 12-27-06

References

  1. Berg, Tymoczko, and Stryer. Biochemistry (BTS): 6th edition (2007, Freeman) Ch.20 (pp.583-589).
  2. Nelson DL, Cox MM. Lehninger Principles of Biochemistry: 4th edition (2005) see pp.549-554
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