Blood, 1 April 2003, Vol. 101, No. 7, pp. 2897-2897
CORRESPONDENCE
To the editor:
The role of erythrocyte peroxiredoxin in detoxifying peroxides
and in stimulating potassium efflux via the Gardos channels
Using mice deficient in glutathione peroxidase, Johnson et al
reported that this enzyme plays an important role within erythrocytes in the detoxification of organic peroxides.1 The authors
extended the discussion to include another family of peroxide
detoxifying enzymes, the peroxiredoxins. Far from being restricted to
micro-organisms, as implied by Johnson et al, peroxiredoxin family
members are widely spread throughout mammalian tissues, including
erythrocytes and macrophages.2,3 Erythrocyte Prx II (also
known as calpromotin, torin, natural killer enhancing factor B,
thiol-specific antioxidant protein, or thioredoxin peroxidase B)
reduces both hydrogen peroxide and organic peroxides, protects the
membrane against lipid peroxidation, and derives its reducing power
from the thioredoxin/thioredoxin reductase/nicotinamide adenine
dinucleotide phosphate system.3 At an estimated
14 million copies per cell, Prx II is one of the most abundant
erythrocyte proteins after hemoglobin.4
In a second mouse model, the Prx II gene has been
deleted.5 These mice showed marked abnormalities, such as
overloading of the spleen with iron and deposition of denatured globin
precipitates within their erythrocytes. These data are consistent with
excessive levels of peroxide, which are known to break down hemoglobin, releasing the iron from the protein in soluble complexes that can react
with peroxides to generate cascades of damaging free radicals.6 Prx II therefore appears to help protect
hemoglobin from free radical damage.
Studies performed with erythrocyte ghosts have demonstrated that Prx II
plays a role in stimulating potassium efflux via the Gardos channels by
interacting with the cytosolic surface of the plasma
membrane.4 Prx II membrane association and Gardos channel activity are markedly up-regulated within sickle dense
cells.7 Sickle dense cells exhibit classic symptoms of
oxidative stress, such as the increased oxidation of membrane thiols
and higher concentrations of the products of lipid
peroxidation.8
Paradoxically for an antioxidant enzyme, a mixture of
structural9 and biochemical studies10
have shown that Prx II itself can fall victim to rising levels of
peroxide through the overoxidation of a catalytic cysteine residue to
cysteine sulphinic acid. This overoxidation event inactivates
the peroxidase activity. The molecular basis by which Prx II stimulates
potassium efflux via the Gardos channels remains to be elucidated.
Ewald Schröder, Thomas Jönsson, and Leslie Poole
Correspondence: Ewald Schröder, Department
of Biochemistry, Wake Forest University School of Medicine,
Winston-Salem, NC 27157; e-mail:
eschrode{at}wfubmc.edu.
References
1.
Johnson RM, Goyette G Jr, Ravindranath Y, Ho YS.
Oxidation of glutathione peroxidase-deficient red cells by organic peroxides [letter].
Blood.
2002;100:1515-1516[Free Full Text].
2.
Schröder E, Willis AC, Ponting CP.
Porcine natural-killer-enhancing factor-B: oligomerisation and identification as a calpain substrate in vitro.
Biochim Biophys Acta.
1998;1383:279-291[CrossRef][Medline]
[Order article via Infotrieve].
3.
Lim YS, Cha MK, Yun CH, Kim HK, Kim K, Kim IH.
Purification and characterization of thiol-specific antioxidant protein from human red blood cell: a new type of antioxidant protein.
Biochem Biophys Res Commun.
1994;199:199-206[CrossRef][Medline]
[Order article via Infotrieve].
4.
Moore RB, Mankad MV, Shriver SK, Mankad VN, Plishker GA.
Reconstitution of Ca(2+)-dependent K+ transport in erythrocyte membrane vesicles requires a cytoplasmic protein.
J Biol Chem.
1991;266:18964-18968[Abstract/Free Full Text].
5.
Yu D-Y, Lee TH, Kim SU, et al.
Peroxiredoxin II induces hemolysis and infertility in mice Proceedings of the 15th international mouse genome conference, Edinburgh, Scotland, United Kingdom, 21-24 October 2001. Oak Ridge, TN: International Mammalian Genome Society; 2001.
6.
Gutteridge JM.
Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides.
FEBS Lett.
1986;201:291-295[CrossRef][Medline]
[Order article via Infotrieve].
7.
Moore RB, Shriver SK, Jenkins LD, Mankad VN, Shah AK, Plishker GA.
Calpromotin, a cytoplasmic protein, is associated with the formation of dense cells in sickle cell anemia.
Am J Hematol.
1997;56:100-106[CrossRef][Medline]
[Order article via Infotrieve].
8.
Joiner CH.
Cation transport and volume regulation in sickle red blood cells.
Am J Physiol.
1993;264:C251-C270[Abstract/Free Full Text].
9.
Schröder E, Littlechild JA, Lebedev AA, Errington N, Vagin AA, Isupov MN.
Crystal structure of decameric 2-Cys peroxiredoxin from human erythrocytes at 1.7 Å resolution.
Structure Fold Des.
2000;8:605-615[Medline]
[Order article via Infotrieve].
10.
Wagner E, Luche S, Penna L, et al.
A method for detection of overoxidation of cysteines: peroxiredoxins are oxidized in vivo at the active-site cysteine during oxidative stress.
Biochem J.
2002;366:777-785[Medline]
[Order article via Infotrieve].
Response:
Red cells have multiple antioxidant defenses
This letter reviews earlier publications on peroxiredoxins
in erythrocytes. The authors remark that Johnson et al (their reference 2) imply that peroxiredoxins occur only in bacteria. This is not quite
correct, since Johnson et al only pointed out that peroxiredoxins were
important players in bacterial metabolism, without commenting on their
possible roles elsewhere. It is reasonable to suppose that
peroxiredoxin protects red cells from free radicals. Thus, peroxiredoxins in red cells are likely to be important, and the final
publication of the work described in the abstract of their reference 7 will be awaited with interest. If it were found that peroxiredoxins
also participate in red cell antioxidant defense, this would not affect
the data of Johnson et al showing that red cells detoxify organic
peroxides with glutathione peroxidase. It is likely that cells will
have more than one antioxidant mechanism.
Robert M. Johnson
Correspondence: Robert M. Johnson, Wayne State
Medical School of Medicine, Department of Biochemistry and Molecular
Biology, 540 E. Canfield, Detroit, MI 48201; e-mail:
rmjohns{at}med.wayne.edu
