Short Communications Genetic mapping of six mouse peroxiredoxin genes and fourteen peroxiredoxin related sequences Myung S. Lyu, 1, * Sue Goo Rhee, 2 Ho Zoon Chae, 2, ** Tae Hoon Lee, 2, † M. Charlene Adamson, 1 Sang Won Kang, 2 Dong-Yan Jin, 1, ‡ Kuan-Teh Jeang, 1 Christine A. Kozak 1 1 Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Building 4, Room 329, 4 Center Drive MSC 0460, Bethesda, MD 20892-0460, USA 2 Laboratory of Cell Signaling, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA Received: 5 March 1999 / Accepted: 8 June 1999 Organisms living in aerobic environments require mechanisms that prevent or limit cellular damage caused by reactive oxygen species (O 2 - ,H 2 O 2 , and HO) that arise from the incomplete reduction of oxygen during respiration. Alternatively, damage can result from exposure to external agents such as light, radiation, redox-cycling drugs, or stimulated host phagocytes (Sies 1993; Halliwell and Gutteridge, 1989). The reactive oxygen species cause damage to all major classes of biological macromolecules leading to protein oxidation, lipid peroxidation, and DNA base modifications and strand breaks. To guard against these destructive processes, organ- isms have developed a battery of antioxidant defenses (Halliwell and Gutteridge 1989; Amstad et al. 1991). The preventive antioxi- dant systems include enzymes that decompose peroxides and su- peroxide anion and compounds that sequester metal ions. These types of antioxidants reduce or eliminate the generation of free radicals. Chain-breaking antioxidants, such as ascorbate and -to- copherol, scavenge transient free radicals and inhibit the attack of these reactive species on biological targets. We have previously purified a 25-kDa enzyme from yeast that prevents damage induced by the thiol oxidation system but not by the ascorbate oxidation system, despite the fact that the degree of oxidative stress is similar for the two systems as judged by the comparable extent of induced inactivation of glutamine synthetase (Kim et al. 1988). Thus, we originally named this protein thiol- specific antioxidant (TSA). Although the exact nature of the oxi- dant eliminated by TSA was not known at that time, the impor- tance of TSA as an antioxidant was readily apparent as the appli- cation of oxidative pressure to yeast resulted in an increase in the synthesis of TSA, and TSA protein constituted 0.7% of total soluble protein from yeast grown aerobically (Kim et al. 1989). Yeast TSA gene was cloned and sequenced (Chae et al. 1993). It shows no significant homology to any known catalase, superoxide dismutase, or peroxidase enzymes. This lack of homology is con- sistent with the observation that TSA does not possess catalytic activity characteristic of conventional antioxidant enzymes. A yeast mutant that cannot produce TSA was constructed by homolo- gous recombination (Chae et al. 1993). The mutant and wild-type strains grew at equal rates under anaerobic conditions. However, under aerobic conditions, especially under oxidative stress, the growth rate of mutant yeast was significantly lower than that of wild-type yeast. A database search revealed a number of proteins from a variety organisms that show similarity to TSA (Chae et al. 1994b). These homologous proteins have now been named the peroxiredoxin (PRDX) family. We recently demonstrated that the antioxidant activity of TSA is attributable to its ability to reduce H 2 O 2 . The apparent specific requirement for a thiol for antioxidant function was due to the fact that an intermolecular disulfide linkage of oxidized TSA can be reduced by a thiol but not by ascorbate. We have shown that thioredoxin (TRX) is the physiological electron donor for the reduction of TSA (Chae et al. 1994a). TSA was thus the first peroxidase to be identified for which TRX is the imme- diate electron donor, and it was therefore renamed TRX peroxidase (TPX). Despite this finding, the TSA homologs (the PRDX gene family) were not termed the TPX family because not all members use TRX as the hydrogen donor. For example, enteric bacteria homolog AhpC and trypanosomatid homolog C22 receive electron from AhpF and C30 proteins, respectively, for the reduction of H 2 O 2 (Jacobson et al. 1989; Montemartini et al. 1998). Further- more, mammalian PRDX-V is capable of reducing H 2 O 2 in the presence of dithiothreitol but not in the presence of TPX (Kang et al. 1998). The complete amino acid sequences of 15 mammalian mem- bers of the PRDX family have been determined: six (PAG, NKEFA, NKEFB, TSA, MER5, and AOE372) from human, six (MSP23, OSF3, TSA, MER5, AOP1, and AOP2) from mouse, two (TSA and HBP23) from rat, and one (SP22) from cow. With the exception of TSA, all mammalian PRDX proteins were initially characterized without reference to antioxidant function (Chae et al., 1994c; Prosperi et al. 1993; Shau et al. 1994; Yamamoto et al. 1989; Jin et al. 1997). Among the six reported human PRDX sequences, there are four distinct human PRDX proteins: PAG/ NKEFA, TSA/NKEFB, MER5, and AOE372. Similarly, the six reported mouse sequences actually correspond to four distinct pro- teins: MSP23/OSF3, TSA, MER5/AOP1, and AOP2. The four human PRDX proteins show only 60–80% sequence identity to each other, but all except AOE372 share >90% identity with a corresponding mouse homolog. Each of the two rat proteins (HBP23 and TSA) and bovine SP22 show >92% sequence identity to one of the human or mouse proteins. Therefore, the mammalian PRDX proteins can be grouped into one of five types: PRDX-I, represented by PAGA; PRDX-II, represented by TSA; PRDX-III, represented by MER5; PRDX-IV, represented by AOE372; and * Present address: Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ** Present address: Department of Microbiology, College of Natural Sci- ences, Chonnam National University, Kwangji 500-757, Korea. † Present address: Korea Research Institute of Bioscience and Biotech- nology, Daejeon 305-333, Korea. ‡ Present address: Institute of Molecular Biology, University of Hong Kong, Hong Kong. Correspondence to: C.A. Kozak © Springer-Verlag New York Inc. 1999 Mammalian Genome 10, 1017–1019 (1999). Incorporating Mouse Genome