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Thionein Can Serve As a Reducing Agent for the Methionine Sulfoxide Reductases

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Thionein Can Serve As a Reducing Agent for the Methionine Sulfoxide Reductases Thionein can serve as a reducing agent for the methionine sulfoxide reductases Daphna Sagher*†, David Brunell*†, J. Fielding Hejtmancik‡, Marc Kantorow*, Nathan Brot§, and Herbert Weissbach*¶ *Center for Molecular Biology and Biotechnology, Florida Atlantic University, Boca Raton, FL 33431; ‡Ophthalmic Genetic and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; and §Department of Microbiology and Immunology, Hospital for Special Surgery, Cornell University Medical Center, New York, NY 10021 Contributed by Herbert Weissbach, April 7, 2006 It has been generally accepted, primarily from studies on methio- not been reported. Most in vitro studies have used DTT as the nine sulfoxide reductase (Msr) A, that the biological reducing agent reducing agent for both MsrA and MsrB, because this agent for the members of the Msr family is reduced thioredoxin (Trx), works very well with the Msr family of proteins. although high levels of DTT can be used as the reductant in vitro. Recently, the human MsrB genes have been of interest to us as Preliminary experiments using both human recombinant MsrB2 part of our studies on the role of the Msr system in protecting lens (hMsrB2) and MsrB3 (hMsrB3) showed that although DTT can and retinal cells against oxidative damage (18–20). Using a color- function in vitro as the reducing agent, Trx works very poorly, imetric assay for Msr activity, based on the reduction of the prompting a more careful comparison of the ability of DTT and Trx individual epimers of 4-N,N-dimethylaminoazobenzene-4-sulfonyl to function as reducing agents with the various members of the (DABS)-Met(o), we were surprised to find that Trx serves very Msr family. Escherichia coli MsrA and MsrB and bovine MsrA poorly as the reducing system for human recombinant MsrB2 efficiently use either Trx or DTT as reducing agents. In contrast, (hMsrB2) and MsrB3 (hMsrB3). This result prompted us to exam- hMsrB2 and hMsrB3 show <10% of the activity with Trx as ine in more detail the reducing requirement for different members compared with DTT, raising the possibility that, in animal cells, Trx of the Msr family and to search for a reducing system in mammalian may not be the direct hydrogen donor or that there may be a cells that could function in place of Trx. A heat-stable factor in Trx-independent reducing system required for MsrB2 and MsrB3 bovine liver was detected that, in the presence of EDTA, could activity. A heat-stable protein has been detected in bovine liver serve as the reducing system for several of the Msr proteins. This that, in the presence of EDTA, can support the Msr reaction in the factor was purified and identified as a zinc-containing metal- absence of either Trx or DTT. This protein has been identified as a lothionein (Zn-MT). The results indicate that loss of zinc from zinc-containing metallothionein (Zn-MT). The results indicate that Zn-MT after treatment with EDTA yields cysteine-rich thionein thionein (T), which is formed when the zinc is removed from Zn-MT, (T), which can provide the reducing power for the Msr enzymes. can function as a reducing system for the Msr proteins because of The possible significance of this finding relative to the redox state its high content of cysteine residues and that Trx can reduce of the cell, oxidative damage, and the role of the Msr system will be oxidized T. discussed. metallothioneins ͉ reducing systems Results Reduced Trx Is Not an Efficient Reducing Agent for hMsrB2 and he methionine sulfoxide reductases (Msrs) are a family of hMsrB3. In the course of developing the DABS colorimetric assay Tproteins that reduce methionine sulfoxide [Met(o)] to me- for Msr activity (see Materials and Methods), it was confirmed thionine (Met) (1). The oxidation of Met to Met(o) results in the that eMsrA and eMsrB could use either DTT or Trx to supply formation of two epimers of Met(o), called Met-S-(o) and the reducing power, with similar or more activity observed with Met-R-(o). In Escherichia coli, there are at least six members of Trx in vitro. However, although both hMsrB2 and hMsrB3 could this family that differ in their substrate specificity and location use DTT as the reducing agent, these proteins showed very little within the bacterial cell (2, 3). The protein that was first isolated activity with Trx. Table 1 compares the activity of several and studied in greatest detail was E. coli MsrA (eMsrA) (4–8), recombinant Msr proteins using either DTT or Trx. It can be which specifically reduces Met-S-(o), whether in peptide linkage seen that eMsrA, bovine MsrA (bMsrA), and eMsrB are active or as a free amino acid (8, 9). MsrB proteins specifically reduce with either DTT or Trx as the reducing system. In fact, eMsrB the Met-R-(o) in proteins but have very weak activity with free was much more active with Trx than with DTT. In contrast, Met-R-(o) (10, 11). In addition, in E. coli, there are specific Msr hMsrB2 and hMsrB3 work very poorly with Trx, having Ͻ10% reductases that reduce free Met-S-(o) and Met-R-(o) (2) as well of the activity seen with DTT. One possibility was that the as membrane-associated activities that can reduce both epimers hMsrB proteins specifically required mammalian Trx and not the of Met(o), whether free or peptide-linked (3). bacterial Trx that was used in these experiments. We therefore The situation in animal cells is somewhat different. It appears tested hMsrB3, as well as eMsrA and eMsrB, with mammalian that there is one gene that codes for MsrA (12, 13) but three Trx and mammalian Trx reductase. Reduced mammalian Trx, separate genes that code for MsrB proteins (14–16). MsrA like the bacterial Trx, gave very poor activity with hMsrB3, but localizes primarily in the mitochondria or cytoplasm (12, 13), whereas the three MsrB proteins have different subcellular localizations (16). MsrB1 (originally called Sel-x) is a seleno- Conflict of interest statement: No conflicts declared. protein that is primarily found in the cytoplasm and nucleus, Abbreviations: Met(o), Met sulfoxide; Msr, Met sulfoxide reductase; Trx, thioredoxin; hMsr, MsrB2 (originally called CBS-1) is present mainly in the mito- human recombinant Msr; eMsr, Escherichia coli Msr; bMsr, bovine Msr; MT, metal- lothionein; Zn-MT, zinc-containing MT; DABS, 4-N,N-dimethylaminoazobenzene-4-sulfo- chondria, and MsrB3 is localized primarily in the endoplasmic nyl; PAR, 4-(2-pyridylazo)resorcinol; T, thionein; T(o), oxidized T. reticulum and mitochondria. The biological reducing system for †D.S. and D.B. contributed equally to this work. MsrA appears to be reduced thioredoxin (Trx) (4, 17), and Trx ¶To whom correspondence should be addressed at: Center for Molecular Biology and has also been assumed to be the biological reductant for the Biotechnology, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431. E-mail: MsrB proteins. However, detailed studies comparing the reduc- [email protected]. ing system requirement for the MsrA and MsrB proteins have © 2006 by The National Academy of Sciences of the USA 8656–8661 ͉ PNAS ͉ June 6, 2006 ͉ vol. 103 ͉ no. 23 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0602826103 Downloaded by guest on September 30, 2021 Table 1. Trx and DTT as reducing agents with various Msr proteins DABS-Met, nmol Msr proteins Trx DTT Trx͞DTT ratio eMsrA 46.8 46.2 1.0 eMsrB 60.3 11.1 5.4 bMsrA 15.8 30.0 0.53 hMsrB2 0.8 31.3 0.03 hMsrB3 1.7 53.8 0.03 DABS-Met-S-(o) was used as substrate with MsrA proteins, and DABS-Met- R-(o) was used as a substrate with MsrB proteins. The incubation conditions and assay are described in Materials and Methods. The amounts of Msr protein used were as follows: eMsrA, 1.6 ␮g; eMsrB, 2.7 ␮g; bMsrA, 2 ␮g; hMsrB2, 2.7 ␮g; hMsrB3, 2.3 ␮g. both eMsrA and eMsrB efficiently used Trx from either source (data not shown). It should be noted that we were not able to test mammalian MsrB1, which differs from MsrB2 and MsrB3 in being a selenoprotein, because all attempts to obtain sufficient amounts of this recombinant protein were unsuccessful. The weak activity of hMsrB2 and hMsrB3 with Trx suggested that there may be another reducing system for these proteins in mammalian cells that either functions in place of Trx or is an intermediate hydrogen carrier between Trx and the human MsrB BIOCHEMISTRY proteins. Zn-MT in the Presence of EDTA Can Serve as a Reducing Agent for Msr. In our attempts to search for a biological factor that was more Fig. 2. Purification and properties of the active factor. (A) Elution profile efficient than Trx in supplying the reducing system for hMsrB2 from a DE-52 column of the factor showing Msr activity and zinc content. Two and hMsrB3, we initially tested an S-100 from bovine liver. Using peaks of reducing activity with hMsrB3 could be separated, and they are hMsrB3, we were able to detect significant reducing activity in labeled MT-1 and MT-2. Activity (F) is expressed as total nanomoles of the liver S-100 fraction, but only in the presence of EDTA. The DABS-Met formed per 1-ml fraction in the Msr reaction using hMsrB3. Zinc concentration (␮M) also is shown (E). (B) Spectra of purified factor at pH 7.4 active material was stable to heating at 80°C for 10 min. Fig. 1 (solid line) and pH 2.0 (dashed line). An extinction coefficient of ␧220 ϭ 48,600 shows the effect of protein concentration of the heated S-100 MϪ1⅐cmϪ1 at pH 2.0 was used to calculate the amount of MT in the fractions.
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