Enzymatic reduction of oxidized alpha-1-proteinase inhibitor restores biological activity.

Abrams, William R.; Weinbaum, George; Weissbach, Lawrence; Weissbach, Herbert; Brot, Nathan

doi:10.1073/pnas.78.12.7483

Cited by 93 publications

(52 citation statements)

References 22 publications

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“…This result was expected from the MsrA DNA sequence that indicates four cysteines at positions 51, 86, 198, and 206. 2 Under native conditions, all four cysteines were also reactive.…”

Section: Biochemical and Enzymatic Properties Of Wild-type And Mutantmentioning

confidence: 99%

“…For instance, this likely is the case for the ␣-proteinase inhibitor whose oxidation of a methionine residue decreases its affinity relative to its protease target (2) and also for calmodulin whose methionine oxidation leads to a decrease in the efficiency of activation of plasma membrane (3). On the other hand the fact that methionine modifications can be also restricted to only surface-exposed residues was interpreted as a way to protect cells against the action of reactive oxygen species (4).…”

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confidence: 99%

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A Sulfenic Acid Enzyme Intermediate Is Involved in the Catalytic Mechanism of Peptide Methionine Sulfoxide Reductase fromEscherichia coli

Boschi‐Muller¹,

Azza²,

Cianférani³

et al. 2000

Journal of Biological Chemistry

182

161

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Methionine oxidation into methionine sulfoxide is known to be involved in many pathologies and to exert regulatory effects on proteins. This oxidation can be reversed by a ubiquitous monomeric enzyme, the peptide methionine sulfoxide reductase (MsrA), whose activity in vivo requires the thioredoxin-regenerating system. Aerobic metabolism produces a great number of activated oxygen species. These species can react with various targets including proteins. In particular, methionine residues can be oxidized into methionine sulfoxide (MetSO).1 Such modifications can alter the biological properties of the targeted proteins (1). For instance, this likely is the case for the ␣-proteinase inhibitor whose oxidation of a methionine residue decreases its affinity relative to its protease target (2) and also for calmodulin whose methionine oxidation leads to a decrease in the efficiency of activation of plasma membrane (3). On the other hand the fact that methionine modifications can be also restricted to only surface-exposed residues was interpreted as a way to protect cells against the action of reactive oxygen species (4). In vivo a ubiquitous enzyme named peptide methionine sulfoxide reductase (MsrA) exists, which reduces both free and protein bound MetSO (5, 6). The fact that the null mutants of both Escherichia coli and yeast showed increased sensitivity against oxidative damage and that overexpression of MsrA gave higher resistance to hydrogen treatment supports an essential role of MsrA in cell viability (7,8). Thus the important biological role attributed to MsrA in vivo justifies a study of the chemical mechanism of the reduction of MetSO by MsrA. The fact that MsrA activity necessitates a thioredoxin recycling system (9 -11) suggested a cysteine residue in the chemical catalysis. Recently, two groups have shown that mutating the invariant cysteine located in the conserved signature Gly-CysPhe-Trp resulted in total loss of enzyme activity (12, 13). Moreover Lowther et al. (13) presented convincing evidence of involvement of intra-thiol-disulfide exchanges in the catalytic mechanism. Based on their data they formulated a reaction mechanism requiring formation of a covalent tetracoordinate intermediate via a nucleophilic attack by the thiolate of the essential cysteine followed by breakdown of the intermediate by means of two thiol-disulfide exchanges, which leads to release of a methionine and a water molecule. In this mechanism, methionine release only occurs if the disulfide exchange is operative. In the present study we show that in fact the nucleophilic attack of the essential cysteine on MetSO leads to formation of a sulfenic acid enzyme intermediate with a concomitant release of methionine. Return of the active site to a reduced state is achieved in vivo via intra-disulfide exchange reactions involving two other cysteines and then by a thioredoxindependent recycling process. EXPERIMENTAL PROCEDURESSite-directed Mutagenesis, Production, and Purification of Wild Type and Mutant E. coli MsrAs-The E. coli strain ...

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“…This result was expected from the MsrA DNA sequence that indicates four cysteines at positions 51, 86, 198, and 206. 2 Under native conditions, all four cysteines were also reactive.…”

Section: Biochemical and Enzymatic Properties Of Wild-type And Mutantmentioning

confidence: 99%

mentioning

confidence: 99%

A Sulfenic Acid Enzyme Intermediate Is Involved in the Catalytic Mechanism of Peptide Methionine Sulfoxide Reductase fromEscherichia coli

Boschi‐Muller¹,

Azza²,

Cianférani³

et al. 2000

Journal of Biological Chemistry

182

161

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“…Repair of oxidized methionine has been shown to protect against oxidative stress in a number of cells, oxidation of methionine may lead to significant changes in protein structure and functions. Eight targets for MsrA have been reported including ribosomal protein L12 , α-1-proteinase inhibitor (Abrams et al, 1981), calmodulin (Sun et al, 1999), Ffh protein in E.coli (Ezraty et al, 2004), HIV-2 protease (Davies, et al, 2000), shaker potassium channel (Ciorba et al, 1997), Hsp 21 (Gustavssson et al, 2002 and recently α-synuclein (Liu et al, 2008) but it is thought that many more targets exist.…”

Section: The Methionine Sulfoxide Reductase Repair Systemmentioning

confidence: 99%

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Brennan¹,

Kantorow²

2009

Experimental Eye Research

162

141

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Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself (Lin and Beal, 2006). In the anterior segment of the eye, oxidative stress has been linked to lens cataract (Truscott, 2005) and glaucoma (Tezel, 2006) while in the posterior segment of the eye oxidative stress has been associated with macular degeneration (Hollyfield et al., 2008). Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O 2 -) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (˙OH), hydrogen peroxide (H 2 O 2 ) and peroxynitrite (OONO -). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria (Hansford et al., 1997). Generation of superoxide at complex I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane (Kakkar and Singh 2007). While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Figure 1.0). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr)

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“…On the other hand, it is well known that methionine sulfoxide residues in proteins can be readily reduced by peptide methionine sulfoxide reductase (PMSR), an enzyme present in microorganisms and plants [11] and practically all mammalian tissues [12]. PMSR has been shown to reactivate the oxidized inactive derivatives of al-protease inhibitor [13], ribosomal protein L12 [11] and Met-enkephalin [l 1].…”

Section: Introductionmentioning

confidence: 99%

Enzymatic repair of oxidative damage to human apolipoprotein A‐I

Sigalov¹,

Stern

1998

FEBS Letters

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Oxidative damage to apolipoprotein A-I that occurs in vivo commonly involves methionine oxidation, and is accompanied by alterations in structure, lipid association, and cholesterol efflux function. We have used the enzyme peptide methionine sulfoxide reductase (PMSR) to reverse this damage, and shown by a variety of criteria that enzyme treatment restores the primary, secondary, and tertiary structure and lipid association characteristic of the native unoxidized protein.Lipid-associated as well as lipid-free apolipoprotein A-I reacts with PMSR, suggesting that enzymatic reduction of oxidized apolipoprotein A-! in high density lipoproteins can result in restoration of biological activity and the ability to promote cholesterol efflux from cells.

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Enzymatic reduction of oxidized alpha-1-proteinase inhibitor restores biological activity.

Abstract: The major serum inhibitor ofproteolytic activity, a-1-proteinase inhibitor (a-i-PI), (or a-l-antitrypsin) can be read-

Cited by 93 publications

References 22 publications

A Sulfenic Acid Enzyme Intermediate Is Involved in the Catalytic Mechanism of Peptide Methionine Sulfoxide Reductase fromEscherichia coli

A Sulfenic Acid Enzyme Intermediate Is Involved in the Catalytic Mechanism of Peptide Methionine Sulfoxide Reductase fromEscherichia coli

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Enzymatic repair of oxidative damage to human apolipoprotein A‐I

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