Thiol Oxidase Activity of Copper,Zinc Superoxide Dismutase

Winterbourn, Christine C.; Peskin, Alexander V.; Parsons-Mair, Helena N.

doi:10.1074/jbc.m107256200

Cited by 94 publications

(57 citation statements)

References 45 publications

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“…Under conditions of oxidative stress, the level of SOD released by astrocytes is increased, thereby enhancing GSH stability and optimizing GSH available in the extracellular environment. Recently CuZn SOD has been reported to display thiol oxidase activity (Winterbourn et al 2002). However, under the conditions employed in our study CuZn SOD does not appear to be enhancing GSH oxidation.…”

Section: Figcontrasting

confidence: 51%

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Preservation of extracellular glutathione by an astrocyte derived factor with properties comparable to extracellular superoxide dismutase

Stewart¹,

Stone²,

Gegg³

et al. 2002

Journal of Neurochemistry

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Cultured rat and human astrocytes and rat neurones were shown to release reduced glutathione (GSH). In addition, GSH oxidation was retarded by the concomitant release of a factor from the cells. One possibility is that this factor is extracellular superoxide dismutase (SOD). In support of this, the factor was found to bind heparin, have a molecular mass estimated to be between 50 and 100 kDa, and CuZn-type SOD protein and cyanide sensitive enzyme activity were demonstrated in the cell-conditioned medium. In addition, supplementation of native medium with exogenous CuZn-type SOD suppressed GSH oxidation. We propose that preservation of released GSH is essential to allow for maximal up-regulation of GSH metabolism in neurones. Furthermore, cytokine stimulation of astrocytes increased release of the extracellular SOD, and enhanced stability of GSH. This may be a protective strategy occurring in vivo under conditions of oxidative stress, and suggests that SOD mimetics may be of therapeutic use.

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Section: Figcontrasting

confidence: 51%

“…However, under the conditions employed in our study CuZn SOD does not appear to be enhancing GSH oxidation. In support of this finding, it should be noted that whilst CuZn SOD displays high oxidase activity for cysteine and cysteamine the rate is much lower with GSH (Winterbourn et al 2002).…”

Section: Figmentioning

confidence: 48%

Preservation of extracellular glutathione by an astrocyte derived factor with properties comparable to extracellular superoxide dismutase

Stewart¹,

Stone²,

Gegg³

et al. 2002

Journal of Neurochemistry

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“…The mechanism of copper catalyzed thiol autoxidation is complex when studied for a single thiol (19). It is even more complex in cells where copper proteins are likely involved (33) and especially for the M. smegmatis mshD::Tn5 mutant with its complex mixture of thiols. But from the present results (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Mycothiol Synthase Mutant of Mycobacterium smegmatis Produces Novel Thiols and Has an Altered Thiol Redox Status

Newton

Fahey

2005

J Bacteriol

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Mycobacteria and other actinomycetes do not produce glutathione but make mycothiol (MSH; AcCys-GlcNIns) that has functions similar to those of glutathione and is essential for growth of Mycobacterium tuberculosis. Mycothiol synthase (MshD) catalyzes N acetylation of Cys-GlcN-Ins to produce MSH in Mycobacterium smegmatis mc 2 155, and Cys-GlcN-Ins is maintained at a low level. The mycothiol synthase mutant, the mshD::Tn5 mutant, produces high levels of Cys-GlcN-Ins along with two novel thiols, N-formyl-Cys-GlcN-Ins and N-succinyl-Cys-GlcN-Ins, and a small amount of MSH. The nonenzymatic reaction of acyl-coenzyme A (CoA) with Cys-GlcN-Ins to produce acyl-Cys-GlcN-Ins is a facile reaction under physiologic conditions, with succinyl-CoA being an order of magnitude more reactive than acetyl-CoA. The uncatalyzed reaction rates are adequate to account for the observed production of N-succinyl-Cys-GlcN-Ins and MSH under physiologic conditions. It was shown that the N-acyl-Cys-GlcN-Ins compounds are maintained in a substantially reduced state in the mutant but that Cys-GlcN-Ins exists in disulfide forms at 5 to 40% at different stages of growth. MSH was able to facilitate reduction of N-succinyl-Cys-GlcN-Ins disulfide through thiol-disulfide exchange, but N-formyl-Cys-GlcN-Ins was ineffective. The oxidized state of Cys-GlcN-Ins in cells appears to result from a high susceptibility to autoxidation and a low capacity of the cell to reduce its disulfide forms. The mutant exhibited no enhanced sensitivity to hydrogen peroxide, tert-butyl hydroperoxide, or cumene hydroperoxide relative to the parent strain, suggesting that the most abundant thiol, N-formyl-Cys-GlcN-Ins, functions as a substitute for MSH.Mycothiol (MSH; AcCys-GlcN-Ins) ( Fig. 1) is the principal thiol in mycobacteria and in most other actinomycetes (12). Mycobacterium smegmatis has proven to be a useful organism for studying the biosynthesis of MSH because it does not require MSH for growth and mutants in MSH biosynthesis are readily isolated and studied (10,14). Previous studies of such mutants have demonstrated that MSH plays an important role in protecting against various toxins, including peroxides, alkylating agents, and certain antibiotics (4,16,21). However, MSH is essential for the growth of Mycobacterium tuberculosis (23), and the enzymes involved in MSH biosynthesis are therefore of potential interest as targets for drugs to treat tuberculosis.The final step of MSH biosynthesis is catalyzed by mycothiol synthase (MshD; Rv0486 in M. tuberculosis) (10) and involves the acetylation of Cys-GlcN-Ins by acetyl-coenzyme A (CoA) (Fig. 1) (3). MshD is a member of the GNAT (for Gcn5-related N-acetyltransferase) family of acetyltransferases (31), and the crystal structure of the M. tuberculosis protein has been determined (32). The mshD gene was identified by transposon mutagenesis of M. smegmatis to produce the mutant mshD::Tn5 (10). In our initial study, we found that the mshD::Tn5 mutant makes only ϳ1% of the normal amount of MSH and accumulates high levels ...

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“…In addition, Cu,Zn-SOD has the potential to act as an oxidase that converts thiols in the assay mixture to disulfide and H 2 O 2 . 60,61 Together the thiol-and H 2 S-oxidase properties 58,60 of Cu,Zn-SOD could explain the increases in strand cleavage observed upon addition of SOD to the assays described here.…”

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confidence: 90%

Possible chemical mechanisms underlying the antitumor activity of S-deoxyleinamycin

Sivaramakrishnan

Gates

2008

Bioorganic & Medicinal Chemistry Letters

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Though less potent than the parent natural product leinamycin, S-deoxyleinamycin displays activity against human cancer cell lines that is comparable to many clinically-used agents. The results reported here suggest that the 1,2-dithiolan-3-one heterocycle found in S-deoxyleinamycin reacts with thiols to generate a persulfide intermediate (RSS − ) that could deliver biologically active polysulfides, hydrogen sulfide, and reactive oxygen species (O 2 • − , H 2 O 2 , and HO•) to the interior of cells.Leinamycin (1) is a structurally interesting natural product that displays impressive, nanomolar IC 50 -values against human cancer cell lines. 1-5 Reaction of thiols with leinamycin leads to ejection of a persulfide intermediate (2) that generates cell-killing reactive oxygen species (Scheme 1). [6][7][8][9] In addition, the 1,2-oxathiolan-5-one derivative (3) formed in this reaction undergoes further rearrangement to an episulfonium ion (4) that efficiently alkylates guanine residues in duplex DNA. 6,10 The resulting 7-alkylguanine residues undergo rapid depurination to generate a burst of cytotoxic abasic sites in duplex DNA. [11][12][13] The reaction with thiols may be central to the potent biological activity of leinamycin because cells contain millimolar concentrations of the thiol-containing tripeptide glutathione 14 that can trigger the release of cell killing reactive intermediates from this natural product.In light of the central role played by leinamycin's sulfoxide oxygen in the generation of cytotoxic reactive intermediates (Scheme 1), it is not surprising that S-deoxyleinamycin (5) is markedly less cytotoxic than leinamycin. For example, 5 displays an IC 50 value of 4 μM against HeLa S3 cells, whereas that for leinamycin is 27 nM. 3 Despite its diminished cytotoxicity relative to leinamycin, it is important to note that the activity of 5 is comparable to some clinically-used anticancer drugs. 15 Accordingly, studies of 5 have the potential to reveal new chemical processes by which organic molecules can elicit anticancer activity.Previous work has shown that 5 does not cause thiol-triggered DNA alkylation; 3 however, our previous experience with related sulfur heterocycles [16][17][18][19] led us to consider the possibility that reactions of thiols with the 1,2-dithiolan-3-one heterocycle in 5 might lead to the generation of superoxide radical (O 2 • − ). Under physiological conditions, superoxide radical decomposes to hydrogen peroxide and, ultimately, hydroxyl radical as shown in the (unbalanced) Eqns 4 -5, where M represents a transition metal such as iron or copper. 20 Intracellular production of *Corresponding author. Tel.: +1-573-882-6763; fax: +1-573-882-2754, e-mail gatesk@missouri.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in ...

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Thiol Oxidase Activity of Copper,Zinc Superoxide Dismutase

Cited by 94 publications

References 45 publications

Preservation of extracellular glutathione by an astrocyte derived factor with properties comparable to extracellular superoxide dismutase

Preservation of extracellular glutathione by an astrocyte derived factor with properties comparable to extracellular superoxide dismutase

A Mycothiol Synthase Mutant of Mycobacterium smegmatis Produces Novel Thiols and Has an Altered Thiol Redox Status

Possible chemical mechanisms underlying the antitumor activity of S-deoxyleinamycin

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