Ovothiol Replaces Glutathione Peroxidase as a Hydrogen Peroxide Scavenger in Sea Urchin Eggs

Turner, Eric E.; Hager, Lisa J.; Shapiro, Bennett M.

doi:10.1126/science.3187533

Cited by 99 publications

(83 citation statements)

References 15 publications

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“…It is evident from what is presently known that ovothiol A in the presence of trypanothione and its reductase would constitute an effective trypanothione peroxidase system [25]. In this regard it is of interest that trypanothione peroxidase activity was not detected in extracts of Trypanosoma cruzi [7].…”

Section: Discussionmentioning

confidence: 81%

“…It was subsequently found that 4-mercaptohistidines occur in millimolar concentrations in the eggs of a variety of echinoderms and molluscs [21,231. Ovothiols and related model mercaptohistidines were shown to be several tenfold more efficient than glutathione as free radical scavengers [24] and to react with hydrogen peroxide at five times the rate measured with glutathione [25]. It was therefore proposed that the high concentrations of ovothiols in the eggs of marine invertebrates serve to protect the contents of the oocyte against oxidative damage which could result from the release of hydrogen peroxide in the oxidative burst triggered by fertilization [26].…”

Section: Discussionmentioning

confidence: 99%

“…It was therefore proposed that the high concentrations of ovothiols in the eggs of marine invertebrates serve to protect the contents of the oocyte against oxidative damage which could result from the release of hydrogen peroxide in the oxidative burst triggered by fertilization [26]. It was, for instance, shown that ovothi01s in conjunction with glutathione reductase constitute an effective glutathione peroxidase system [25]. This is of particular interest since a survey of the distribution of glutathione peroxidase suggested that the enzyme appeared relatively late in the evolutionary development of the eukaryotes [27].…”

Section: Discussionmentioning

confidence: 99%

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Identification of a major low‐molecular‐mass thiol of the trypanosomatid Crithidia fasciculata as ovothiol A

Steenkamp

Spies

1994

European Journal of Biochemistry

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An unidentified low-molecular-mass thiol, U23, previously detected as the 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin derivative in extracts of the trypanosome Crithidiu fusciculutu, was purified as the bimane derivative. Resonances attributable to U23 were discerned from those of the bimane label by comparison of the 'H-and IT-NMR spectra of monobromobimane and U23-bimane. The complete 'H-and I3C-NMR spectra of U23-bimane were assigned by means of 'H-'H correlation spectroscopy, 'H-''C correlation spectroscopy and 13C multiplicity determinations. The results indicated identity of U23 with 1-N-methyl-4-mercaptohistidine (ovothiol A), previously isolated from marine sources. This assignment was confirmed by NOE difference experiments, fast-atom-bombardment mass spectrometry of U23-bimane and ultraviolet/visible spectrophotometry of U23, which was isolated as the disulfide. The isolation of ovothiol A from a parasitic protozoan suggest that the 4-mercaptohistidines may have a wider distribution and function as Several antioxidant thi& than was hitherto realized. mechanisms which enable trypanosomes to withstand oxidative killing by phagocytic macrophages seem to be operative. The microbicidal effects of reactive oxygen species released by the macrophages can be evaded by interference with signal transduction processes which trigger the respiratory burst. Such a mechanism probably accounted for the observed reduction in the magnitude of the respiratory burst when neutrophils were incubated with the surface membrane acid phosphatase of Leishmania donovuni [l]. In addition trypanosomes, like other organisms exposed to an aerobic environment, depend on both enzymic and non-enzymic mechanisms for the removal of reactive oxygen species (reviewed in [2] and [3]). However, while they possess superoxide dismutase, trypanosomes are deficient in catalase and various peroxidases, including glutathione peroxidase, which, in mammalian cells, are responsible for the removal of hydrogen peroxide, the product of the superoxide-dismutase-catalysed reaction [4]. Hydrogen peroxide is the immediate precursor of the reactive hydroxyl radical, which can be regarded as the most damaging of the reactive oxygen intermediates [5]. A peroxidase activity dependent on the unique trypanosomal metabolite, trypanothione [2, 51, has been detected [6, 71. The enzyme, however, has not yet been characterized and its activity was estimated to be quite low when compared with glutathione peroxidase in mammalian tissues [3]. The lack of adequate enzymatic mechanisms for the detoxification of hydrogen peroxide is thought to render trypanosomes susceptible to oxidative stress and to form the basis for the anti-trypanosomal activity of several drugs [3].On the other hand, evidence was presented that trypanosomes are able to metabolize exogenously added peroxide [7, 81 and that this process is inhibited by sulfhydryl reagents. Low-molecular-mass thiols, and particularly trypanothione [2, 31, are, therefore, thought to play an important role in ...

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of a major low‐molecular‐mass thiol of the trypanosomatid Crithidia fasciculata as ovothiol A

Steenkamp

Spies

1994

European Journal of Biochemistry

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“…The GSH Px-like activity of ebselen results from two consecutive reactions: the oxidation of the thiols by peroxide and the reduction of the disulphides by glutathione. The consumption of NADPH 11,12) upon the addition of H 2 O 2 in the absence of test compounds was 0.8 mM NADPH/min. There was no detectable activity with the solvent DMSO alone.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Ebselen and Its Acyclic Derivatives

Chang

Huang

Hsu

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Biological systems use enzymatic (superoxide dismutase, glutathione peroxidase, etc.) and nonenzymatic (uric acid, creatinine, polyamine, retinal, etc.) antioxidant systems to prevent oxidative stress. However, once the systems are disturbed the uncontrolled oxidative stresses initiate a series of harmful biochemical events, or generate them as a consequence of earlier tissue injury, thus aggravating the final damages. Such damages include brain dysfunction, cancer, and cardiovascular disease and inflammation. 1,2) Glutathione peroxidase (GSH Px, EC 1.11.1.9), a selenoenzyme, is one of the enzymes in the mammalian antioxidant systems, which perform the reduction of H 2 O 2 and other hydroperoxides.3) It is well accepted that selenium (as selenocysteine), an essential component of the active sites of glutathione peroxidase, is responsible for the scavenging of reactive oxygen species and protecting biomembrane from oxidative stress. Although possessing potent antioxidative activity, like other protein drugs GSH Px is limited for the clinical use because of its instability, poor availability, and easy metabolism. Therefore many efforts have been directed to design and synthesize small selenium-containing organic molecules with GSH Px activity. 4) Ebselen (2-phenyl-1,2-benzisoselenazole-3(2H)-one), a nontoxic low molecular weight selenium-containing heterocyclic compound, has been reported to mediate the reduction of hydroperoxides by glutathione, thereby mimicking the enzymatic activity of GSH Px.5) Beside possessing antioxidative activity, ebselen also demonstrate a number of pharmacologic activities, such as antiinflammatory, antiatherosclerotic, and cytoprotective properties.6) Studies in our laboratory have recently focused on the design and synthesis of antioxidants as potential antiinflammatory agents. Based on the unique structure of ebselen, we speculated that simple modification of the chemical structure of ebselen might provide potent antioxidative activity. In this study, the ebselen molecule and its acyclic derivative were modified and their ability to scavenge free radicals and GSH Px-like effects were also investigated.Chemistry Ebselen has been prepared previously by several methods. 7) In the earliest approach 2,2Ј-diselenobis (benzoic acid) was converted to selenyl chloride benzoyl chloride, which was treated with aniline to give ebselen. More recent advance involves ortholithiation of benzanilide, subsequent insertion of selenium into benzanilide-derived dianion and cyclization of selenium-containing dianion to ebselen.7) Because of the short synthetic and easy handling steps, the latter method has been used in our synthetic work. Chart 1 summarizes our results and illustrates the structures of the new products obtained from benzoic acid. The N-substituted benzoylamides were conveniently synthesized by the treatment of benzoic acid with thionyl chloride, followed by substituted arylamine. Lithiation of N-substituted benzoylamides with two equivalents of n-butyllithium at room temperature in dry...

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“…5,6 Ovothiols are considered to be the most potent natural antioxidants, 7,8 presumably due to their low thiolate basicity and the concomitant ready oxidizability. They act as protective antioxidants 9,10 in many parasitic protozoa. [11][12][13][14][15] These peculiarities have attracted pharmaceutical interest to create prospective antitrypanosomal chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

A cost-effective synthesis of enantiopure ovothiol A from L-histidine, its natural precursor

Mirzahosseini

Hosztafi

Tóth

et al. 2014

Arkivoc

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Ovothiol A is a naturally occurring 4-mercaptohistidine derivative, and one of the most potent thiol-containing antioxidants. The synthesis of ovothiol A was elaborated by introducing the thiol group onto protected 3-methyl-L-histidine via halogenation and Ullmann reaction. This enantiopure synthesis of ovothiol A, which uses L-histidine as starting material, requires only five steps, and compared to prior synthesis, is both cost and time effiecent.

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Ovothiol Replaces Glutathione Peroxidase as a Hydrogen Peroxide Scavenger in Sea Urchin Eggs

Cited by 99 publications

References 15 publications

Identification of a major low‐molecular‐mass thiol of the trypanosomatid Crithidia fasciculata as ovothiol A

Identification of a major low‐molecular‐mass thiol of the trypanosomatid Crithidia fasciculata as ovothiol A

Synthesis and Biological Evaluation of Ebselen and Its Acyclic Derivatives

A cost-effective synthesis of enantiopure ovothiol A from L-histidine, its natural precursor

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