The Redox Potential of Selenocystine in Unconstrained Cyclic Peptides

Besse, Dörthe; Siedler, Frank; Diercks, Tammo; Kessler, Horst; Moröder, Luis

doi:10.1002/anie.199708831

Cited by 138 publications

(130 citation statements)

References 12 publications

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“…This result is consistent with the redox potential of Trx(C32U-C35U), which was previously estimated to be somewhere between Trx (−270 mV) and DTT (−323 mV), 37 and with the monoselenol selenocystamine (−348 mV) 54 but is significantly higher than previous diselenide-peptide studies (−380 mV). 40 Although the redox potential of the diselenide analog, Grx3(C11U-C14U), is lower than that of Trx, at equilibrium ~19% of this analog is in the reduced form ( Figure 2D), which suggests that Trx can act as an effective reductant for diselenide bonds in proteins. The ~9000-fold increase in k −1 for the diselenide, combined with a physiologically compatible redox potential, suggests that diselenide selenoenzymes may have a role in biological catalysis.…”

Section: The Diselenide Enzyme Grx3(c11u-c14u) Has a Low Redox Potementioning

confidence: 99%

Synthetic Seleno-Glutaredoxin 3 Analogues Are Highly Reducing Oxidoreductases with Enhanced Catalytic Efficiency

2006

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Selenoenzymes have a central role in maintaining cellular redox potential. These enzymes have selenenylsulfide bonds in their active sites that catalyze the reduction of peroxides, sulfoxides and disulfides. The selenol/disufide exchange reaction is common to all of these enzymes and the active site redox potential reflects the ratio between the forward and reverse rates of this reaction. The preparation of enzymes containing selenocysteine (Sec) is experimentally challenging. As a result, little is known about the kinetic role of selenols in enzyme active sites, and the redox potential of a selenenylsulfide or diselenide bond in a protein has not been experimentally determined. In order to fully evaluate the effects of Sec on oxidoreductase redox potential and kinetics, glutaredoxin 3 (Grx3) and all three Sec variants of its conserved 11 CXX 14 C active site were chemically synthesized. Grx3, Grx3(C11U) and Grx3(C14U) exhibited redox potentials of −194, −260 and −275 mV, respectively. The position of redox equilibrium between Grx3(C11U-C14U) (−309 mV) and thioredoxin (Trx) (−270 mV) suggests a possible role for diselenide bonds in biological systems. Kinetic analysis is consistent with the hypothesis that the lower redox potentials of the Sec variants result primarily from the greater nucleophilicity of the active site selenium rather than its role as either a leaving group or a 'central atom' in the exchange reaction. The 10 2 to 10 4 -fold increase in the rate of Trx reduction by the seleno-Grx3 analogs demonstrates that Oxidoreductases containing either selenenylsulfide or diselenide bonds can have physiologically compatible redox potentials and enhanced reduction kinetics in comparison with their sulfide counterparts.

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Section: The Diselenide Enzyme Grx3(c11u-c14u) Has a Low Redox Potementioning

confidence: 99%

Synthetic Seleno-Glutaredoxin 3 Analogues Are Highly Reducing Oxidoreductases with Enhanced Catalytic Efficiency

2006

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“…The selenol group of selenocysteine has a pK a of 5.2 (compare to 8.5 for a typical thiol) and is thus ionized at physiological pH [33]. The redox potential of a diselenide bond (−380 mV) and a mixed selenylsulfide bond (−326 mV) are much lower than that of a typical disulfide bond (−180 mV) [34]. Hence, selenium compounds will quickly oxidize in oxygenated buffer and favor the formation of a diselenide bond.…”

Section: Physico-chemical Properties Of Selenocysteinementioning

confidence: 99%

Incorporation of Selenocysteine into Proteins Using Peptide Ligation

Hondal

2005

PPL

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Expressed protein ligation has become a frequently used technique to insert non-standard amino acids into proteins. The technique has been adapted to insert selenocysteine residues in place of cysteine residue in proteins, taking advantage of the similarity in the chemistries of sulfur and selenium. This replacement can confer unique structural and catalytic properties to enzymes and proteins. The development of this technique also allows for naturally occurring selenoproteins to be produced semisynthetically. KeywordsSelenocysteine; expressed protein ligation; thioredoxin reductase; semisynthetic Selenium, the mysterious moon-metalThe Swedish chemist, J.J. Berzilius discovered the 34 th element of the periodic table in 1817 and named it after the Greek goddess of the moon, Selene [1]. It is wholly appropriate that he named this element after the moon-goddess, because selenium, like the moon, has remained mysterious to science until the modern eraThe biological role of selenium began to be realized when Schwarz discovered a dietary factor that was necessary to prevent liver necrosis in rats [2]. He called this mysterious nutritional requirement, "Factor 3". He then determined that this dietary factor was the trace element selenium. In the 1970's, Chinese scientists reported that selenium could prevent a childhood cardiomyopathy known as Keshan disease [3], much like vitamin C can prevent the onset of scurvy. Beck and Levander later showed that both influenza and coxsackie viruses accumulate genetic mutations when these viruses have infected animal hosts that are deficient in selenium or vitamin E [4][5]. Keshan disease is caused when coxsackie virus mutates to a more virulent strain in a host deficient in selenium. In the 1980's, it was discovered that selenium is the only trace element that is incorporated directly into proteins as part of the polypeptide chain. [6]. The incorporation of selenium into proteins, known as selenoproteins, is beginning to explain the important role that selenium plays in human health. A number of important examples can be cited. Selenium is vital to the function of the thyroid gland. The key enzyme in the thyroid gland, which converts thyroxin (T4) to triidothyronine (T3), contains selenium [7]. Selenium is absolutely essential to human male fertility because an enzyme in the testes containing selenium protects developing sperm from oxidative injury [8]. There has long been anecdotal evidence that selenium offers † This work was supported by grant GM070742-01 NIH Public Access Selenium and the split personality of the genetic codeMany of the health benefits of selenium can be explained by its incorporation into proteins as the "21 st " amino acid, selenocysteine [12][13]. This amino acid, though rare, is ubiquitous in all of the kingdoms of life being found in eukarya, prokarya, and archea [14][15]. Examples of selenocysteine-containing proteins are found in plants, fungi, mammals, bacteria, and fish [16]. Like the other standard proteinogenic amino acids, selenocysteine i...

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“…Reactions with selenocysteine occur much faster than cysteine at pH 5.0, suggesting that selenocysteine can be selectively oxidized over cysteine at lower pH (20). The redox potential relative to glutaredoxin for the diselenide bond (Ϫ381 mV) is significantly lower than that of the disulfide bond (Ϫ180 mV), requiring stronger reducing conditions, such as a large excess of dithiothreitol or sodium borohydride, to induce its cleavage (21). Furthermore, the redox potential for a mixed sulfide/selenide bond is higher than that of a diselenide bond (Ϫ321 mV), suggesting that its formation is unfavorable.…”

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confidence: 99%

α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists

Armishaw

Daly

Nevin

et al. 2006

Journal of Biological Chemistry

173

198

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]ImI) disulfide bonds with a diselenide bond. Each analogue demonstrated remarkable stability to reduction or scrambling under a range of chemical and biological reducing conditions. Three-dimensional structural characterization by NMR and CD spectroscopy indicates conformational preferences that are very similar to those of native ImI, suggesting fully isomorphic structures. Additionally, full bioactivity was retained at the ␣ 7 nicotinic acetylcholine receptor, with each selenoanalogue exhibiting a dose-response curve that overlaps with wild-type ImI, thus further supporting an isomorphic structure. These results demonstrate that selenoconotoxins can be used as highly stable scaffolds for the design of new drugs.

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The Redox Potential of Selenocystine in Unconstrained Cyclic Peptides

Cited by 138 publications

References 12 publications

Synthetic Seleno-Glutaredoxin 3 Analogues Are Highly Reducing Oxidoreductases with Enhanced Catalytic Efficiency

Synthetic Seleno-Glutaredoxin 3 Analogues Are Highly Reducing Oxidoreductases with Enhanced Catalytic Efficiency

Incorporation of Selenocysteine into Proteins Using Peptide Ligation

α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists

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