Synthesis of selenocysteine-containing dipeptides modeling the active site of thioredoxin reductase

Shimodaira, Shingo; Iwaoka, Michio

doi:10.1080/10426507.2019.1603721

Cited by 13 publications

(7 citation statements)

References 10 publications

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“…The other is the presence of an intramolecular NH···Se hydrogen bond for transienti ntermediate I',a ss hown in Figure 8a, which would suppress the reverse reaction to SeÀS ox and promote the nucleophilic attack of as econd thiol at the S atom to produce intermediate I.I waoka and co-workers previously proposed that as imilar NH···Se hydrogen bond in as elenenyl sulfide speciesc an accelerate cleavage of the SeÀSb ond duringt he GPx-like catalytic cycle of diselenide selenoglutathione( GSeSeG) [17] and dipeptide SecÀCys. [18] Ab initio calculation at HF/6-31 ++G(d,p) in water revealed that the most stable conformation has aN H···Se hydrogen bond for both selenenyls ulfides 12 and 13,a ss hown in Figure 8a. The relative stabilities of compounds 12 and 13 were comparable with each other (DE =+0.70 kcal mol À1 for 12).…”

Section: Resultsmentioning

confidence: 96%

Modeling Thioredoxin Reductase‐Like Activity with Cyclic Selenenyl Sulfides: Participation of an NH⋅⋅⋅Se Hydrogen Bond through Stabilization of the Mixed Se−S Intermediate

Arai

Matsunaga

Ueno

et al. 2019

Chemistry A European J

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At the redox-active centero ft hioredoxin reductase (TrxR), as elenenyl sulfide( SeÀS) bond is formed between Cys497 and Sec498, which is activated into the thiolselenolate state ([SH,Se À ]) by reactingw ith an earby dithiol motif ([SH Cys59 ,SH Cys64 ]) presenti nt he other subunit. This process is achievedt hrough two reversible steps:a na ttack of a cysteinyl thiol of Cys59 at the Se atom of the SeÀSb ond and as ubsequenta ttack of ar emaining thiol at the Sa tom of the generated mixed SeÀSi ntermediate. However,i ti s not clearh ow the kinetically unfavorable second step pro-gresses smoothly in the catalytic cycle. Am odel study that used synthetic selenenyl sulfides, which mimic the active site structure of human TrxR comprising Cys497, Sec498, and His472, suggested that His472 can play ak ey role by forming ah ydrogen bond with the Se atom of the mixed SeÀS intermediate to facilitatet he seconds tep. In addition, the selenenyl sulfides exhibited ad efensive ability against H 2 O 2induced oxidative stress in cultured cells, which suggests the possibility for medicinal applications to control the redox balance in cells.[a] Dr.

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Section: Resultsmentioning

confidence: 96%

Modeling Thioredoxin Reductase‐Like Activity with Cyclic Selenenyl Sulfides: Participation of an NH⋅⋅⋅Se Hydrogen Bond through Stabilization of the Mixed Se−S Intermediate

Arai

Matsunaga

Ueno

et al. 2019

Chemistry A European J

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“…The Sec–SeH form of the Sec model ( 3a ) was synthesized by the reduction of selenocysteine derivative 2 (Scheme a). The analogous form of the Sec-Gly-Gly model ( 3b ) was synthesized from selenopeptide 4 − via the route shown in Scheme b, which involves selenenyl iodide 5 as a synthetic intermediate.…”

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confidence: 99%

Modeling the Catalytic Cycle of Glutathione Peroxidase by Nuclear Magnetic Resonance Spectroscopic Analysis of Selenocysteine Selenenic Acids

et al. 2021

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Although selenocysteine selenenic acids (Sec–SeOHs) have been recognized as key intermediates in the catalytic cycle of glutathione peroxidase (GPx), examples of the direct observation of Sec–SeOH in either protein or small-molecule systems have remained elusive so far, mostly due to their instability. Here, we report the first direct spectroscopic (1H and 77Se NMR) evidence for the formation of Sec–SeOH in small-molecule selenocysteine and selenopeptide model systems with a cradle-type protective group. The catalytic cycle of GPx was investigated using NMR-observable Sec–SeOH models. All the hitherto proposed chemical processes, i.e., not only those of the canonical catalytic cycle but also those involved in the bypass mechanism, including the intramolecular cyclization of Sec–SeOH to the corresponding five-membered ring selenenyl amide, were examined in a stepwise manner.

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“…2 As tractable model compounds, they provide insight into TrxR’s active site chemistry, which is otherwise notoriously challenging to study by biochemical methods. 3 4 5…”

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confidence: 99%

Efficient and Scalable Syntheses of 1,2-Thiaselenane-4-amine and 1,2-Thiaselenane-5-amine

Zeisel¹,

Maier²,

Thorn‐Seshold³

2023

Synthesis

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We develop the first regioselective syntheses of 1,2-thiaselenane-4-amine (TSA4) and 1,2-thiaselenane-5-amine (TSA5): redox-active motifs with high value in chemical biology, that until now were hindered by tedious synthesis. We leverage an aziridine intermediate and a kinetically controlled S-acylation for regioselective chalcogen installations. We optimise short, fast sequences with just one or two chromatographic steps that cheaply deliver these motifs on scale for high-throughput inhibitor screening, and provide a robust methodology for assembling other selenenylsulfides.

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Synthesis of selenocysteine-containing dipeptides modeling the active site of thioredoxin reductase

Cited by 13 publications

References 10 publications

Modeling Thioredoxin Reductase‐Like Activity with Cyclic Selenenyl Sulfides: Participation of an NH⋅⋅⋅Se Hydrogen Bond through Stabilization of the Mixed Se−S Intermediate

Modeling Thioredoxin Reductase‐Like Activity with Cyclic Selenenyl Sulfides: Participation of an NH⋅⋅⋅Se Hydrogen Bond through Stabilization of the Mixed Se−S Intermediate

Modeling the Catalytic Cycle of Glutathione Peroxidase by Nuclear Magnetic Resonance Spectroscopic Analysis of Selenocysteine Selenenic Acids

Efficient and Scalable Syntheses of 1,2-Thiaselenane-4-amine and 1,2-Thiaselenane-5-amine

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