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

Abstract

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.

Basic Amino Acid Conjugates of 1,2‐Diselenan‐4‐amine with Protein Disulfide Isomerase‐like Functions as a Manipulator of Protein Quality Control

“…Interestingly, the E °′ of compound 1 was significantly increased via the conjugation of amino acids, suggesting that compounds 2 a – d function as good oxidants for SS‐formation in proteins. 77 Se NMR spectra of the compounds showed that the chemical shifts of 1 (δ Se =281 ppm) and 2 a – d were almost comparable (see supporting information), implying that the increase in E °′ values would be due to the thermodynamic stabilization of the reduced state by a weak interaction, such as NH•••Se hydrogen bond, which is found in the reduced form of cyclic Se−S compounds . Unexpectedly, Ala‐conjugation further raised the E °′ compared to that with Lys‐ and Arg‐conjugations.…”

“…77 Se NMR spectra of the compounds showed that the chemical shifts of 1 (δ Se = 281 ppm [7b] ) and 2 a-d were almost comparable (see supporting information), implying that the increase in E°' values would be due to the thermodynamic stabilization of the reduced state by a weak interaction, such as NH *** Se hydrogen bond, which is found in the reduced form of cyclic SeÀ S compounds. [9] Unexpectedly, Ala-conjugation further raised the E°' compared to that with Lys-and Arg-conjugations. This is because that α-amino group also participates in the formation of NH *** Se hydrogen bonds.…”

“…Amino acid conjugates 2 a – d were prepared by a condensation reaction of 1 with the corresponding amino acids as per the previous report (see the experimental section for details). The E °′ values of the compounds were first estimated utilizing the equilibrium redox reaction of the compounds with dithiothreitol, as described previously (Figure S1), and are summarized in Table . Interestingly, the E °′ of compound 1 was significantly increased via the conjugation of amino acids, suggesting that compounds 2 a – d function as good oxidants for SS‐formation in proteins.…”

“…In addition, we have recently reported that selenenyl sulfide (Se−S) analogues of 1 , which is a model compound of the thioredoxin reductase active center composed of C497 and selenocysteine (U) 498, catalyzes the reduction of H 2 O 2 , a reactive oxygen species, and protein SS bonds in the presence of a dithiol activator . This model study revealed that neighboring His472 at the active center kinetically accelerates the reduction of the Se−S bond between C497 and U498, and thermodynamically stabilizes the generated reactive selenolate (Se − ) state by forming intramolecular NH•••Se hydrogen bond.…”

Infosys‐Preis: G. Mugesh / ICS‐Adama‐Preis: N. G. Lemcoff / Hellmann‐Preis und Haage‐Preis: T.‐C. Jagau

“…Seine Gruppe beschäftigt sich auch mit den molekularen Mechanismen und komplexen Stoffwechselpfaden der Schilddrüsenhormone. Er veröffentlichte kürzlich eine Zuschrift in der Angewandten Chemie über den Nachweis einer Seleninsäure in lebenden Zellen und ein Full Paper in Chemistry — A European Journal über ein Modell der Thioredoxin‐Reduktase‐artigen Aktivität mit cyclischen Selensulfiden . Mugesh war Mitglied des Internationalen Beirats von ChemPlusChem (2012–2015), und er wird ab 2020 dem Redaktionsbeirat von Chemistry—A European Journal angehören.…”