RESUMEN
Cell-free heme (CFH) is a product of hemoglobin, myoglobin and hemoprotein degradation, which is a hallmark of pathologies associated with extensive hemolysis and tissue damage. CHF and iron collectively induce cytokine storm, lung injury, respiratory distress and infection susceptibility in the lungs suggesting their key role in the progression of lung disease pathology. We have previously demonstrated that heme-mediated reactive oxygen species (ROS) induces platelet activation and ferroptosis. However, interaction of ferroptotic platelets and neutrophils, the mechanism of action and associated complications remain unclear. In this study, we demonstrate that heme-induced P-selectin expression and Phosphatidylserine (PS) externalization in platelets via ASK-1-inflammasome axis increases platelet-neutrophil aggregates in circulation, resulting in Neutrophil extracellular traps (NET) formation in vitro and in vivo. Further, heme-induced platelet activation in mice increased platelet-neutrophil aggregates and accumulation of NETs in the lungs causing pulmonary damage. Thus, connecting CFH-mediated platelet activation to NETosis and pulmonary thrombosis. As lung infections induce acute respiratory stress, thrombosis and NETosis, we propose that heme -mediated platelet activation and ferroptosis might be crucial in such clinical manifestations. Further, considering the ability of redox modulators and ferroptosis inhibitors like FS-1, Lpx-1 and DFO to inhibit heme-induced ferroptotic platelets-mediated NETosis and pulmonary thrombosis. They could be potential adjuvant therapy to regulate respiratory distress-associated clinical complications.
Asunto(s)
Ferroptosis , Enfermedades Pulmonares , Síndrome de Dificultad Respiratoria , Trombosis , Ratones , Animales , Hemo , Activación Plaquetaria , Pulmón/patología , Trombosis/patologíaRESUMEN
Mammalian selenoenzymes, iodothyronine deiodinases (DIOs), catalyze the tyrosyl and phenolic ring deiodination of thyroid hormones (THs) and play an important role in maintaining the TH concentration throughout the body. These enzymes also accept the decarboxylated thyroid hormone metabolites, iodothyronamines (TAMs), as substrates for deiodination. Naphthalene-based selenium and/or sulphur-containing small molecules have been shown to mediate the regioselective tyrosyl ring deiodination of thyroid hormones and their metabolites. Herein, we report on the structure-activity relationship studies of a series of peri-substituted selenium-containing naphthalene derivatives for the deiodination of thyroid hormones and iodothyronamines. Single crystal X-ray crystallographic and 77Se NMR spectroscopic studies indicated that the intramolecular SeX (X = N, O and S) interactions play an important role in the deiodinase activity of the synthetic mimics. Furthermore, the decarboxylated metabolites, TAMs, have been observed to undergo slower tyrosyl ring deiodination than THs by naphthyl-based selenium and/or sulphur-containing synthetic deiodinase mimics and this has been explained on the basis of the strength of SeI halogen bonding formed by THs and TAMs.
Asunto(s)
Biomimética , Naftalenos/química , Hormonas Tiroideas/química , Tironinas/química , Halogenación , Selenio/química , Relación Estructura-ActividadRESUMEN
Glutathione Peroxidase (GPx) is a key selenoenzyme that protects biomolecules from oxidative damage. Extensive research has been carried out to design and synthesize small organoselenium compounds as functional mimics of GPx. While the catalytic mechanism of the native enzyme itself is poorly understood, the synthetic mimics follow different catalytic pathways depending upon the structures and reactivities of various intermediates formed in the catalytic cycle. The steric as well as electronic environments around the selenium atom not only modulate the reactivity of these synthetic mimics towards peroxides and thiols, but also the catalytic mechanisms. The catalytic cycle of small GPx mimics is also dependent on the nature of peroxides and thiols used in the study. In this review, we discuss how the catalytic mechanism varies with the substituents attached to the selenium atom.
Asunto(s)
Materiales Biomiméticos/química , Glutatión Peroxidasa/metabolismo , Catálisis , Humanos , Estructura Molecular , Peróxidos/química , Peróxidos/metabolismo , Selenio/química , Selenio/metabolismo , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/metabolismoRESUMEN
Spirodiazaselenuranes are structurally interesting compounds and the stability of these compounds depends highly on the nature of the substituents attached to the nitrogen atoms. Aromatic substituents are known to play important roles in stabilizing the Se-N bonds in spiro compounds. In this study, several spirodiazaselenuranes are synthesized by introducing benzylic and aliphatic substituents to understand their effect on the stability of the Se-N bonds and the antioxidant activity. Replacement of phenyl substituent by benzyl/alkyl groups significantly reduces the stability of the spirodiazaselenuranes and slows down the oxidative cyclization process. The selenium centre in the spiro compounds undergoes further oxidation to produce the corresponding selenurane oxides, which are stable at room temperature. Comparison of the glutathione peroxidase (GPx) mimetic activity of the compounds showed that the diaryl selenides having heterocyclic rings are significantly more active due to the facile oxidation of the selenium centre. However, the activity is reduced significantly for compounds having aliphatic substituents. In addition to GPx activity, the compounds also inhibit peroxynitrite-mediated nitration and oxidation reaction of protein and small molecules, respectively. The experimental observations suggest that the antioxidant activity is increased considerably upon substitution of the aromatic group with the benzylic/aliphatic substituents on the nitrogen atoms.
Asunto(s)
Antioxidantes/química , Antioxidantes/farmacología , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Antioxidantes/síntesis química , Cristalografía por Rayos X , Glutatión Peroxidasa/química , Modelos Moleculares , Compuestos de Organoselenio/síntesis química , Oxidación-Reducción/efectos de los fármacos , Ácido Peroxinitroso/antagonistas & inhibidores , Ácido Peroxinitroso/química , Fenoles , Selenio/química , Relación Estructura-ActividadRESUMEN
Reactive oxygen species (ROS)-mediated diseased states are of major concern in modern day life. Under oxidative stress conditions, the cellular antioxidants deplete, leading to several biological disorders. Small molecule mimics of different antioxidant enzymes are found to be useful in supplementing the biological systems to detoxify ROS. In this study, we have synthesized a series of amine or amide-based diselenides containing an additional amino group as glutathione peroxidase (GPx) mimetics. These diselenides act as a catalytic triad model of the native GPx featuring two basic amino groups near the selenium centre. A comparison of the catalytic activities reveals that the additional amino group increases the activity significantly in the presence of aromatic thiols. Deprotonation of thiol by an additional amine either stabilizes the selenolate intermediate or facilitates the nucleophilic attack of thiol in other intermediates. The (77)Se NMR experiments and DFT calculations show that the amino group does not have any significant effect on the catalytic intermediates. Although the amino moiety increases the nucleophilicity of the thiol, it does not prevent the thiol exchange reactions that take place in the selenenyl sulfide intermediates.
Asunto(s)
Antioxidantes/farmacología , Glutatión Peroxidasa/metabolismo , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Especies Reactivas de Oxígeno/metabolismo , Amidas/química , Aminas/química , Catálisis , Humanos , Espectroscopía de Resonancia Magnética , Oxidación-Reducción , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/metabolismoRESUMEN
Halogenated nucleosides can be incorporated into the newly synthesized DNA of replicating cells and therefore are commonly used in the detection of proliferating cells in living tissues. Dehalogenation of these modified nucleosides is one of the key pathways involved in DNA repair mediated by the uracil-DNA glycosylase. Herein, we report the first example of a selenium-mediated dehalogenation of halogenated nucleosides. We also show that the mechanism for the debromination is remarkably different from that of deiodination and that the presence of a ribose or deoxyribose moiety in the nucleosides facilitates the deiodination. The results described herein should help in understanding the metabolism of halogenated nucleosides in DNA and RNA.
Asunto(s)
Reparación del ADN , ADN/metabolismo , Nucleósidos/química , Selenio/química , Cristalografía por Rayos X , ADN/química , Halogenación , Conformación Molecular , Nucleósidos/metabolismo , Electricidad Estática , Uracil-ADN Glicosidasa/metabolismoRESUMEN
Structural studies on the polymorphs of the organoselenium antioxidant ebselen and its derivative show the potential of organic selenium to form unusually short Seâ â â O chalcogen bonds that lead to conserved supramolecular recognition units. Seâ â â O interactions observed in these polymorphs are the shortest such chalcogen bonds known for organoselenium compounds. The FTIR spectral evolution characteristics of this interaction from solution state to solid crystalline state further validates the robustness of this class of supramolecular recognition units. The strength and electronic nature of the Seâ â â O chalcogen bonds were explored using high-resolution X-ray charge density analysis and atons-in-molecules (AIM) theoretical analysis. A charge density study unravels the strong electrostatic nature of Seâ â â O chalcogen bonding and soft-metal-like behavior of organoselenium. An analysis of the charge density around Se-N and Se-C covalent bonds in conjunction with the Seâ â â O chalcogen bonding modes in ebselen and its analogues provides insights into the mechanism of drug action in this class of organoselenium antioxidants. The potential role of the intermolecular Seâ â â O chalcogen bonding in forming the intermediate supramolecular assembly that leads to the bond cleavage mechanism has been proposed in terms of electron density topological parameters in a series of molecular complexes of ebselen with reactive oxygen species (ROS).
Asunto(s)
Antioxidantes/química , Azoles/química , Modelos Moleculares , Nitrógeno/química , Compuestos de Organoselenio/química , Selenio/química , Cristalografía por Rayos X , Isoindoles , Estructura Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad EstáticaRESUMEN
Human somatic angiotensin I-converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin-angiotensin aldosterone system. It is a well-known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org. Biomol. Chem. (2011) 9, 1356-1365], it was shown that the selenium analogues of captopril (a well-known clinical inhibitor of ACE) not only inhibit ACE, but also protect against peroxynitrite-mediated nitration of peptides and proteins. Here, we report the crystal structures of human testis ACE (tACE) and a homologue of ACE, known as AnCE, from Drosophila melanogaster in complex with the most promising selenium analogue of captopril (SeCap) determined at 2.4 and 2.35 Å resolution, respectively. The inhibitor binds at the active site of tACE and AnCE in an analogous fashion to that observed for captopril and provide the first examples of a protein-selenolate interaction. These new structures of tACE-SeCap and AnCE-SeCap inhibitor complexes presented here provide important information for further exploration of zinc coordinating selenium-based ACE inhibitor pharmacophores with significant antioxidant activity.
Asunto(s)
Captopril/análogos & derivados , Proteínas de Drosophila/química , Drosophila melanogaster/enzimología , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Selenio/química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Animales , Captopril/metabolismo , Dominio Catalítico , Proteínas de Drosophila/metabolismo , Humanos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Conformación Proteica , Testículo/enzimología , Difracción de Rayos XRESUMEN
The first examples of stable spirodiazaselenurane and spirodiazatellurane were synthesized by oxidative spirocyclization of the corresponding diaryl selenide and telluride and were structurally characterized. X-ray crystal structures of the spirodiazaselenurane and spirodiazatellurane suggest that the structures are distorted trigonal bipyramidal (TBP) with the electronegative nitrogen atoms occupying the apical positions and two carbon atoms and the lone pair of Se/Te occupying the equatorial positions. Interestingly, the spirodiazatellurane underwent spontaneous chiral resolution during crystallization, and the absolute configurations of its enantiomers were confirmed by single-crystal X-ray analyses. A detailed mechanistic study indicates that the cyclization to spirodiazaselenurane and spirodiazatellurane occurs via selenoxide and telluroxide intermediates. The chalcogenoxides cyclize to the corresponding spiro compounds in a stepwise manner via the involvement of hydroxyl chalcogenurane intermediates, and the activation energy for the spirocyclization reaction decreases in the order S > Se > Te. In addition to the synthesis, characterization, and mechanism of cyclization, the glutathione peroxidase (GPx) mimetic activity of the newly synthesized compounds was evaluated. These studies suggest that the tellurium compounds are more effective as GPx mimics than their selenium counterparts due to the fast oxidation of the tellurium center in the presence of peroxide and the involvement of an efficient redox cycle between the telluride and telluroxide intermediate.
Asunto(s)
Antioxidantes/síntesis química , Glutatión Peroxidasa/metabolismo , Compuestos Organometálicos/síntesis química , Compuestos de Organoselenio/síntesis química , Antioxidantes/metabolismo , Ciclización , Depuradores de Radicales Libres/síntesis química , Compuestos Organometálicos/metabolismo , Compuestos de Organoselenio/metabolismo , Oxidación-Reducción , Ácido Peroxinitroso/química , Selenio , Telurio , TermodinámicaRESUMEN
In this paper, the effect of some commonly used antithyroid drugs and their analogues on peroxynitrite-mediated nitration of proteins is described. The nitration of tyrosine residues in bovine serum albumin (BSA) and cytochrome c was studied by Western blot analysis. These studies reveal that the antithyroid drugs methimazole (MMI), 6-n-propyl-2-thiouracil (PTU), and 6-methyl-2-thiouracil (MTU), which contain thione moieties, significantly reduce the tyrosine nitration of both BSA and cytochrome c. While MMI exhibits good peroxynitrite (PN) scavenging activity, the thiouracil compounds PTU and MTU are slightly less effective than MMI. The S- and Se- methylated compounds show a weak inhibitory effect in the nitration of tyrosine, indicating that the presence of a thione or selone moiety is important for an efficient inhibition. Similarly, the replacement of N-H moiety in MMI by N-methyl or N-m-methoxybenzyl substituents dramatically reduces the antioxidant activity of the parent compound. Theoretical studies indicate that the substitution of N-H moiety by N-Me significantly increases the energy required for the oxidation of sulfur center by PN. However, such substitution in the selenium analogue of MMI increases the activity of parent compound. This is due to the facile oxidation of the selone moiety to the corresponding selenenic and seleninic acids. Unlike N,N'-disubstituted thiones, the corresponding selones efficiently scavenge PN, as they predominantly exist in their zwitterionic forms in which the selenium atom carries a large negative charge.
Asunto(s)
Antitiroideos/química , Citocromos c/química , Ácido Peroxinitroso/química , Albúmina Sérica Bovina/química , Tiouracilo/análogos & derivados , Tirosina/química , Animales , Antitiroideos/farmacología , Bovinos , Metimazol/química , Metimazol/farmacología , Selenio/química , Termodinámica , Tiouracilo/química , Tiouracilo/farmacologíaRESUMEN
The importance of selenium as an essential trace element is now well recognized. In proteins, the redox-active selenium moiety is incorporated as selenocysteine (Sec), the 21st amino acid. In mammals, selenium exerts its redox activities through several selenocysteine-containing enzymes, which include glutathione peroxidase (GPx), iodothyronine deiodinase (ID), and thioredoxin reductase (TrxR). Although these enzymes have Sec in their active sites, they catalyze completely different reactions and their substrate specificity and cofactor or co-substrate systems are significantly different. The antioxidant enzyme GPx uses the tripeptide glutathione (GSH) for the catalytic reduction of hydrogen peroxide and organic peroxides, whereas the larger and more advanced mammalian TrxRs have cysteine moieties in different subunits and prefer to utilize these internal cysteines as thiol cofactors for their catalytic activity. On the other hand, the nature of in vivo cofactor for the deiodinating enzyme ID is not known, although the use of thiols as reducing agents has been well-documented. Recent studies suggest that molecular recognition and effective binding of the thiol cofactors at the active site of the selenoenzymes and their mimics play crucial roles in the catalytic activity. The aim of this perspective is to present an overview of the thiol cofactor systems used by different selenoenzymes and their mimics.
Asunto(s)
Coenzimas/metabolismo , Glutatión Peroxidasa/metabolismo , Selenio/metabolismo , Selenocisteína/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Animales , Sitios de Unión , Coenzimas/química , Glutatión Peroxidasa/química , Humanos , Imitación Molecular , Estructura Molecular , Selenio/química , Selenocisteína/química , Compuestos de Sulfhidrilo/química , Reductasa de Tiorredoxina-Disulfuro/químicaRESUMEN
Areneselenenyl iodide stabilised by internal chelation has been synthesized and evaluated as a substrate of thioredoxin reductase (TrxR). The reactivity of TrxR obtained from human placenta towards selenenyl iodide was found to be much higher than that of the E. coli enzyme, indicating the essential nature of a selenocysteine residue in the active site of the human enzyme. The addition of thioredoxin (Trx) significantly enhanced the TrxR-catalysed reduction of selenenyl iodide 1. These studies on the reduction of a selenenyl iodide by the thioredoxin system suggest that stable selenenyl iodides could be new substrates for human TrxR. The Trx system could act as a cofactor for iodothyronine deiodinase by reducing the selenenyl iodide intermediate in the second-half of the deiodinase catalytic cycle to regenerate the active site. The TrxR-catalysed reduction of 1 was not inhibited by the anti-thyroid drug, PTU, suggesting that the involvement of the Trx system in the deiodinase cycle may be responsible for the insensitivity of certain deiodinases towards clinically useful thiourea drugs.
Asunto(s)
Yoduros/metabolismo , Compuestos de Selenio/metabolismo , Selenio/química , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Escherichia coli/enzimología , Humanos , Yoduro Peroxidasa/antagonistas & inhibidores , Yoduro Peroxidasa/química , Yoduro Peroxidasa/metabolismo , Yoduros/química , Propiltiouracilo/metabolismo , Tiroxina/metabolismoRESUMEN
Enzyme mimetic studies on the crucial intermediate (E-SeI) of the iodothyronine deiodinase cycle have been carried out by using an areneselenenyl iodide stabilized by intramolecular Se.N interactions. Treatment of this compound with aromatic thiols and thiobenzoxazole in the presence of NEt(3) affords areneselenenyl sulfides that are stable towards disproportionation reactions. The structures of three of the areneselenenyl sulfides were determined by X-ray crystallography. In one case, in the absence of NEt(3), a diselenide can be formed rather than the selenenyl sulfide. The areneselenenyl iodide also reacts with a related selenol to produce the corresponding diselenide, and this reaction is found to be much faster than that with thiols. The high reactivity of the selenenyl iodide with the selenol suggests that a reduced selenol group (R'-SeH) may react with the E-SeI intermediate to produce a diselenide (E-Se-Se-R') without any thiol cosubstrate. The intermediacy of selenenyl sulfides during the reduction of selenenyl iodide by thiols and its possible relevance to the iodothyronine deiodinase catalytic cycle is also described.