Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Activation of NO donors in mitochondria: peroxidase metabolism of (2-hydroxyamino-vinyl)-triphenyl-phosphonium by cytochrome c releases NO and protects cells against apoptosis.

ABSTRACT: In mitochondrial apoptosis, the formation of cytochrome c-cardiolipin complex ([CL-cyt c]) with peroxidase properties is an early event in the cascade of reactions that leads to cell death. Herein, we report the synthesis of a new prodrug, (2-hydroxyamino-vinyl)-triphenyl-phosphonium (HVTP), which compartmentalizes exclusively into mitochondria, undergoes a [CL-cyt c]-catalyzed bioactivation to nitric oxide (NO), inhibits peroxidase activity, and protects cells from apoptosis.

SUBMITTER: Stoyanovsky DA

PROVIDER: S-EPMC2275320 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Activation of NO donors in mitochondria: peroxidase metabolism of (2-hydroxyamino-vinyl)-triphenyl-phosphonium by cytochrome c releases NO and protects cells against apoptosis.

Stoyanovsky Detcho A DA Vlasova Irina I II Belikova Natalia A NA Kapralov Alexandr A Tyurin Vladimir V Greenberger Joel S JS Kagan Valerian E VE

FEBS letters 20080205 5

In mitochondrial apoptosis, the formation of cytochrome c-cardiolipin complex ([CL-cyt c]) with peroxidase properties is an early event in the cascade of reactions that leads to cell death. Herein, we report the synthesis of a new prodrug, (2-hydroxyamino-vinyl)-triphenyl-phosphonium (HVTP), which compartmentalizes exclusively into mitochondria, undergoes a [CL-cyt c]-catalyzed bioactivation to nitric oxide (NO), inhibits peroxidase activity, and protects cells from apoptosis. ...[more]

PMID: 18258194

Similar Datasets

Suppression of B-Raf<sup>V600E</sup> melanoma cell survival by targeting mitochondria using triphenyl-phosphonium-conjugated nitroxide or ubiquinone.

Project description:Most BRAF-mutated melanomas initially responsive to the FDA-approved inhibitors preferentially targeting B-Raf mutated in Val600 residue eventually relapse, requiring additional therapeutic modalities. Recent studies report the significance of metabolic reprograming in mitochondria for maintenance of BRAF-mutated melanomas and for development of their drug resistance to B-Raf inhibitors, providing a rationale for targeting mitochondria as a potential therapeutic strategy for melanoma. We therefore determined whether mitochondria-targeted metabolism-interfering agents can effectively suppress human B-RafV600E melanoma cell lines and their dabrafenib/PLX4032-resistant progenies using mitochondria-targeted carboxy-proxyl (Mito-CP) and ubiquinone (Mito-Q). These agents exhibited comparable efficacy to PLX4032 in suppressing SK-MEL28, A375, and RPMI-7951 cells in vitro. As determined in SK-MEL28 and A375 cells, Mito-CP induced apoptotic cell death mediated by mitochondrial membrane depolarization and subsequent oxidative stress, which PLX4032 could not induce. Of note, Mito-CP also effectively suppressed PLX4032-resistant progenies of SK-MEL28 and A375. Moreover, when orally administered, Mito-CP suppressed SK-MEL28 xenografts in mice as effectively as PLX4032 without serious adverse effects. These data demonstrate that mitochondria-targeted agents have therapeutic potential to effectively suppress BRAF-mutated melanomas via an effect(s) distinct from those of B-Raf inhibitors.

| S-EPMC5362989 | biostudies-literature

A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death.

Project description:The risk of radionuclide release in terrorist acts or exposure of healthy tissue during radiotherapy demand potent radioprotectants/radiomitigators. Ionizing radiation induces cell death by initiating the selective peroxidation of cardiolipin in mitochondria by the peroxidase activity of its complex with cytochrome c leading to release of haemoprotein into the cytosol and commitment to the apoptotic program. Here we design and synthesize mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic and stearic acids that blocked peroxidase activity of cytochrome c/cardiolipin complex by specifically binding to its haem-iron. We show that both compounds inhibit pro-apoptotic oxidative events, suppress cyt c release, prevent cell death, and protect mice against lethal doses of irradiation. Significant radioprotective/radiomitigative effects of imidazole-substituted oleic acid are observed after pretreatment of mice from 1?h before through 24?h after the irradiation.

| S-EPMC3557495 | biostudies-literature

Respiration triggers heme transfer from cytochrome c peroxidase to catalase in yeast mitochondria.

Project description:In exponentially growing yeast, the heme enzyme, cytochrome c peroxidase (Ccp1) is targeted to the mitochondrial intermembrane space. When the fermentable source (glucose) is depleted, cells switch to respiration and mitochondrial H2O2 levels rise. It has long been assumed that CCP activity detoxifies mitochondrial H2O2 because of the efficiency of this activity in vitro. However, we find that a large pool of Ccp1 exits the mitochondria of respiring cells. We detect no extramitochondrial CCP activity because Ccp1 crosses the outer mitochondrial membrane as the heme-free protein. In parallel with apoCcp1 export, cells exhibit increased activity of catalase A (Cta1), the mitochondrial and peroxisomal catalase isoform in yeast. This identifies Cta1 as a likely recipient of Ccp1 heme, which is supported by low Cta1 activity in ccp1Δ cells and the accumulation of holoCcp1 in cta1Δ mitochondria. We hypothesized that Ccp1's heme is labilized by hyperoxidation of the protein during the burst in H2O2 production as cells begin to respire. To test this hypothesis, recombinant Ccp1 was hyperoxidized with excess H2O2 in vitro, which accelerated heme transfer to apomyoglobin added as a surrogate heme acceptor. Furthermore, the proximal heme Fe ligand, His175, was found to be ∼ 85% oxidized to oxo-histidine in extramitochondrial Ccp1 isolated from 7-d cells, indicating that heme labilization results from oxidation of this ligand. We conclude that Ccp1 responds to respiration-derived H2O2 via a previously unidentified mechanism involving H2O2-activated heme transfer to apoCta1. Subsequently, the catalase activity of Cta1, not CCP activity, contributes to mitochondrial H2O2 detoxification.

| S-EPMC4267377 | biostudies-literature

Triphenyl[(triphenylphosphoranylidene)amino]phosphonium tetra-kis-(penta-fluoro-phen-yl)borate.

Project description:In the title molecular salt, C36H30NP2(+)·C24BF20(-), the P-N bond lengths in the cation are equal [1.573?(2) and 1.572?(2)?Å], indicating a resonance structure and the P-N-P bond angle is 144.79?(12)°. In the crystal, weak C-H?F interactions link the cations and the anions.

| S-EPMC3588361 | biostudies-literature

Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids.

Project description:Mitochondria have emerged as the major regulatory platform responsible for the coordination of numerous metabolic reactions as well as cell death processes, whereby the execution of intrinsic apoptosis includes the production of reactive oxygen species fueling oxidation of cardiolipin (CL) catalyzed by cytochrome (Cyt) c. As this oxidation occurs within the peroxidase complex of Cyt c with CL, the latter represents a promising target for the discovery and design of drugs with antiapoptotic mechanisms of action. In this work, we designed and synthesized a new group of mitochondria-targeted imidazole-substituted analogs of stearic acid TPP-n-ISAs with various positions of the attached imidazole group on the fatty acid (n = 6, 8, 10, 13, and 14). By using a combination of absorption spectroscopy and EPR protocols (continuous wave electron paramagnetic resonance and electron spin echo envelope modulation) we demonstrated that TPP-n-ISAs indeed were able to potently suppress CL-induced structural rearrangements in Cyt c, paving the way to its peroxidase competence. TPP-n-ISA analogs preserved the low-spin hexa-coordinated heme-iron state in Cyt c/CL complexes whereby TPP-6-ISA displayed a significantly more effective preservation pattern than TPP-14-ISA. Elucidation of these intermolecular stabilization mechanisms of Cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of Cyt c/CL complexes with a significant antiapoptotic potential realized in mouse embryonic cells exposed to ionizing irradiation. These experimental findings were detailed and supported by all-atom molecular dynamics simulations. Based on the experimental data and computation predictions, we identified TPP-6-ISA as a candidate drug with optimized antiapoptotic potency.

| S-EPMC4216591 | biostudies-literature

The m-AAA protease processes cytochrome c peroxidase preferentially at the inner boundary membrane of mitochondria.

Project description:The m-AAA protease is a conserved hetero-oligomeric complex in the inner membrane of mitochondria. Recent evidence suggests a compartmentalization of the contiguous mitochondrial inner membrane into an inner boundary membrane (IBM) and a cristae membrane (CM). However, little is known about the functional differences of these subdomains. We have analyzed the localizations of the m-AAA protease and its substrate cytochrome c peroxidase (Ccp1) within yeast mitochondria using live cell fluorescence microscopy and quantitative immunoelectron microscopy. We find that the m-AAA protease is preferentially localized in the IBM. Likewise, the membrane-anchored precursor form of Ccp1 accumulates in the IBM of mitochondria lacking a functional m-AAA protease. Only upon proteolytic cleavage the mature form mCcp1 moves into the cristae space. These findings suggest that protein quality control and proteolytic activation exerted by the m-AAA protease take place preferentially in the IBM pointing to significant functional differences between the IBM and the CM.

| S-EPMC2626558 | biostudies-literature

Engineering ascorbate peroxidase activity into cytochrome c peroxidase.

Project description:Cytochrome c peroxidase (CCP) and ascorbate peroxidase (APX) have very similar structures, and yet neither CCP nor APX exhibits each other's activities with respect to reducing substrates. APX has a unique substrate binding site near the heme propionates where ascorbate H-bonds with a surface Arg and one heme propionate (Sharp et al. (2003) Nat. Struct. Biol. 10, 303-307). The corresponding region in CCP has a much longer surface loop, and the critical Arg residue that is required for ascorbate binding in APX is Asn in CCP. In order to convert CCP into an APX, the ascorbate-binding loop and critical arginine were engineered into CCP to give the CCP2APX mutant. The mutant crystal structure shows that the engineered site is nearly identical to that found in APX. While wild-type CCP shows no APX activity, CCP2APX catalyzes the peroxidation of ascorbate at a rate of approximately 12 min (-1), indicating that the engineered ascorbate-binding loop can bind ascorbate.

| S-EPMC2770236 | biostudies-literature

Leishmania major peroxidase is a cytochrome c peroxidase.

Project description:Leishmania major peroxidase (LmP) exhibits both ascorbate and cytochrome c peroxidase activities. Our previous results illustrated that LmP has a much higher activity against horse heart cytochrome c than ascorbate, suggesting that cytochrome c may be the biologically important substrate. To elucidate the biological function of LmP, we have recombinantly expressed, purified, and determined the 2.08 Å crystal structure of L. major cytochrome c (LmCytc). Like other types of cytochrome c, LmCytc has an electropositive surface surrounding the exposed heme edge that serves as the site of docking with redox partners. Kinetic assays performed with LmCytc and LmP show that LmCytc is a much better substrate for LmP than horse heart cytochrome c. Furthermore, unlike the well-studied yeast system, the reaction follows classic Michaelis-Menten kinetics and is sensitive to an increasing ionic strength. Using the yeast cocrystal as a control, protein-protein docking was performed using Rosetta to develop a model for the binding of LmP and LmCytc. These results suggest that the biological function of LmP is to act as a cytochrome c peroxidase.

| S-EPMC3799847 | biostudies-literature

Trialkyl(vinyl)phosphonium Chlorophenol Derivatives as Potent Mitochondrial Uncouplers and Antibacterial Agents.

Project description:Trialkyl phosphonium derivatives of vinyl-substituted p-chlorophenol were synthesized here by a recently developed method of preparing quaternary phosphonium salts from phosphine oxides using Grignard reagents. All the derivatives with a number (n) of carbon atoms in phosphonium alkyl substituents varying from 4 to 7 showed pronounced uncoupling activity in isolated rat liver mitochondria at micromolar concentrations, with a tripentyl derivative being the most effective both in accelerating respiration and causing membrane potential collapse, as well as in provoking mitochondrial swelling in a potassium-acetate medium. Remarkably, the trialkyl phosphonium derivatives with n from 4 to 7 also proved to be rather potent antibacterial agents. Methylation of the chlorophenol hydroxyl group suppressed the effects of P555 and P444 on the respiration and membrane potential of mitochondria but not those of P666, thereby suggesting a mechanistic difference in the mitochondrial uncoupling by these derivatives, which was predominantly protonophoric (carrier-like) in the case of P555 and P444 but detergent-like with P666. The latter was confirmed by the carboxyfluorescein leakage assay on model liposomal membranes.

| S-EPMC8359139 | biostudies-literature

Phosphonium Ionic Liquid-Infused Poly(vinyl chloride) Surfaces Possessing Potent Antifouling Properties.

Project description:Microbial fouling is a costly issue, which impacts a wide range of industries, such as healthcare, food processing, and construction industries, and improved strategies to reduce the impact of fouling are urgently required. Slippery liquid-infused porous surfaces (SLIPSs) have recently been developed as a bioinspired approach to prevent antifouling. Here, we report the development of slippery, superhydrophilic surfaces by infusing roughened poly(vinyl chloride) (PVC) substrates with phosphonium ionic liquids (PILs). These surfaces were capable of reducing viable bacterial adherence by Staphylococcus aureus and Pseudomonas aeruginosa by >6 log10 cfu mL-1 after 24 h under static conditions relative to control PVC. Furthermore, we report the potential of a series of asymmetric quaternary alkyl PILs with varying alkyl chain lengths (C4-C18) and counteranions to act as antimicrobial agents against both Gram +ve and Gram -ve bacteria and illustrate their potential as antimicrobial alternatives to traditional fluorinated lubricants commonly used in the synthesis of SLIPSs.

| S-EPMC7160832 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data