P24 Cystathionine-γ-lyase/hydrogen sulfide system maintains cellular redox homeostasis via glutathione recycling

Nitric Oxide ◽  
2013 ◽  
Vol 31 ◽  
pp. S45
Author(s):  
Zheng-Wei Lee ◽  
Yi-Lian Low ◽  
Tianxiao Wang ◽  
Lih-Wen Deng
Keyword(s):  
Hydrogen Sulfide ◽  
Redox Homeostasis ◽  
Cellular Redox

scholarly journals A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionineβ-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity?

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
João B. Vicente ◽  
Henrique G. Colaço ◽  
Francesca Malagrinò ◽  
Paulo E. Santo ◽  
André Gutierres ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Redox Homeostasis ◽  
Crystallographic Structure ◽  
Wild Type ◽  
Gene Encoding ◽  
Cellular Redox ◽  
Transsulfuration Pathway ◽  
Key Enzyme ◽  
A Minor ◽  
Ferrous Heme

The human disease classical homocystinuria results from mutations in the gene encoding the pyridoxal 5′-phosphate- (PLP-) dependent cystathionineβ-synthase (CBS), a key enzyme in the transsulfuration pathway that controls homocysteine levels, and is a major source of the signaling molecule hydrogen sulfide (H2S). CBS activity, contributing to cellular redox homeostasis, is positively regulated byS-adenosyl-L-methionine (AdoMet) but fully inhibited upon CO or NO• binding to a noncatalytic heme moiety. Despite extensive studies, the molecular basis of several pathogenicCBSmutations is not yet fully understood. Here we found that the ferrous heme of the reportedly mild p.P49L CBS variant has altered spectral properties and markedly increased affinity for CO, making the protein much more prone than wild type (WT) CBS to inactivation at physiological CO levels. The higher CO affinity could result from the slightly higher flexibility in the heme surroundings revealed by solving at 2.80-Å resolution the crystallographic structure of a truncated p.P49L. Additionally, we report that p.P49L displays impaired H2S-generating activity, fully rescued by PLP supplementation along the purification, despite a minor responsiveness to AdoMet. Altogether, the results highlight how increased propensity to CO inactivation of an otherwise WT-like variant may represent a novel pathogenic mechanism in classical homocystinuria.

scholarly journals Hydrogen Sulfide and Cellular Redox Homeostasis

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Zhi-Zhong Xie ◽  
Yang Liu ◽  
Jin-Song Bian
Keyword(s):  
Hydrogen Sulfide ◽  
Antioxidant Defense ◽  
Redox Homeostasis ◽  
Antioxidant Defense System ◽  
Ros Generation ◽  
Cellular Redox ◽  
Wide Range ◽  
Underlying Mechanisms ◽  
Antioxidant Effects

Intracellular redox imbalance is mainly caused by overproduction of reactive oxygen species (ROS) or weakness of the natural antioxidant defense system. It is involved in the pathophysiology of a wide array of human diseases. Hydrogen sulfide (H2S) is now recognized as the third “gasotransmitters” and proved to exert a wide range of physiological and cytoprotective functions in the biological systems. Among these functions, the role of H2S in oxidative stress has been one of the main focuses over years. However, the underlying mechanisms for the antioxidant effect of H2S are still poorly comprehended. This review presents an overview of the current understanding of H2S specially focusing on the new understanding and mechanisms of the antioxidant effects of H2S based on recent reports. Both inhibition of ROS generation and stimulation of antioxidants are discussed. H2S-induced S-sulfhydration of key proteins (e.g., p66Shc and Keap1) is also one of the focuses of this review.

scholarly journals Role of Hydrogen Sulfide in NRF2- and Sirtuin-Dependent Maintenance of Cellular Redox Balance

Antioxidants ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 129 ◽  
Author(s):  
Tiziana Corsello ◽  
Narayana Komaravelli ◽  
Antonella Casola
Keyword(s):  
Hydrogen Sulfide ◽  
Redox Homeostasis ◽  
Antioxidant Properties ◽  
Redox Balance ◽  
Cellular Redox ◽  
Endogenous Production ◽  
Organ Specific ◽  
Mercaptopyruvate Sulfurtransferase ◽  
Antioxidant Effects

Hydrogen sulfide (H2S) has arisen as a critical gasotransmitter signaling molecule modulating cellular biological events related to health and diseases in heart, brain, liver, vascular systems and immune response. Three enzymes mediate the endogenous production of H2S: cystathione β-synthase (CBS), cystathione γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). CBS and CSE localizations are organ-specific. 3-MST is a mitochondrial and cytosolic enzyme. The generation of H2S is firmly regulated by these enzymes under normal physiological conditions. Recent studies have highlighted the role of H2S in cellular redox homeostasis, as it displays significant antioxidant properties. H2S exerts antioxidant effects through several mechanisms, such as quenching reactive oxygen species (ROS) and reactive nitrogen species (RNS), by modulating cellular levels of glutathione (GSH) and thioredoxin (Trx-1) or increasing expression of antioxidant enzymes (AOE), by activating the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2). H2S also influences the activity of the histone deacetylase protein family of sirtuins, which plays an important role in inhibiting oxidative stress in cardiomyocytes and during the aging process by modulating AOE gene expression. This review focuses on the role of H2S in NRF2 and sirtuin signaling pathways as they are related to cellular redox homeostasis.

scholarly journals Hydrogen Sulfide in Plants: Crosstalk with Other Signal Molecules in Response to Abiotic Stresses

2021 ◽  
Vol 22 (21) ◽  
pp. 12068
Author(s):  
Chunlei Wang ◽  
Yuzheng Deng ◽  
Zesheng Liu ◽  
Weibiao Liao
Keyword(s):  
Hydrogen Sulfide ◽  
Abiotic Stresses ◽  
Metal Ion ◽  
Current Knowledge ◽  
Redox Homeostasis ◽  
Environmental Damage ◽  
Signal Molecules ◽  
Cellular Redox ◽  
Biochemical Processes ◽  
Physiological And Biochemical

Hydrogen sulfide (H2S) has recently been considered as a crucial gaseous transmitter occupying extensive roles in physiological and biochemical processes throughout the life of plant species. Furthermore, plenty of achievements have been announced regarding H2S working in combination with other signal molecules to mitigate environmental damage, such as nitric oxide (NO), abscisic acid (ABA), calcium ion (Ca2+), hydrogen peroxide (H2O2), salicylic acid (SA), ethylene (ETH), jasmonic acid (JA), proline (Pro), and melatonin (MT). This review summarizes the current knowledge within the mechanism of H2S and the above signal compounds in response to abiotic stresses in plants, including maintaining cellular redox homeostasis, exchanging metal ion transport, regulating stomatal aperture, and altering gene expression and enzyme activities. The potential relationship between H2S and other signal transmitters is also proposed and discussed.

Mitochondria-Targeted Ratiometric Fluorescent Imaging of Cysteine

The Analyst ◽  
2021 ◽  
Author(s):  
Ya-Nan Wei ◽  
Bo Lin ◽  
Yang Shu ◽  
Jian-Hua Wang
Keyword(s):  
Reactive Oxygen Species ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Fluorescent Imaging ◽  
Oxygen Species ◽  
Cellular Redox ◽  
Critical Part ◽  
Physiological Processes

As an indispensable biothiol, cysteine (Cys) plays a critical part in cellular redox homeostasis, pathological and physiological processes. One of the main sources of reactive oxygen species (ROS) in human...

scholarly journals Micro RNAs in Regulation of Cellular Redox Homeostasis

2021 ◽  
Vol 22 (11) ◽  
pp. 6022
Author(s):  
Sylwia Ciesielska ◽  
Izabella Slezak-Prochazka ◽  
Patryk Bil ◽  
Joanna Rzeszowska-Wolny
Keyword(s):  
Target Genes ◽  
Redox Homeostasis ◽  
Messenger Rnas ◽  
Cellular Redox ◽  
Cell Responses ◽  
Regulatory Circuits ◽  
Micro Rnas ◽  
Cellular Behaviors ◽  
Homeostasis Regulation ◽  
Thioredoxin Reductases

In living cells Reactive Oxygen Species (ROS) participate in intra- and inter-cellular signaling and all cells contain specific systems that guard redox homeostasis. These systems contain both enzymes which may produce ROS such as NADPH-dependent and other oxidases or nitric oxide synthases, and ROS-neutralizing enzymes such as catalase, peroxiredoxins, thioredoxins, thioredoxin reductases, glutathione reductases, and many others. Most of the genes coding for these enzymes contain sequences targeted by micro RNAs (miRNAs), which are components of RNA-induced silencing complexes and play important roles in inhibiting translation of their targeted messenger RNAs (mRNAs). In this review we describe miRNAs that directly target and can influence enzymes responsible for scavenging of ROS and their possible role in cellular redox homeostasis. Regulation of antioxidant enzymes aims to adjust cells to survive in unstable oxidative environments; however, sometimes seemingly paradoxical phenomena appear where oxidative stress induces an increase in the levels of miRNAs which target genes which are supposed to neutralize ROS and therefore would be expected to decrease antioxidant levels. Here we show examples of such cellular behaviors and discuss the possible roles of miRNAs in redox regulatory circuits and further cell responses to stress.

scholarly journals Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption

2020 ◽  
Author(s):  
Carla Umansky ◽  
Agustín Morellato ◽  
Marco Scheidegger ◽  
Matthias Rieckher ◽  
Manuela R. Martinefski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Redox Homeostasis ◽  
Thiol Group ◽  
Cellular Damage ◽  
Repair Pathway ◽  
Cellular Redox ◽  
Redox Active ◽  
Development And Aging

AbstractFormaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify the ADH5-ortholog gene in Caenorhabditis elegans and show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthy BRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.

scholarly journals Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma

2016 ◽  
Vol 213 (5) ◽  
pp. 859-875 ◽  
Author(s):  
Chun Yang ◽  
Ye-xiong Tan ◽  
Guang-zhen Yang ◽  
Jian Zhang ◽  
Yu-fei Pan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Redox Homeostasis ◽  
Feedback Regulation ◽  
Cellular Redox ◽  
Intracellular Ros ◽  
Oxidative Stress Status ◽  
Kelch Domain ◽  
Cellular Stressors ◽  
Hcc Cells

Oxidative stress status has a key role in hepatocellular carcinoma (HCC) development and progression. Normally, reactive oxygen species (ROS) levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors. How HCC cells respond to excessive oxidative stress remains elusive. Here, we identified a feedback loop between gankyrin, an oncoprotein overexpressed in human HCC, and Nrf2 maintaining the homeostasis in HCC cells. Mechanistically, gankyrin was found to interact with the Kelch domain of Keap1 and effectively competed with Nrf2 for Keap1 binding. Increased expression of gankyrin in HCC cells blocked the binding between Nrf2 and Keap1, inhibiting the degradation of Nrf2 by proteasome. Interestingly, accumulation and translocation of Nrf2 increased the transcription of gankyrin through binding to the ARE elements in the promoter of gankyrin. The positive feedback regulation involving gankyrin and Nrf2 modulates a series of antioxidant enzymes, thereby lowering intracellular ROS and conferring a steadier intracellular environment, which prevents mitochondrial damage and cell death induced by excessive oxidative stress. Our results indicate that gankyrin is a regulator of cellular redox homeostasis and provide a link between oxidative stress and the development of HCC.

scholarly journals S-Adenosylmethionine Deficiency and Brain Accumulation of S-Adenosylhomocysteine in Thioacetamide-Induced Acute Liver Failure

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2135
Author(s):  
Anna Maria Czarnecka ◽  
Wojciech Hilgier ◽  
Magdalena Zielińska
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Redox Homeostasis ◽  
Cerebral Function ◽  
Total Glutathione ◽  
Cellular Redox ◽  
Therapeutic Value ◽  
Transsulfuration Pathway ◽  
Subsequent Hydrolysis ◽  
The Brain

Background: Acute liver failure (ALF) impairs cerebral function and induces hepatic encephalopathy (HE) due to the accumulation of neurotoxic and neuroactive substances in the brain. Cerebral oxidative stress (OS), under control of the glutathione-based defense system, contributes to the HE pathogenesis. Glutathione synthesis is regulated by cysteine synthesized from homocysteine via the transsulfuration pathway present in the brain. The transsulfuration-transmethylation interdependence is controlled by a methyl group donor, S-adenosylmethionine (AdoMet) conversion to S-adenosylhomocysteine (AdoHcy), whose removal by subsequent hydrolysis to homocysteine counteract AdoHcy accumulation-induced OS and excitotoxicity. Methods: Rats received three consecutive intraperitoneal injections of thioacetamide (TAA) at 24 h intervals. We measured AdoMet and AdoHcy concentrations by HPLC-FD, glutathione (GSH/GSSG) ratio (Quantification kit). Results: AdoMet/AdoHcy ratio was reduced in the brain but not in the liver. The total glutathione level and GSH/GSSG ratio, decreased in TAA rats, were restored by AdoMet treatment. Conclusion: Data indicate that disturbance of redox homeostasis caused by AdoHcy in the TAA rat brain may represent a deleterious mechanism of brain damage in HE. The correction of the GSH/GSSG ratio following AdoMet administration indicates its therapeutic value in maintaining cellular redox potential in the cerebral cortex of ALF rats.

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