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Academic literature on the topic 'Transsulfuration pathway cystathionine-β-synthase cystathionine-γ-lyase hydrogen sulfide'
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Journal articles on the topic "Transsulfuration pathway cystathionine-β-synthase cystathionine-γ-lyase hydrogen sulfide"
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Bearden, Shawn E., Richard S. Beard, and Jean C. Pfau. "Extracellular transsulfuration generates hydrogen sulfide from homocysteine and protects endothelium from redox stress." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 5 (November 2010): H1568—H1576. http://dx.doi.org/10.1152/ajpheart.00555.2010.
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Homocysteine, a cardiovascular and neurocognitive disease risk factor, is converted to hydrogen sulfide, a cardiovascular and neuronal protectant, through the transsulfuration pathway. Given the damaging effects of free homocysteine in the blood and the importance of blood homocysteine concentration as a prognosticator of disease, we tested the hypotheses that the blood itself regulates homocysteine-hydrogen sulfide metabolism through transsulfuration and that transsulfuration capacity and hydrogen sulfide availability protect the endothelium from redox stress. Here we show that the transsulfuration enzymes, cystathionine β-synthase and cystathionine γ-lyase, are secreted by microvascular endothelial cells and hepatocytes, circulate as members of the plasma proteome, and actively produce hydrogen sulfide from homocysteine in human blood. We further demonstrate that extracellular transsulfuration regulates cell function when the endothelium is challenged with homocysteine and that hydrogen sulfide protects the endothelium from serum starvation and from hypoxia-reoxygenation injury. These novel findings uncover a unique set of opportunities to explore innovative clinical diagnostics and therapeutic strategies in the approach to homocysteine-related conditions such as atherosclerosis, thrombosis, and dementia.
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Berry, Thomas, Eid Abohamza, and Ahmed A. Moustafa. "Treatment-resistant schizophrenia: focus on the transsulfuration pathway." Reviews in the Neurosciences 31, no. 2 (January 28, 2020): 219–32. http://dx.doi.org/10.1515/revneuro-2019-0057.
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AbstractTreatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. The severity of illness is positively related to homocysteine levels, with high homocysteine levels due to the low activity of the transsulfuration pathway, which metabolizes homocysteine in synthesizing L-cysteine. Glutathione levels are low in schizophrenia, which indicates shortages of L-cysteine and low activity of the transsulfuration pathway. Hydrogen sulfide (H2S) levels are low in schizophrenia. H2S is synthesized by cystathionine β-synthase and cystathionine γ-lyase, which are the two enzymes in the transsulfuration pathway. Iron-sulfur proteins obtain sulfur from L-cysteine. The oxidative phosphorylation (OXPHOS) pathway has various iron-sulfur proteins. With low levels of L-cysteine, iron-sulfur cluster formation will be dysregulated leading to deficits in OXPHOS in schizophrenia. Molybdenum cofactor (MoCo) synthesis requires sulfur, which is obtained from L-cysteine. With low levels of MoCo synthesis, molybdenum-dependent sulfite oxidase (SUOX) will not be synthesized at appropriate levels. SUOX detoxifies sulfite from sulfur-containing amino acids. If sulfites are not detoxified, there can be sulfite toxicity. The transsulfuration pathway metabolizes selenomethionine, whereby selenium from selenomethionine can be used for selenoprotein synthesis. The low activity of the transsulfuration pathway decreases selenoprotein synthesis. Glutathione peroxidase (GPX), with various GPXs being selenoprotein, is low in schizophrenia. The dysregulations of selenoproteins would lead to oxidant stress, which would increase the methylation of genes and histones leading to epigenetic changes in TRS. An add-on treatment to mainline antipsychotics is proposed for TRS that targets the dysregulations of the transsulfuration pathway and the dysregulations of other pathways stemming from the transsulfuration pathway being dysregulated.
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Werge, Mikkel Parsberg, Adrian McCann, Elisabeth Douglas Galsgaard, Dorte Holst, Anne Bugge, Nicolai J. Wewer Albrechtsen, and Lise Lotte Gluud. "The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease." Journal of Clinical Medicine 10, no. 5 (March 5, 2021): 1081. http://dx.doi.org/10.3390/jcm10051081.
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The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.
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Zatsepina, Olga G., Lyubov N. Chuvakova, Ekaterina A. Nikitina, Alexander P. Rezvykh, Alexey S. Zakluta, Svetlana V. Sarantseva, Nina V. Surina, et al. "Genes Responsible for H2S Production and Metabolism Are Involved in Learning and Memory in Drosophila melanogaster." Biomolecules 12, no. 6 (May 26, 2022): 751. http://dx.doi.org/10.3390/biom12060751.
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The gasotransmitter hydrogen sulfide (H2S) produced by the transsulfuration pathway (TSP) is an important biological mediator, involved in many physiological and pathological processes in multiple higher organisms, including humans. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) enzymes play a central role in H2S production and metabolism. Here, we investigated the role of H2S in learning and memory processes by exploring several Drosophila melanogaster strains with single and double deletions of CBS and CSE developed by the CRISPR/Cas9 technique. We monitored the learning and memory parameters of these strains using the mating rejection courtship paradigm and demonstrated that the deletion of the CBS gene, which is expressed predominantly in the central nervous system, and double deletions completely block short- and long-term memory formation in fruit flies. On the other hand, the flies with CSE deletion preserve short- and long-term memory but fail to exhibit long-term memory retention. Transcriptome profiling of the heads of the males from the strains with deletions in Gene Ontology terms revealed a strong down-regulation of many genes involved in learning and memory, reproductive behavior, cognition, and the oxidation–reduction process in all strains with CBS deletion, indicating an important role of the hydrogen sulfide production in these vital processes.
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Xu, Zhibin, Gamika Prathapasinghe, Nan Wu, Sun-Young Hwang, Yaw L. Siow, and Karmin O. "Ischemia-reperfusion reduces cystathionine-β-synthase-mediated hydrogen sulfide generation in the kidney." American Journal of Physiology-Renal Physiology 297, no. 1 (July 2009): F27—F35. http://dx.doi.org/10.1152/ajprenal.00096.2009.
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Cystathionine-β-synthase (CBS) catalyzes the rate-limiting step in the transsulfuration pathway for the metabolism of homocysteine (Hcy) in the kidney. Our recent study demonstrates that ischemia-reperfusion reduces the activity of CBS leading to Hcy accumulation in the kidney, which in turn contributes to renal injury. CBS is also capable of catalyzing the reaction of cysteine with Hcy to produce hydrogen sulfide (H2S), a gaseous molecule that plays an important role in many physiological and pathological processes. The aim of the present study was to examine the effect of ischemia-reperfusion on CBS-mediated H2S production in the kidney and to determine whether changes in the endogenous H2S generation had any impact on renal ischemia-reperfusion injury. The left kidney of Sprague-Dawley rat was subjected to 45-min ischemia followed by 6-h reperfusion. The ischemia-reperfusion caused lipid peroxidation and cell death in the kidney. The CBS-mediated H2S production was decreased, leading to a significant reduction in the renal H2S level. The activity of cystathionine-γ-lyase, another enzyme responsible for endogenous H2S generation, was not significantly altered in the kidney upon ischemia-reperfusion. Partial restoration of CBS activity by intraperitoneal injection of the nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide not only increased renal H2S levels but also alleviated ischemia-reperfusion-induced lipid peroxidation and reduced cell damage in the kidney tissue. Furthermore, administration of an exogenous H2S donor, NaHS (100 μg/kg), improved renal function. Taken together, these results suggest that maintenance of tissue H2S level may offer a renal protective effect against ischemia-reperfusion injury.
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O, Karmin, and Yaw L. Siow. "Metabolic Imbalance of Homocysteine and Hydrogen Sulfide in Kidney Disease." Current Medicinal Chemistry 25, no. 3 (January 30, 2018): 367–77. http://dx.doi.org/10.2174/0929867324666170509145240.
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Homocysteine (Hcy) and hydrogen sulfide (H2S) are important molecules produced during the metabolism of sulfur-containing amino acids. Hcy metabolism is central to the supply of methyl groups that are essential for biological function. Hcy can be either regenerated to methionine or metabolized to cysteine, a precursor for glutathione synthesis. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) play a crucial role in metabolizing Hcy to cysteine through the transsulfuration pathway. These two enzymes are also responsible for H2S generation through desulfuration reactions. H2S, at physiological levels serves as a gaseous mediator and has multifaceted effects. Metabolic imbalance of Hcy and H2S has been implicated in pathological conditions including oxidative stress, inflammation, cardiovascular and cerebral dysfunction, fatty liver disease and ischemiareperfusion injury. Organs such as liver, kidney, gut and pancreas contain all the enzymes that are required for Hcy metabolism. The kidney plays an important role in removing Hcy from the circulation. Hyperhomocysteinemia, a condition of elevated blood Hcy level, is a common clinical finding in patients with chronic kidney disease (CKD) or acute kidney injury (AKI), the latter is often caused by ischemia-reperfusion. This paper reviews exiting literatures regarding (1) the role of kidney in regulating Hcy and H2S metabolism; (2) disruption of sulfur-containing amino acid metabolism during ischemiareperfusion; (3) impact of metabolic imbalance of Hcy and H2S on kidney function. Better understanding of molecular mechanisms that regulate Hcy and H2S metabolism under physiological and pathophysiological conditions will help improve therapeutic strategies for patients with kidney disease or other organ injuries.
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Hwang, Sun-Young, Lindsei K. Sarna, Yaw L. Siow, and Karmin O. "High-fat diet stimulates hepatic cystathionine β-synthase and cystathionine γ-lyase expression." Canadian Journal of Physiology and Pharmacology 91, no. 11 (November 2013): 913–19. http://dx.doi.org/10.1139/cjpp-2013-0106.
Full textAbstract:
Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) catalyze homocysteine (Hcy) metabolism via the trans-sulfuration pathway. They are also responsible for hydrogen sulfide (H2S) production via desulfuration reactions. The liver contributes significantly to the regulation of Hcy and H2S homeostasis, which might participate in many physiological and pathological processes. The aim of this study was to investigate the effect of a high-fat diet (HFD) on hepatic CBS and CSE expression and its impact on Hcy and H2S metabolism. Mice (C57BL/6) fed a HFD (60% kcal fat) for 5 weeks developed fatty liver. The mRNA and protein levels of CBS and CSE in the liver were significantly elevated in mice fed a HFD. Subsequently the metabolism of Hcy by CBS and CSE was increased in the liver, and its level decreased in the circulation. Increased CBS and CSE expression also caused a significant elevation in H2S production in the liver. The level of lipid peroxides was elevated, indicating oxidative stress, while the level of total glutathione remained unchanged in the liver of HFD-fed mice. Upregulation of the trans-sulfuration pathway might play an adaptive role against oxidative stress by maintaining total glutathione levels in the liver.
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Yadav, Pramod K., Victor Vitvitsky, Hanseong Kim, Andrew White, Uhn-Soo Cho, and Ruma Banerjee. "S-3-Carboxypropyl-l-cysteine specifically inhibits cystathionine γ-lyase–dependent hydrogen sulfide synthesis." Journal of Biological Chemistry 294, no. 28 (June 3, 2019): 11011–22. http://dx.doi.org/10.1074/jbc.ra119.009047.
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Hydrogen sulfide (H2S) is a gaseous signaling molecule, which modulates a wide range of mammalian physiological processes. Cystathionine γ-lyase (CSE) catalyzes H2S synthesis and is a potential target for modulating H2S levels under pathophysiological conditions. CSE is inhibited by propargylglycine (PPG), a widely used mechanism-based inhibitor. In this study, we report that inhibition of H2S synthesis from cysteine, but not the canonical cystathionine cleavage reaction catalyzed by CSE in vitro, is sensitive to preincubation of the enzyme with PPG. In contrast, the efficacy of S-3-carboxpropyl-l-cysteine (CPC) a new inhibitor described herein, was not dependent on the order of substrate/inhibitor addition. We observed that CPC inhibited the γ-elimination reaction of cystathionine and H2S synthesis from cysteine by human CSE with Ki values of 50 ± 3 and 180 ± 15 μm, respectively. We noted that CPC spared the other enzymes involved either directly (cystathionine β-synthase and mercaptopyruvate sulfurtransferase) or indirectly (cysteine aminotransferase) in H2S biogenesis. CPC also targeted CSE in cultured cells, inhibiting transsulfuration flux by 80–90%, as monitored by the transfer of radiolabel from [35S]methionine to GSH. The 2.5 Å resolution crystal structure of human CSE in complex with the CPC-derived aminoacrylate intermediate provided a structural framework for the molecular basis of its inhibitory effect. In summary, our study reveals a previously unknown confounding effect of PPG, widely used to inhibit CSE-dependent H2S synthesis, and reports on an alternative inhibitor, CPC, which could be used as a scaffold to develop more potent H2S biogenesis inhibitors.
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Kolluru, Gopi K., Xinggui Shen, and Christopher G. Kevil. "Reactive Sulfur Species." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 4 (April 2020): 874–84. http://dx.doi.org/10.1161/atvbaha.120.314084.
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Hydrogen sulfide has emerged as an important gaseous signaling molecule and a regulator of critical biological processes. However, the physiological significance of hydrogen sulfide metabolites such as persulfides, polysulfides, and other reactive sulfur species (RSS) has only recently been appreciated. Emerging evidence suggests that these RSS molecules may have similar or divergent regulatory roles compared with hydrogen sulfide in various biological activities. However, the chemical nature of persulfides and polysulfides is complex and remains poorly understood within cardiovascular and other pathophysiological conditions. Recent reports suggest that RSS can be produced endogenously, with different forms having unique chemical properties and biological implications involving diverse cellular responses such as protein biosynthesis, cell-cell barrier functions, and mitochondrial bioenergetics. Enzymes of the transsulfuration pathway, CBS (cystathionine beta-synthase) and CSE (cystathionine gamma-lyase), may also produce RSS metabolites besides hydrogen sulfide. Moreover, CARSs (cysteinyl-tRNA synthetase) are also able to generate protein persulfides via cysteine persulfide (CysSSH) incorporation into nascently formed polypeptides suggesting a new biologically relevant amino acid. This brief review discusses the biochemical nature and potential roles of RSS, associated oxidative stress redox signaling, and future research opportunities in cardiovascular disease.
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González-García, Pilar, Agustín Hidalgo-Gutiérrez, Cristina Mascaraque, Eliana Barriocanal-Casado, Mohammed Bakkali, Marcello Ziosi, Ussipbek Botagoz Abdihankyzy, et al. "Coenzyme Q10 modulates sulfide metabolism and links the mitochondrial respiratory chain to pathways associated to one carbon metabolism." Human Molecular Genetics 29, no. 19 (September 25, 2020): 3296–311. http://dx.doi.org/10.1093/hmg/ddaa214.
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Abstract Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine β-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.
Dissertations / Theses on the topic "Transsulfuration pathway cystathionine-β-synthase cystathionine-γ-lyase hydrogen sulfide"
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ROCCHICCIOLI, MARCO. "Assessment of transsulfuration enzymes pattern in a human astrocytoma cell line." Doctoral thesis, Università di Siena, 2016. http://hdl.handle.net/11365/1005175.
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La via di transulfurazione è centrale nel metabolismo degli amminoacidi solforati, questa, attraverso l'azione di due enzimi, la cistationina-β-sintasi e la cistationine-γ-liasi permette la sintesi di cisteina a partire da serina e omocisteina. Entrambi gli enzimi catalizzano anche la produzione di acido solfidrico attraverso una serie di reazioni a partire da substrati non canonici.
In questo lavoro è stato sviluppato un nuovo metodo colorimetrico accoppiato alla cistationine-γ-liasi come enzima ancillare per la misurazione della cistationina-β-sintasi. Il metodo è stato usato per dimostrare la presenza di una via di transulfurazione completa in una linea di astrocitoma umano. Inoltre è stata studiata la risposta dell'enzima limitante la via di transulfurazione, la cistationina-γ-liasi in condizioni di forte deplezione di cisteina.
Per analizzare il ruolo degli enzimi della via di transulfurazione sulla produzione endogena di acido solfidrico è stata messa a punto una camera di reazione per la misurazione del suddetto gas. Con questo nuovo approccio, l'acido solfidrico prodotto in soluzione dalla cistationine-γ-liasi è stato misurato nella fase gassosa attraverso un sensore amperometrico. Usando questo sistema le reazioni che producono acido solfidrico a partire da cisteina e da omocisteina sono state caratterizzate dal punto di vista cinetico.The transsulfuration pathway is the key pathway in the sulfur-containing amino acid metabolism, that, through the action of two enzymes, cystathionine-β-synthase and cystathionine-γ-lyase allows the synthesis of cysteine. Both cystathionine-β-synthase and cystathionine-γ-lyase catalyze also H2S production, in a series of reactions, from non-canonical substrates. In this study a novel enzyme-coupled colorimetric assay for cystathionine-β-synthase was developed, based on the use of cystathione-γ-lyase as ancillary enzyme. The method was adopted to demonstrate the presence of the complete transsulfuration enzyme machinery in a human astrocytoma cell line. The response of the rate limiting enzyme of the transsulfuration pathway, cystathione-γ-lyase, to a severe cysteine depletion was also evaluated. In addition, to unveil the H2S producing role of the transsulfuration pathway enzymes, a reaction chamber for measuring hydrogen sulfide was developed. With this new approach, the H2S produced in the liquid phase by cystathionine-γ-lyase, was measured in the gas phase of the chamber headspace. Adopting this system the reactions leading to H2S from cysteine and homocysteine were kinetically characterized.