The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Ruma Banerjee - One of the best experts on this subject based on the ideXlab platform.
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catalytic promiscuity and heme dependent redox regulation of h2s synthesis
Current Opinion in Chemical Biology, 2017Co-Authors: Ruma BanerjeeAbstract:The view of enzymes as punctilious catalysts has been shifting as examples of their promiscuous behavior increase. However, unlike a number of cases where the physiological relevance of breached substrate specificity is questionable, the very synthesis of H2S relies on substrate and reaction promiscuity, which presents the enzymes with a multitude of substrate and reaction choices. The Transsulfuration Pathway, a major source of H2S, is inherently substrate-ambiguous. A heme-regulated switch embedded in the first enzyme in the Pathway can help avert the stochastic production of cysteine versus H2S and control switching between metabolic tracks to meet cellular needs. This review discusses the dominant role of enzyme promiscuity in Pathways that double as sulfur catabolic and H2S synthetic tracks.
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heme dependent metabolite switching regulates h2s synthesis in response to endoplasmic reticulum er stress
Journal of Biological Chemistry, 2016Co-Authors: Omer Kabil, Vinita Yadav, Ruma BanerjeeAbstract:Substrate ambiguity and relaxed reaction specificity underlie the diversity of reactions catalyzed by the Transsulfuration Pathway enzymes, cystathionine β-synthase (CBS) and γ-cystathionase (CSE). These enzymes either commit sulfur metabolism to cysteine synthesis from homocysteine or utilize cysteine and/or homocysteine for synthesis of H2S, a signaling molecule. We demonstrate that a kinetically controlled heme-dependent metabolite switch in CBS regulates these competing reactions where by cystathionine, the product of CBS, inhibits H2S synthesis by the second enzyme, CSE. Under endoplasmic reticulum stress conditions, induction of CSE and up-regulation of the CBS inhibitor, CO, a product of heme oxygenase-1, flip the operating preference of CSE from cystathionine to cysteine, transiently stimulating H2S production. In contrast, genetic deficiency of CBS leads to chronic stimulation of H2S production. This metabolite switch from cystathionine to cysteine and/or homocysteine renders H2S synthesis by CSE responsive to the known modulators of CBS: S-adenosylmethionine, NO, and CO. Used acutely, it regulates H2S synthesis; used chronically, it might contribute to disease pathology.
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vitamin b 6 restriction reduces the production of hydrogen sulfide and its biomarkers by the Transsulfuration Pathway in cultured human hepatoma cells
Journal of Nutrition, 2014Co-Authors: Barbara N Deratt, Omer Kabil, Ruma Banerjee, Maria Ralat, Yuehyun Chi, Jesse F. GregoryAbstract:Background: Pyridoxal 5′-phosphate (PLP) functions as a coenzyme in many cellular processes including one-carbon metabolism and the interconversion and catabolism of amino acids. PLP-dependent enzymes, cystathionine β-synthase and cystathionine γ-lyase, function in Transsulfuration but also have been implicated in the production of the endogenous gaseous signaling molecule hydrogen sulfide (H2S) concurrent with the formation of the biomarkers lanthionine and homolanthionine. Objective: Our objective was to determine if H2S production and concurrent biomarker production is affected by vitamin B-6 restriction in a cell culture model. Methods: We used cultured human hepatoma cells and evaluated static intracellular profiles of amino acids and in vivo kinetics of H2S biomarker formation. Cells were cultured for 6 wk in media containing concentrations of pyridoxal that represented severe vitamin B-6 deficiency (15 nmol/L pyridoxal), marginal deficiency (56 nmol/L pyridoxal), adequacy (210 nmol/L pyridoxal), and standard medium formulation providing a supraphysiologic pyridoxal concentration (1800 nmol/L pyridoxal). Results: Intracellular concentrations of lanthionine and homolanthionine in cells cultured at 15 nmol/L pyridoxal were 50% lower (P < 0.002) and 47% lower (P < 0.0255), respectively, than observed in cells cultured at 1800 nmol/L pyridoxal. Extracellular homocysteine and cysteine were 58% and 46% higher, respectively, in severely deficient cells than in adequate cells (P < 0.002). Fractional synthesis rates of lanthionine (P < 0.01) and homolanthionine (P < 0.006) were lower at 15 and 56 nmol/L pyridoxal than at both higher pyridoxal concentrations. The rate of homocysteine remethylation and the fractional rate of homocysteine production from methionine were not affected by vitamin B-6 restriction. In vitro studies of cell lysates using direct measurement of H2S also had a reduced extent of H2S production in the 2 lower vitamin B-6 conditions. Conclusion: In view of the physiologic roles of H2S, these results suggest a mechanism that may be involved in the association between human vitamin B-6 inadequacy and its effects on human health.
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integrated stress response modulates cellular redox state via induction of cystathionine γ lyase cross talk between integrated stress response and thiol metabolism
Journal of Biological Chemistry, 2012Co-Authors: Jeffrey G Dickhout, Ruma Banerjee, Rachel E Carlisle, Danielle E Jerome, Zahraa Mohammedali, Hua Jiang, Guangdong Yang, Sarathi Mani, Sanjay K Garg, Randal J KaufmanAbstract:The integrated stress response mediated by eukaryotic translation initiation factor 2α (eIF2α) phosphorylation maintains cellular homeostasis under endoplasmic reticulum (ER) stress. eIF2α phosphorylation induces activating transcription factor 4 (ATF4), a basic leucine zipper transcription factor that regulates the expression of genes responsible for amino acid metabolism, cellular redox state, and anti-stress responses. Cystathionine γ-lyase (CSE) and cystathionine β-synthase are critical enzymes in the Transsulfuration Pathway, which also regulate cellular redox status by modulating glutathione (GSH) levels. To determine the link between the integrated stress response and the Transsulfuration Pathway, we used homocysteine (Hcy) as an inducer of eIF2α phosphorylation and ATF4 gene induction. Mouse embryonic fibroblasts (MEFs) lacking ATF4 (ATF4−/−) had reduced GSH levels and increased reactive oxygen species and were susceptible to apoptotic cell death under normal culture conditions. Further, ATF4−/− MEFs were more sensitive to Hcy-induced cytotoxicity and showed significantly reduced intracellular GSH levels associated with apoptosis. ATF4−/− MEFs could be rescued from l-Hcy-induced apoptosis by β-mercaptoethanol medium supplementation that increases cysteine levels and restores GSH synthesis. ATF4−/− MEFs showed little or no CSE protein but did express cystathionine β-synthase. Further, ER stress-inducing agents, including tunicamycin and thapsigargin, induced the expression of CSE in ATF4+/+ MEFs. Consistent with ATF4−/− MEFs, CSE−/− MEFs showed significantly greater apoptosis when treated with tunicamycin, thapsigargin, and l-Hcy, compared with CSE+/+ MEFs. Liver and kidney GSH levels were also reduced in CSE−/− mice, suggesting that CSE is a critical factor in GSH synthesis and may act to protect the liver and kidney from a variety of conditions that cause ER stress.
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increased Transsulfuration mediates longevity and dietary restriction in drosophila
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Omer Kabil, Ruma Banerjee, Hadise Kabil, Lawrence G Harshman, Steven D PletcherAbstract:The mechanisms through which dietary restriction enhances health and longevity in diverse species are unclear. The Transsulfuration Pathway (TSP) is a highly conserved mechanism for metabolizing the sulfur-containing amino acids, methionine and cysteine. Here we show that Drosophila cystathionine β-synthase (dCBS), which catalyzes the rate-determining step in the TSP, is a positive regulator of lifespan in Drosophila and that the Pathway is required for the effects of diet restriction on animal physiology and lifespan. dCBS activity was up-regulated in flies exposed to reduced nutrient conditions, and ubiquitous or neuron-specific transgenic overexpression of dCBS enhanced longevity in fully fed animals. Inhibition of the TSP abrogated the changes in lifespan, adiposity, and protein content that normally accompany diet restriction. RNAi-mediated knockdown of dCBS also limited lifespan extension by diet. Diet restriction reduced levels of protein translation in Drosophila, and we show that this is largely caused by increased metabolic commitment of methionine cycle intermediates to Transsulfuration. However, dietary supplementation of methionine restored normal levels of protein synthesis to restricted animals without affecting lifespan, indicating that global reductions in translation alone are not required for diet-restriction longevity. Our results indicate a mechanism by which dietary restriction influences physiology and aging.
Alessandra F. Perna - One of the best experts on this subject based on the ideXlab platform.
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Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium.
International journal of molecular sciences, 2019Co-Authors: Carmela Vigorito, Miriam Zacchia, Francesco Trepiccione, Evgeniya Anishchenko, Diego Ingrosso, Patrizia Lombari, Luigi Mele, Giovanna Capolongo, Rosanna Capasso, Alessandra F. PernaAbstract:(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of Transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.
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The sulfur metabolite lanthionine: Evidence for a role as a novel Uremic Toxin
Toxins, 2017Co-Authors: Alessandra F. Perna, Miriam Zacchia, Francesco Trepiccione, Diego IngrossoAbstract:Lanthionine is a nonproteinogenic amino acid, composed of two alanine residues that are crosslinked on their β-carbon atoms by a thioether linkage. It is biosynthesized from the condensation of two cysteine molecules, while the related compound homolanthionine is formed from the condensation of two homocysteine molecules. The reactions can be carried out by either cystathionine-β-synthase (CBS) or cystathionine-γ-lyase (CSE) independently, in the alternate reactions of the Transsulfuration Pathway devoted to hydrogen sulfide biosynthesis. Low plasma total hydrogen sulfide levels, probably due to reduced CSE expression, are present in uremia, while homolanthionine and lanthionine accumulate in blood, the latter several fold. Uremic patients display a derangement of sulfur amino acid metabolism with a high prevalence of hyperhomocysteinemia. Uremia is associated with a high cardiovascular mortality, the causes of which are still not completely explained, but are related to uremic toxicity, due to the accumulation of retention products. Lanthionine inhibits hydrogen sulfide production in hepatoma cells, possibly through CBS inhibition, thus providing some basis for the biochemical mechanism, which may significantly contribute to alterations of metabolism sulfur compounds in these subjects (e.g., high homocysteine and low hydrogen sulfide). We therefore suggest that lanthionine is a novel uremic toxin.
Diego Ingrosso - One of the best experts on this subject based on the ideXlab platform.
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Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium.
International journal of molecular sciences, 2019Co-Authors: Carmela Vigorito, Miriam Zacchia, Francesco Trepiccione, Evgeniya Anishchenko, Diego Ingrosso, Patrizia Lombari, Luigi Mele, Giovanna Capolongo, Rosanna Capasso, Alessandra F. PernaAbstract:(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of Transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.
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The sulfur metabolite lanthionine: Evidence for a role as a novel Uremic Toxin
Toxins, 2017Co-Authors: Alessandra F. Perna, Miriam Zacchia, Francesco Trepiccione, Diego IngrossoAbstract:Lanthionine is a nonproteinogenic amino acid, composed of two alanine residues that are crosslinked on their β-carbon atoms by a thioether linkage. It is biosynthesized from the condensation of two cysteine molecules, while the related compound homolanthionine is formed from the condensation of two homocysteine molecules. The reactions can be carried out by either cystathionine-β-synthase (CBS) or cystathionine-γ-lyase (CSE) independently, in the alternate reactions of the Transsulfuration Pathway devoted to hydrogen sulfide biosynthesis. Low plasma total hydrogen sulfide levels, probably due to reduced CSE expression, are present in uremia, while homolanthionine and lanthionine accumulate in blood, the latter several fold. Uremic patients display a derangement of sulfur amino acid metabolism with a high prevalence of hyperhomocysteinemia. Uremia is associated with a high cardiovascular mortality, the causes of which are still not completely explained, but are related to uremic toxicity, due to the accumulation of retention products. Lanthionine inhibits hydrogen sulfide production in hepatoma cells, possibly through CBS inhibition, thus providing some basis for the biochemical mechanism, which may significantly contribute to alterations of metabolism sulfur compounds in these subjects (e.g., high homocysteine and low hydrogen sulfide). We therefore suggest that lanthionine is a novel uremic toxin.
Yolande Surdinkerjan - One of the best experts on this subject based on the ideXlab platform.
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cysteine biosynthesis in saccharomyces cerevisiae occurs through the Transsulfuration Pathway which has been built up by enzyme recruitment
Journal of Bacteriology, 1993Co-Authors: H Cherest, David D Thomas, Yolande SurdinkerjanAbstract:The Transsulfuration Pathways allow the interconversion of homocysteine and cysteine with the intermediary formation of cystathionine. The various organisms studied up to now incorporate reduced sulfur into a three- or a four-carbon chain and use differently the Transsulfuration Pathways to synthesize sulfur amino acids. In enteric bacteria, the synthesis of cysteine is the first step of organic sulfur metabolism and homocysteine is derived from cysteine. Fungi are capable of incorporating reduced sulfur into a four-carbon chain, and they possess two operating Transsulfuration Pathways. By contrast, synthesis of cysteine from homocysteine is the only existing Transsulfuration Pathway in mammals. In Saccharomyces cerevisiae, genetic, phenotypic, and enzymatic study of mutants has allowed us to demonstrate that homocysteine is the first sulfur amino acid to be synthesized and cysteine is derived only from homocysteine (H. Cherest and Y. Surdin-Kerjan, Genetics 130:51-58, 1992). We report here the cloning of genes STR4 and STR1, encoding cystathionine beta-synthase and cystathionine gamma-lyase, respectively. The only phenotypic consequence of the inactivation of STR1 or STR4 is cysteine auxotrophy. The sequencing of gene STR4 has allowed us to compare all of the known sequences of Transsulfuration enzymes and enzymes catalyzing the incorporation of reduced sulfur in carbon chains. These comparisons reveal a partition into two families based on sequence motifs. This partition mainly correlates with similarities in the catalytic mechanisms of these enzymes.
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genetic analysis of a new mutation conferring cysteine auxotrophy in saccharomyces cerevisiae updating of the sulfur metabolism Pathway
Genetics, 1992Co-Authors: Hilene Cherest, Yolande SurdinkerjanAbstract:We have identified a mutation in a gene of Saccharomyces cerevisiae, STR1, that leads to a strict nutritional requirement for cysteine. The str1-1 mutation decreases to an undetectable level the cystathionine gamma-lyase activity. This enzyme catalyzes one of the two reactions involved in the Transsulfuration Pathway that yields cysteine from homocysteine with the intermediary formation of cystathionine. The phenotype induced by this mutation implies that, in S. cerevisiae, the sulfur atom of sulfide resulting from the reductive assimilation of sulfate is incorporated into a four carbon backbone yielding homocysteine, which, in turn, is the precursor of the biosynthesis of both cysteine and methionine. This also reveals that the direct synthesis of cysteine by incorporation of the sulfur atom into a three carbon backbone as found in Escherichia coli does not occur in S. cerevisiae. The study of the meiotic progeny of diploid strains heterozygous at the STR1 locus has shown that the str1-1 mutation undergoes a particularly high frequency of meiotic gene conversion.
Bindu D Paul - One of the best experts on this subject based on the ideXlab platform.
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neuroprotective roles of the reverse Transsulfuration Pathway in alzheimer s disease
Frontiers in Aging Neuroscience, 2021Co-Authors: Bindu D PaulAbstract:The reverse Transsulfuration Pathway has emerged as a central hub that integrates the metabolism of sulfur-containing amino acids and redox homeostasis. Transsulfuration involves the transfer of sulfur from homocysteine to cysteine. Cysteine serves as the precursor for several sulfur-containing molecules, which play diverse roles in cellular processes. Recent evidence shows that disruption of the flux through the Pathway has deleterious consequences. In this review article, I will discuss the actions and regulation of the reverse Transsulfuration Pathway and its links to other metabolic Pathways, which are disrupted in Alzheimer's disease (AD). The potential nodes of therapeutic intervention are also discussed, which may pave the way for the development of novel treatments.
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regulators of the Transsulfuration Pathway
British Journal of Pharmacology, 2019Co-Authors: Juan I Sbodio, Solomon H. Snyder, Bindu D PaulAbstract:The Transsulfuration Pathway is a metabolic Pathway where transfer of sulfur from homocysteine to cysteine occurs. The Pathway leads to the generation of several sulfur metabolites, which include cysteine, GSH and the gaseous signalling molecule hydrogen sulfide (H2 S). Precise control of this Pathway is critical for maintenance of optimal cellular function and, therefore, the key enzymes of the Pathway, cystathionine β-synthase and cystathionine γ-lyase, are regulated at multiple levels. Disruption of the Transsulfuration Pathway contributes to the pathology of several conditions such as vascular dysfunction, Huntington's disease and during ageing. Treatment with donors of hydrogen sulfide and/or stimulation of this Pathway have proved beneficial in several of these disorders. In this review, we focus on the regulation of the Transsulfuration Pathway pertaining to cysteine and H2 S, which could be targeted to develop novel therapeutics. LINKED ARTICLES: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.
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Gasotransmitter hydrogen sulfide signaling in neuronal health and disease
Biochemical Pharmacology, 2018Co-Authors: Bindu D Paul, Solomon H. SnyderAbstract:Hydrogen sulfide is a gaseous signaling molecule or gasotransmitter which plays important roles in a wide spectrum of physiologic processes in the brain and peripheral tissues. Unlike nitric oxide and carbon monoxide, the other major gasotransmitters, research on hydrogen sulfide is still in its infancy. One of the modes by which hydrogen sulfide signals is via a posttranslational modification termed sulfhydration/persulfidation, which occurs on reactive cysteine residues on target proteins, where the reactive –SH group is converted to an –SSH group. Sulfhydration is a substantially prevalent modification, which modulates the structure or function of proteins being modified. Thus, precise control of endogenous hydrogen sulfide production and metabolism is critical for maintenance of optimal cellular function, with excess generation and paucity, both contributing to pathology. Dysregulation of the reverse Transsulfuration Pathway which generates hydrogen sulfide occurs in several neurodegenerative diseases such as Parkinson's disease, Huntington's disease and Alzheimer's disease. Accordingly, treatment with donors of hydrogen sulfide or stimulation of the reverse Transsulfuration have proved beneficial in several neurodegenerative states. In this review we focus on hydrogen sulfide mediated neuronal signaling processes that contribute to neuroprotection.
