S-Glutathionylation Enhances Human Cystathionine β-Synthase Activity Under Oxidative Stress Conditions

Niu, Wei; Yadav, Pramod Kumar; Adamec, Jiřı́; Banerjee, Ruma

doi:10.1089/ars.2014.5891

Cited by 93 publications

(87 citation statements)

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“…Along with the CS de novo pathway, the RTS pathway has also been considered an alternative source for supplying redox potential to parasite cells under oxidative stress (45). Our findings concerning the regulation of LbrCS and LbrC␤S are the first report of the activation of these enzymes under oxidative and nitrosative stress.…”

Section: Discussionmentioning

confidence: 63%

Upregulation of Cysteine Synthase and Cystathionine β-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress

Romero

Téllez

Romanha

et al. 2015

Antimicrob Agents Chemother

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Cysteine metabolism is considered essential for the crucial maintenance of a reducing environment in trypanosomatids due to its importance as a precursor of trypanothione biosynthesis. Expression, activity, functional rescue, and overexpression of cysteine synthase (CS) and cystathionine ␤-synthase (C␤S) were evaluated in Leishmania braziliensis promastigotes and intracellular amastigotes under in vitro stress conditions induced by hydrogen peroxide (H 2 O 2 ), S-nitroso-N-acetylpenicillamine, or antimonial compounds. Our results demonstrate a stage-specific increase in the levels of protein expression and activity of L. braziliensis CS (LbrCS) and L. braziliensis C␤S (LbrC␤S), resulting in an increment of total thiol levels in response to both oxidative and nitrosative stress. The rescue of the CS activity in Trypanosoma rangeli, a trypanosome that does not perform cysteine biosynthesis de novo, resulted in increased rates of survival of epimastigotes expressing the LbrCS under stress conditions compared to those of wild-type parasites. We also found that the ability of L. braziliensis promastigotes and amastigotes overexpressing LbrCS and LbrC␤S to resist oxidative stress was significantly enhanced compared to that of nontransfected cells, resulting in a phenotype far more resistant to treatment with the pentavalent form of Sb in vitro. In conclusion, the upregulation of protein expression and increment of the levels of LbrCS and LbrC␤S activity alter parasite resistance to antimonials and may influence the efficacy of antimony treatment of New World leishmaniasis.T he intracellular protozoan parasite Leishmania causes a neglected infectious disease commonly referred to as leishmaniasis. Depending on the infecting species and the immune status of the host, leishmaniasis can result in a variety of clinical manifestations with cutaneous, mucocutaneous, or visceral involvement (1-3). Leishmania (Viannia) braziliensis, the causative agent of cutaneous leishmaniasis and mucocutaneous leishmaniasis, is the most prevalent species infecting humans in the Americas (4, 5).Leishmania spp. have a digenetic life cycle, alternating between flagellated promastigote forms in the midgut of the sand fly and obligatory intracellular amastigotes within macrophages of the mammalian host (6, 7). During this complex life cycle, these parasites are exposed to variable oxidative or nitrosative stresses induced by reactive oxygen species (ROS) or reactive nitrogen species (RNS), respectively, generated by the host immune system to avoid infection (8, 9). Antimonial compounds, such as sodium stibogluconate or Sb (Pentostan) or meglumine antimoniate (Glucantime), are still the first-choice drugs for human leishmaniasis treatment (10). Among these, the Sb pentavalent form (Sb V ) has been reported to indirectly induce oxidative and nitrosative stress on the parasite by stimulating infected macrophages (M) to generate ROS and nitric oxide (NO) via activation of phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), and mitogenactivated ...

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Section: Discussionmentioning

confidence: 63%

Upregulation of Cysteine Synthase and Cystathionine β-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress

Romero

Téllez

Romanha

et al. 2015

Antimicrob Agents Chemother

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“…Its nuclear translocation is related to posttranslational modification by small ubiquitin-like modifier, which inhibits its activity (49). Moreover, CBS activity is regulated by other small molecules, including its activation by S-adenosylmethionine and glutathione (46,86) and inhibition by NO and CO (28,49,115). Relatively less is known about regulation of CSE and 3-MST.…”

Section: H 2 S Formation: Enzymatic and Nonenzymatic Pathwaysmentioning

confidence: 99%

Working with nitric oxide and hydrogen sulfide in biological systems

Yuan

Patel

Kevil

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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(H 2S) are gasotransmitter molecules important in numerous physiological and pathological processes. Although these molecules were first known as environmental toxicants, it is now evident that that they are intricately involved in diverse cellular functions with impact on numerous physiological and pathogenic processes. NO and H 2S share some common characteristics but also have unique chemical properties that suggest potential complementary interactions between the two in affecting cellular biochemistry and metabolism. Central among these is the interactions between NO, H 2S, and thiols that constitute new ways to regulate protein function, signaling, and cellular responses. In this review, we discuss fundamental biochemical principals, molecular functions, measurement methods, and the pathophysiological relevance of NO and H 2S. thiol; oxidation; redox; pulmonary; cardiovascular HISTORICALLY CONSIDERED ONLY as industrial pollutants, nitric oxide (NO) and hydrogen sulfide (H 2 S) are now appreciated as two key physiologically produced signaling molecules that control multiple cellular functions. Appreciation that dysfunction in how these solvated gases affect these functions, through either deficient formation or downstream reactivity, has opened up new therapeutic avenues for a host of diseases in all major organ systems including the lung. Our understanding of NO homeostasis mechanisms are relatively advanced compared with H 2 S, primarily because of the latter's discovery as a biologically relevant entity being postdated by a decade or more compared with NO. Although they are chemically distinct, there are intriguing parallel mechanisms/concepts in NO and H 2 S biology that include overlapping functions, technical challenges in how each of these gases are measured in biological milieu, appreciation of the mechanisms and factors that modulate how metabolism of each of these is regulated, and therapeutic potential for either inhibiting or repleting NO or H 2 S. In this article, and within the framework outlined above, we provide a general overview of NO and H 2 S biology. Nitric Oxide Formation: Enzymatic and Nonenzymatic SourcesEnzymatic sources. Nitric oxide is synthesized by one of three different isoforms of nitric oxide synthase (NOS) that differ in enzymatic activity, in how they are regulated (transcriptional, translational, and posttranslational mechanisms), and in how they are expressed/compartmentalized in tissues as well as the subcellular level. These are called NOS I, II, and III, corresponding to the inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) isoforms, typically with high, mid, and low activities, respectively. In the systemic and pulmonary vasculature, eNOS plays a key role in controlling blood flow and maintaining an antithrombotic and anti-inflammatory luminal surface. On the other hand, iNOS is induced by inflammatory stimuli in leukocytes, airway epithelial cells, and alveolar macrophages to mediate pathogen killing. However, production of NO at higher concentrations in ...

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“…Glutathionylation of cysteine 346 increases CBS activity threefold. 50) By contrast, the binding of NO or CO to the heme group at the amino terminus of CBS suppresses CBS activity. 51) This regulation plays a key role in microcirculation in the brain.…”

Section: Endogenous H 2 Smentioning

confidence: 99%

“…50),171) Oxidative stress depletes GSH and cysteine, which in turn enhances the activity of CBS to stimulate the production of H 2 S, cysteine, and GSH, which protect cells from oxidative stress. 50) …”

Section: Other Roles Of H 2 S and Therapeutic Applicationsmentioning

confidence: 99%

Hydrogen sulfide and polysulfides as signaling molecules

Kimura

2015

Nitric Oxide

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Hydrogen sulfide (H 2 S) is a familiar toxic gas that smells of rotten eggs. After the identification of endogenous H 2 S in the mammalian brain two decades ago, studies of this molecule uncovered physiological roles in processes such as neuromodulation, vascular tone regulation, cytoprotection against oxidative stress, angiogenesis, anti-inflammation, and oxygen sensing. Enzymes that produce H 2 S, such as cystathionine O-synthase, cystathionine .-lyase, and 3-mercaptopyruvate sulfurtransferase have been studied intensively and well characterized. Polysulfides, which have a higher number of inner sulfur atoms than that in H 2 S, were recently identified as potential signaling molecules that can activate ion channels, transcription factors, and tumor suppressors with greater potency than that of H 2 S. This article focuses on our contribution to the discovery of these molecules and their metabolic pathways and mechanisms of action.

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S-Glutathionylation Enhances Human Cystathionine β-Synthase Activity Under Oxidative Stress Conditions

Cited by 93 publications

References 57 publications

Upregulation of Cysteine Synthase and Cystathionine β-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress

Upregulation of Cysteine Synthase and Cystathionine β-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress

Working with nitric oxide and hydrogen sulfide in biological systems

Hydrogen sulfide and polysulfides as signaling molecules

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