A Functional Transsulfuration Pathway in the Brain Links to Glutathione Homeostasis

Vitvitsky, Victor; Thomas, Mark; Ghorpade, Anuja; Gendelman, Howard Eliot; Banerjee, Ruma

doi:10.1074/jbc.m602799200

Cited by 203 publications

(158 citation statements)

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“…pathway is an important determinant of intracellular cysteine concentration and accounts for *40%-50% of the cysteine that is tied up in the GSH pool in some cell types (36,54). An important role of GSH is the removal of H 2 O 2 catalyzed by GSH peroxidase.…”

Section: Discussionmentioning

confidence: 99%

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

Niu

Yadav

Adamec

et al. 2015

Antioxidants & Redox Signaling

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Aims: Cystathionine b-synthase (CBS) catalyzes the first and rate-limiting step in the two-step trans-sulfuration pathway that converts homocysteine to cysteine. It is also one of three major enzymes responsible for the biogenesis of H 2 S, a signaling molecule. We have previously demonstrated that CBS is activated in cells challenged by oxidative stress, but the underlying molecular mechanism of this regulation has remained unclear. Results: Here, we demonstrate that S-glutathionylation of CBS enhances its activity *2-fold in vitro. Loss of this post-translational modification in the presence of dithiothreitol results in reversal to basal activity. Cys346 was identified as the site for S-glutathionylation by a combination of mass spectrometric, mutagenesis, and activity analyses. To test the physiological relevance of S-glutathionylation-dependent regulation of CBS, HEK293 cells were oxidatively challenged with peroxide, which is known to enhance the trans-sulfuration flux. Under these conditions, CBS glutathionylation levels increased and were correlated with a *3-fold increase in CBS activity. Innovation: Collectively, our results reveal a novel post-translational modification of CBS, that is, glutathionylation, which functions as an allosteric activator under oxidative stress conditions permitting enhanced synthesis of both cysteine and H 2 S. Conclusions: Our study elucidates a molecular mechanism for increased cysteine and therefore glutathione, synthesis via glutathionylation of CBS. They also demonstrate the potential for increased H 2 S production under oxidative stress conditions, particularly in tissues where CBS is a major source of H 2 S. Antioxid. Redox Signal. 22,[350][351][352][353][354][355][356][357][358][359][360][361]

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Section: Discussionmentioning

confidence: 99%

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

Niu

Yadav

Adamec

et al. 2015

Antioxidants & Redox Signaling

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“…In fact, it is widely assumed, based on the reported absences of CSE in the brain (15) and of H 2 S in the brain of CBS knock-out mice (16), that CBS is the primary source of H 2 S in this organ, whereas CSE plays the equivalent role in the peripheral vasculature (3). However, recent studies have demonstrated that CSE is both present and active in the brain (17,18) and that H 2 S is in fact detected in the brains of transgenic mice lacking CBS (19). The major role of CSE in H 2 S biogenesis in the peripheral system has been convincingly demonstrated in CSE knock-out mice, which exhibit significantly reduced H 2 S levels in the serum and lower H 2 S production rates in aorta and heart (20).…”

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confidence: 99%

H2S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia

Chiku

Padovani

Zhu

et al. 2009

Journal of Biological Chemistry

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Although there is a growing recognition of the significance of hydrogen sulfide (H 2 S) as a biological signaling molecule involved in vascular and nervous system functions, its biogenesis and regulation are poorly understood. It is widely assumed that desulfhydration of cysteine is the major source of H 2 S in mammals and is catalyzed by the transsulfuration pathway enzymes, cystathionine ␤-synthase and cystathionine ␥-lyase (CSE). In this study, we demonstrate that the profligacy of human CSE results in a variety of reactions that generate H 2 S from cysteine and homocysteine. The ␥-replacement reaction, which condenses two molecules of homocysteine, yields H 2 S and a novel biomarker, homolanthionine, which has been reported in urine of homocystinuric patients, whereas a ␤-replacement reaction, which condenses two molecules of cysteine, generates lanthionine. Kinetic simulations at physiologically relevant concentrations of cysteine and homocysteine, reveal that the ␣,␤-elimination of cysteine accounts for ϳ70% of H 2 S generation. However, the relative importance of homocysteinederived H 2 S increases progressively with the grade of hyperhomocysteinemia, and under conditions of severely elevated homocysteine (200 M), the ␣,␥-elimination and ␥-replacement reactions of homocysteine together are predicted to account for ϳ90% of H 2 S generation by CSE. Excessive H 2 S production in hyperhomocysteinemia may contribute to the associated cardiovascular pathology.H 2 S is the newest member of a growing list of gaseous signaling molecules that modulate physiological functions (1-3). Concentrations of H 2 S ranging from 50 to 160 M have been reported in the brain (4), where it appears to function as a neuromodulator by potentiating the activity of the N-methyl-Daspartate receptor and by altering induction of long term potentiation in the hippocampus, important for memory and learning (5). H 2 S levels in human plasma are reported to be ϳ50 M, and in vitro studies suggest that it functions as a vasodilator by opening K ATP channels in vascular smooth muscle cells (6).A recent in vivo study has demonstrated the efficacy of H 2 S in attenuating myocardial ischemia-reperfusion injury by protecting mitochondrial function (7). The role of H 2 S in inflammation is suggested by several studies (8 -11); however, the underlying mechanism is unknown. Remarkably, H 2 S can also induce a state of suspended animation in mice by decreasing the metabolic rate and the core body temperature presumably by inhibiting cytochrome c oxidase in the respiratory chain (12).Endogenous H 2 S is presumed to be generated primarily by desulfhydration of cysteine catalyzed by the two pyridoxal phosphate (PLP) 3 -dependent enzymes in the transsulfuration pathway: cystathionine ␤-synthase (CBS) and cystathionine ␥-lyase (CSE) (13,14). In fact, it is widely assumed, based on the reported absences of CSE in the brain (15) and of H 2 S in the brain of CBS knock-out mice (16), that CBS is the primary source of H 2 S in this organ, whereas CSE plays the...

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“…The presence of large amounts of Cysta in affected human brain and in developing brain has been demonstrated [16]. Thus, the surplus of Cysta level in AD brain could be used to increase cysteine pool for glutathione synthesis, the major redox buffer in mammalian cells [17,18]. A decrease in Arg content, for instance, may have the slowdown of the citrulline-NO cycle as a consequence [19].…”

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confidence: 99%

Alzheimer’s disease: amino acid levels and brain metabolic status

2013

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To study brain free amino acids and their relation with dementia we measured, by high-performance liquid chromatography (HPLC), the concentration of eight free amino acids, amines and related compounds. We used temporal cortex (TC) samples obtained from 13 Alzheimer's disease (AD) patients and an equal number of agematched controls (AC). The patterns of free amino acids, amines and related compounds showed significant quantitative changes in AD conditions with respect to healthy ones. In Alzheimer patients, lower levels of GABA were found in the TC (-57 %). Amino acids glutamate (Glu), and aspartate (Asp) concentrations, also appeared significantly reduced in the TC of AD patients (Glu: -30 %; Asp: -40 %) when compared with controls. The significant gap between methionine (Met: -30 %) and cystathionine (Cysta: ?60 %) levels in TC of AD people to controls, might suggest an under/over activity of the transmethylation and transsulphuration pathways, respectively. Glutamine (Gln) and Urea were an exception to this trend because their content was higher in AD patients than in controls. Albeit these compounds may have particular physiological roles, including the possible mediation of synaptic transmission, changes in amino acid levels and related compounds (detected in steady state) suggest a modified metabolic status in brains of AD patients that reveals a reduced function of synaptic transmission. Because several evidences show that patients might display quite different concentrations of neurotransmitters in brain areas, assessing metabolites in different and well-characterized AD stages should be investigated further.

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A Functional Transsulfuration Pathway in the Brain Links to Glutathione Homeostasis

Cited by 203 publications

References 50 publications

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

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

H2S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia

Alzheimer’s disease: amino acid levels and brain metabolic status

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