Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation

Raju, Karthik; Doulias, Paschalis‐Thomas; Evans, Perry; Krizman, Elizabeth; Jackson, Jordan E.; Horyn, Oksana; Daikhin, Yevgeny; Nissim, Ilana; Yudkoff, Marc; Nissim, Itzhak; Sharp, Kim A.; Robinson, Michael B.; Ischiropoulos, Harry

doi:10.1126/scisignal.aaa4312

Cited by 114 publications

(83 citation statements)

References 87 publications

(150 reference statements)

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“…Accordingly, VLCAD is S-nitrosylated under basal conditions with low levels of NO, i.e., in the absence of cell stress or disease. Additionally, this same group of Harry Ischiropoulos found that several enzymes involved in glutamate metabolism are S-nitrosylated under basal conditions in mouse brain [48]. One such enzyme, glutamate dehydrogenase (GDH) oxidizes glutamate to α-ketoglutarate, which can feed into the TCA cycle.…”

Section: Tca Cycle Enzymes As Targets Of S-nitrosylationmentioning

confidence: 99%

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

Nakamura

Lipton

2017

Trends in Endocrinology & Metabolism

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The prevalence of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, is currently a major public health concern due to the lack of efficient disease-modifying therapeutic options. Recent evidence suggests that mitochondrial dysfunction and nitrosative/oxidative stress are key common mediators of pathogenesis. In this review, we highlight molecular mechanisms linking nitric oxide (NO)-dependent post-translational modifications, such as cysteine S-nitrosylation and tyrosine nitration, to abnormal mitochondrial metabolism. We further discuss the hypothesis that pathological levels of NO compromise brain energy metabolism via aberrant S-nitrosylation of key enzymes in the tricarboxylic acid cycle and oxidative phosphorylation, contributing to neurodegenerative conditions. A better understanding of these pathophysiological events may provide a potential pathway for designing novel therapeutics to ameliorate neurodegenerative disorders.

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Section: Tca Cycle Enzymes As Targets Of S-nitrosylationmentioning

confidence: 99%

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

Nakamura

Lipton

2017

Trends in Endocrinology & Metabolism

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“…Using these approaches, over 300 endogenous S-nitrosylation sites on ϳ200 proteins were identified from mouse liver (63). Ischiropoulos and colleagues further utilized this phenylmercury-based SNO-capture approach to identify up to 1,000 S-nitrosylation sites on hundreds of proteins in various mouse tissues (64,65). The number of S-nitrosylation sites in vivo to nitric oxide were found to be substantially dependent on endothelial nitric oxide synthase (eNOS) or neuronal nitric oxide synthase (nNOS) (64,65).…”

Section: The Expanding Landscape Of the Thiol Redox Proteomementioning

confidence: 99%

The Expanding Landscape of the Thiol Redox Proteome

Yang

Carroll

Liebler

2016

Molecular & Cellular Proteomics

185

111

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Cysteine occupies a unique place in protein chemistry. The nucleophilic thiol group allows cysteine to undergo a broad range of redox modifications beyond classical thiol-disulfide redox equilibria, including S-sulfenylation (-SOH), S-sulfinylation (-SO 2 H), S-sulfonylation (-SO 3 H), S-nitrosylation (-SNO), S-sulfhydration (-SSH), S-glutathionylation (-SSG), and others. Emerging evidence suggests that these post-translational modifications (PTM) are important in cellular redox regulation and protection against oxidative damage. Identification of protein targets of thiol redox modifications is crucial to understanding their roles in biology and disease. However, analysis of these highly labile and dynamic modifications poses challenges. Recent advances in the design of probes for thiol redox forms, together with innovative mass spectrometry based chemoproteomics methods make it possible to perform global, site-specific, and quantitative analyses of thiol redox modifications in complex proteomes.

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“…3A); these residues may be required for base-catalyzed transnitrosation (1,46). To test the robustness of the motif, we performed pLOGO analysis using an independently published SNO-proteome from brains of wild-type (C57BL/6J) mice (47) and found an enrichment of the basic residues-Lys (K), Arg (R), and His (H)-surrounding the SNO-Cys position (Fig. S2C, -6, -5, -1, +3, and +4).…”

Section: S1mentioning

confidence: 99%

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

Seneviratne

Nott

Bhat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Protein S-nitrosation (SNO-protein), the nitric oxide-mediated posttranslational modification of cysteine thiols, is an important regulatory mechanism of protein function in both physiological and pathological pathways. A key first step toward elucidating the mechanism by which S-nitrosation modulates a protein's function is identification of the targeted cysteine residues. Here, we present a strategy for the simultaneous identification of SNO-cysteine sites and their cognate proteins to profile the brain of the CK-p25-inducible mouse model of Alzheimer's disease-like neurodegeneration. The approach-SNOTRAP (SNO trapping by triaryl phosphine)-is a direct tagging strategy that uses phosphine-based chemical probes, allowing enrichment of SNO-peptides and their identification by liquid chromatography tandem mass spectrometry. SNOTRAP identified 313 endogenous SNO-sites in 251 proteins in the mouse brain, of which 135 SNO-proteins were detected only during neurodegeneration. S-nitrosation in the brain shows regional differences and becomes elevated during early stages of neurodegeneration in the CK-p25 mouse. The SNO-proteome during early neurodegeneration identified increased S-nitrosation of proteins important for synapse function, metabolism, and Alzheimer's disease pathology. In the latter case, proteins related to amyloid precursor protein processing and secretion are S-nitrosated, correlating with increased amyloid formation. Sequence analysis of SNO-cysteine sites identified potential linear motifs that are altered under pathological conditions. Collectively, SNOTRAP is a direct tagging tool for global elucidation of the SNO-proteome, providing functional insights of endogenous SNO proteins in the brain and its dysregulation during neurodegeneration.S-nitrosation | Alzheimer's disease | secretase pathway | presenilin pathway | neurodegeneration P rotein S-nitrosation (SNO-protein), in which a cysteine (Cys) thiol is converted to a nitrosothiol (RSNO), is an important posttranslational modification (PTM). Cys residues targeted for S-nitrosation often impact enzyme activity, protein localization, and protein-protein interactions (1). SNO begins with the production of nitric oxide radicals (NO • ) via conversion of L-arginine to L-citrulline by nitric oxide synthase 1 (NOS1) (neuronal), NOS2 (inducible), and NOS3 (endothelial). NO-mediated SNO PTMs are thought to occur in vivo predominantly through radical recombination between NO • and a thiyl radical, transnitrosation by low-molecular weight NO carriers such as S-nitrosoglutathione (GSNO), or protein-assisted transnitrosation (2-8). In the healthy brain, low levels of NO and normal SNO PTMs play important roles in regulating synaptic plasticity, gene expression, and neuronal survival. In contrast, elevated NO levels associated with aging and environmental stress have been linked to neurological pathologies, including Alzheimer's (AD), Parkinson's, and Huntington's disease (9). AD is the most prevalent form of human dementia, with a frequency that progressiv...

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Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation

Cited by 114 publications

References 87 publications

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

The Expanding Landscape of the Thiol Redox Proteome

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

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