The Yeast HAL2 Nucleotidase Is an in Vivo Target of Salt Toxicity

Murguía, José Ramón; Bellés, José María; Serrano, Ramón

doi:10.1074/jbc.271.46.29029

Cited by 133 publications

(129 citation statements)

References 37 publications

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“…However, when the wild-type cells were treated for 8 h with 100 mM LiCl in the absence of methionine, the PAP concentration increased to 42.9 nmol/mg, an increase of at least 85.8-fold (Fig. 3A), which is consistent with the increase found in previous analyses (13). Moreover, when methionine (20 g/ml) was included in the media, the concentration of PAP increased to only 2.3 nmol/mg in the presence of lithium (Fig.…”

Section: ј-Nucleotidase and Lithium Toxicitysupporting

confidence: 81%

“…3A). This suppression of lithium-induced PAP accumulation by methionine supplementation is consistent with data that suggest that methionine suppresses PAP synthesis through transcriptional down-regulation of the MET3 promoter (20), decreases PAPS production (19), and moderates the effects of lithium (13,14).To verify that this effect is due to the loss of ATP sulfurylase activity, we next measured lithium-induced PAP accumulation in the presence of chlorate, a widely used cell-permeable inhibitor of mammalian and yeast ATP sulfurylase activity (21,22). Chlorate has been used in mammalian cells to specifically decrease levels of PAPS in order to block downstream sulfurylation of biomolecules (for examples, see .…”

supporting

confidence: 74%

“…3Ј-Nucleotidase Modulates Lithium-mediated Toxicity-Inhibition of bisphosphate 3Ј-nucleotidase activity in yeast has been implicated as an integral element of lithium's toxicity and cellular effects (13,14). We and others have suggested that the effects of lithium in mammalian systems (toxic and possibly therapeutic) may be mediated through the inhibition of BPNT1 (1-3).…”

Section: Resultsmentioning

confidence: 99%

“…Zuker and colleagues provided genetic evidence in Drosophila melanogaster that the loss of INPP1 phenocopies lithium's alteration of neuromuscular junction physiology (10). In yeast, bisphosphate 3Јnucleotidase activity (encoded by MET22, also known as HAL2) has been linked to the cellular toxicity of lithium (11)(12)(13)(14). Met22/Hal2 is functionally orthologous to BPNT1, having 3Ј-nucleotidase activity toward 3Ј-phosphoadenosine 5Ј-phosphate (PAP) and 3Ј-phosphoadenosine 5Ј-phosphosulfate (PAPS), and it is a key regulator of the sulfur assimilation pathway (Fig.…”

mentioning

confidence: 99%

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Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Spiegelberg¹,

Cruz

Law

et al. 2005

Journal of Biological Chemistry

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Bisphosphate 3 -nucleotidase (BPNT1 in mammals and Met22/Hal2 in yeast) is one of five members of a family of signaling phosphatases united through a common tertiary structure and inhibition by subtherapeutic doses of the antibipolar drug lithium. Here we report a role for 3 -nucleotidase and its substrate, 3 -phosphoadenosine 5 -phosphate (PAP), in mediating the cellular effects of lithium. Lithium-induced inhibition of growth in yeast cells may be overcome by dose-dependent heterologous expression of human BPNT1. Disruption of the yeast 3 -nucleotidase gene or treatment of cells with lithium results in a >80-fold accumulation of PAP and leads to potent growth inhibition. These data indicate that the accumulation of a 3 -nucleotidase substrate, such as PAP, mediates the toxicity of lithium. To further probe this model we examined the growth inhibitory effects of lithium under conditions in which PAP biosynthetic machinery was concomitantly down-regulated. Disruption of met3 or met14 genes (ATP sulfurylase or phosphosulfate kinase), transcriptional down-regulation of MET3 through methionine addition, or administration of chlorate, a widely used cell-permeable sulfurylase inhibitor, function to reduce lithium-induced intracellular PAP accumulation and lithium toxicity; all of these effects were reversed by heterologous expression of human sulfurylase and kinase. Collectively, our data support a role for 3 -nucleotidase activity and PAP metabolism in aspects of lithium's mechanism of action and provide a platform for development of novel pharmacological modulators aimed at improving therapies for the treatment of bipolar disorder.Lithium has been widely used for over 50 years to treat bipolar disorder (manic depressive disease). Despite its success, the mechanisms by which lithium exerts therapeutic and toxic effects remain unclear. Insights into lithium pharmacology have come with the identification of a signaling phosphatase family whose members are inhibited potently by lithium at subtherapeutic concentrations. Family members have relatively weak overall sequence similarities (Ͻ25%) but are unified by a conserved core three-dimensional structure and the conserved pattern motif D(X) n EE(X) n DP(I/L)D(S/G/A)T(X) n -WD(X) 11 GG (1). This motif has been used to identify novel family members, for example human and mouse bisphosphate 3Ј-nucleotidase 1 (BPNT1), 1 through the scanning of emerging genomic databases and "reverse" biochemical characterization of the gene product (2). Importantly BPNT1 is potently inhibited by lithium (2, 3) and, to our knowledge, ranks among the most sensitive lithium targets described in the literature to date, including the glycogen synthase kinase-3 isoforms (4, 5). There are five distinct branches in the complete family of human and mouse signaling phosphatases (Fig. 1A), including inositol monophosphatase (IMP1 and IMP2), inositol polyphosphate 1-phosphatase (INPP1), fructose 1,6-bisphosphatase (FBP1 and FBP2), BPNT1, and a novel gene product (GenBank TM accession number AY032885) d...

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Section: ј-Nucleotidase and Lithium Toxicitysupporting

confidence: 81%

supporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Spiegelberg¹,

Cruz

Law

et al. 2005

Journal of Biological Chemistry

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“…Many enzymatic systems are inhibited by salt under in vitro conditions but most of them are only sensitive to non-physiological concentrations of NaCl (greater than 100 mM) and there is no genetic evidence for their participation in the inhibition of cell growth by salt . The only identified target of salt toxicity is Hal2p (Gläser et al, 1993;Murguia et al, 1996). Hal2p is a specific phosphatase acting on 3k-phosphoadenosine-5k-phosphate (PAP) and sensitive to inhibition by physiological concentrations of sodium.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Nst1p/YNL091w and Msl1p, a U2B″ splicing factor, in Saccharomyces cerevisiae salt tolerance

Goossens¹,

Forment²,

Serrano³

2002

Yeast

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Cell tolerance to salt stress depends on many physiological functions, including the best characterized of osmotic adjustment, ion transport and sodium-sensitive sulphate metabolism. From a screening designed to identify novel determinants of salt tolerance we have isolated the YNL091w gene, probably an Ascomycete-specific gene encoding a protein of unknown function. This gene negatively affects salt tolerance and therefore has been designated NST1. The salt tolerance mechanism of nst1 mutants is novel because it is not related to osmoregulation, altered cation accumulation or sulphate metabolism. Genome-wide two-hybrid analysis has suggested that Nst1p interacts with the splicing factor Msl1p and, accordingly, the impact of NST1 on salt tolerance is dependent on a functional MSL1 gene. Loss of MSL1 and NST1 function has pleiotropic phenotypes including increased sensitivity to divalent cations (manganese and zinc) and to caffeine (a cell wall-weakening agent). On the other hand, msl1 mutants but not nst1 mutants are sensitive to thiabendazole (a microtubule-destabilizing agent) and to osmotic stress.

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Yeast as a Molecular Genetic System for Improvement of Plant Salt Tolerance

Matsumoto

Bressan

Hasegawa

et al. 2002

Plant Breeding Reviews

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The Yeast HAL2 Nucleotidase Is an in Vivo Target of Salt Toxicity

Abstract: The yeast halotolerance gene HAL2 encodes a nucleotidase that dephosphorylates 3-phosphoadenosine 5-phosphate (PAP) and 3-phosphoadenosine 5-phosphosulfate (PAPS), intermediates of the sulfate assimilation pathway. This nucleotidase is inhibited by Na ؉ and Li

Cited by 133 publications

References 37 publications

Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Involvement of Nst1p/YNL091w and Msl1p, a U2B″ splicing factor, in Saccharomyces cerevisiae salt tolerance

Yeast as a Molecular Genetic System for Improvement of Plant Salt Tolerance

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