Two Phenol Sulfotransferase Species from One cDNA: Nature of the Differences

Yang, Yuh‐Shyong; Marshall, A. David; McPhie, Peter; Guo, Wei; Xie, Xiaofu; Chen, Xiang; Jakoby, William B.

doi:10.1006/prep.1996.0120

Cited by 31 publications

(66 citation statements)

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“…To internally validate the method, we determined the dissociation constant of PAP with GST-PST. The observed K d was ϳ35 nM (data not shown), consistent with the apparent K d found for the nonfusion recombinant rat PST (18). Note that PAPS is acid-labile, and the cells to be analyzed are lysed in a strong acid solution; therefore, this technique measures the sum of intracellular PAP and PAPS.…”

Section: ј-Nucleotidase and Lithium Toxicitysupporting

confidence: 75%

“…Measurement of Intracellular PAP Concentrations-The concentration of PAP in lysates was determined by competition for binding of radiolabeled PAP to the enzyme phenol sulfotransferase (PST), which uses PAP as a cofactor (18). The open reading frame of IMAGE Consortium Clone expressed sequence tag 1924316 (mouse PST; accession number AI316417) was amplified by PCR, ligated into the pCR2.1, and subcloned into pGEX4T-1 (Amersham Biosciences) to create a bacterial expression vector in which PST was downstream of glutathione Stransferase (GST-PST).…”

Section: Overexpression Of Human Bpnt1 In 3ј-nucleotidase-deficientmentioning

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: 75%

Section: Overexpression Of Human Bpnt1 In 3ј-nucleotidase-deficientmentioning

confidence: 99%

Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Spiegelberg¹,

Cruz

Law

et al. 2005

Journal of Biological Chemistry

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“…To take advantage of the ease of colorimetric assays, the activities of SULT1A1 and its V270E mutant were determined according to a procedure reported previously (Yang et al, 1996;Burkart and Wong, 1999;Lin and Yang, 2000) using pNPS as the initial sulfuryl group donor. The reaction was monitored by the production of pNP, which gives strong absorption at 400 nm ( ϭ 10,500 at pH 7).…”

Section: Methodsmentioning

confidence: 99%

Dimerization Is Responsible for the Structural Stability of Human Sulfotransferase 1A1

Lu¹,

Chiang²,

Chen³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Cytosolic sulfotransferases (SULTs) are responsible for the metabolism of a variety of drugs, xenobiotics, and endogenous compounds. Most cytosolic SULTs are found to be homodimers. However, transformation between monomeric and dimeric SULTs can be achieved by a single amino acid mutation. The importance of quaternary structure for cytosolic sulfotransferase was investigated using recombinant human SULT1A1, a homodimer, and its monomeric mutant (V270E). The differences between dimeric and monomeric SULT1A1 were examined by size-exclusion liquid chromatography, enzyme kinetics, substrate binding affinity, thermal inactivation, conformational stability, and circular dichroism. Variations, especially on their secondary structures and stability, between homodimer and monomer of human SULT1A1 were observed. It was found that the active site of SULT1A1 was not significantly perturbed after the change of its quaternary structure according to SULT1A1 kinetics and substrate binding affinity. However, the stability of monomeric SULT1A1 is significantly decreased. We proposed that the importance of human SULT1A1 as a homodimer was to maintain its structural stability, and the change of secondary structure was responsible for alternating its quaternary structure.

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“…The fluorescence of 4-methylumbelliferone at 460 nm was measured upon excitation at 355 nm. The reaction mixture with a final volume of 1 ml consisted of 100 mM potassium phosphate buffer at pH 7.0, 5 mM 2-mercaptoethanol, 20 M PAPS, 2 mM MUS, 5.4 g of K65ER68G (Yang et al, 1996) of rat SULT1A1, SULT2A1, and 5 M of DHEA or ADT at 37°C. A linear response was obtained when 1.49 to 14.9 nM (0.1-1 g) SULT2A1 was added in the standard assay condition.…”

Section: Methodsmentioning

confidence: 99%

Identification and Characterization of Two Amino Acids Critical for the Substrate Inhibition of Human Dehydroepiandrosterone Sulfotransferase (SULT2A1)

Hsieh

Liu

et al. 2007

Mol Pharmacol

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Substrate inhibition is a characteristic feature of many cytosolic sulfotransferases. The differences between the complex structures of SULT2A1/DHEA and SULT2A1/PAP or SULT2A1/ADT (Protein Data Bank codes are 1J99, 1EFH, and 1OV4, respectively) have enabled us to elucidate the specific amino acids responsible for substrate inhibition. Based on the structural analyses, substitution of the smaller residue alanine for Tyr-238 (Y238A) significantly increases the K i value for dehydroepiandrosterone (DHEA) and totally eliminates substrate inhibition for androsterone (ADT). In addition, Met-137 was proposed to regulate the binding orientations of DHEA and ADT in SULT2A1. Complete elimination or regeneration of substrate inhibition for SULT2A1 with DHEA or ADT as substrate, respectively, was demonstrated with the mutations of Met-137 on Y238A mutant. Analysis of the Met-137 mutants and Met-137/ Tyr-238 double mutants uncovered the relationship between substrate binding orientations and inhibition in SULT2A1. Our data indicate that, in the substrate inhibition mode, Tyr-238 regulates the release of bound substrate, and Met-137 controls substrate binding orientation of DHEA and ADT in SULT2A1. The proposed substrate inhibition mechanism is further confirmed by the crystal structures of SULT2A1 mutants at Met-137. We propose that both substrate binding orientations exhibited substrate inhibition. In addition, a corresponding residue in other cytosolic sulfotransferases was shown to have a function similar to that of Tyr-238 in SULT2A1.

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Two Phenol Sulfotransferase Species from One cDNA: Nature of the Differences

Cited by 31 publications

References 0 publications

Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Dimerization Is Responsible for the Structural Stability of Human Sulfotransferase 1A1

Identification and Characterization of Two Amino Acids Critical for the Substrate Inhibition of Human Dehydroepiandrosterone Sulfotransferase (SULT2A1)

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