The Isolation and Characterization of cDNA Encoding the Mouse Bifunctional ATP Sulfurylase-Adenosine 5′-Phosphosulfate Kinase

Li, Hao; Deyrup, Andrea T.; Mensch, James; Domowicz, Miriam S.; Konstantinidis, Alexandros K.; Schwartz, Nancy B.

doi:10.1074/jbc.270.49.29453

Cited by 89 publications

(63 citation statements)

References 42 publications

(45 reference statements)

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“…Cloning of human PAPS synthase [4,7,8] revealed that it is 98 % and 95 % identical at the amino acid level with the mouse [6] and guinea-pig (unpublished work) PAPS synthases respectively, indicating that the protein is highly conserved. Following the initial cloning of PAPS synthase, a second isoform (PAPS synthase 2) was reported for human [9] and mouse [9,10] species.…”

Section: Introductionmentioning

confidence: 95%

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Characterization and expression of human bifunctional 3′-phosphoadenosine 5′-phosphosulphate synthase isoforms

Fuda

Shimizu

Lee

et al. 2002

Biochemical Journal

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Sulphonation, a fundamental process essential for normal growth and development, requires the sulphonate donor molecule 3h-phosphoadenosine 5h-phosphosulphate (PAPS), which is produced from ATP and inorganic sulphate by the bifunctional enzyme PAPS synthase. In humans, two genes encode isoenzymes that are 77 % identical at the amino acid level, and alternative splicing creates two subtypes of PAPS synthase 2. The question as to whether distinctions in amino acid composition are reflected in differences in activity has been examined. The specific activity of the PAPS synthase 2 subtypes is 10-to 15-fold higher than that for PAPS synthase 1. The greater catalytic efficiency of the PAPS synthase 2 subtypes is demonstrated further by the 3-to 6-fold higher k cat \K m ratios for ATP and inorganic sulphate as compared with the ratios for PAPS synthase 1. In humans, PAPS synthase 1 is expressed ubiquitously, and is the dominant isoform in most tissues, whereas expression of the PAPS synthase 2

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Section: Introductionmentioning

confidence: 95%

“…Bifunctional PAPS synthase was originally cloned from the marine worm [5] and the mouse [6]. Cloning of human PAPS synthase [4,7,8] revealed that it is 98 % and 95 % identical at the amino acid level with the mouse [6] and guinea-pig (unpublished work) PAPS synthases respectively, indicating that the protein is highly conserved.…”

Section: Introductionmentioning

confidence: 99%

Characterization and expression of human bifunctional 3′-phosphoadenosine 5′-phosphosulphate synthase isoforms

Fuda

Shimizu

Lee

et al. 2002

Biochemical Journal

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“…To further demonstrate the similarity between yeast and mammalian nucleotide synthesis machinery, we tested the ability of human PAPS synthesis enzymes to functionally replace those of yeast. In mammals, the ATP sulfurylase and APS kinase activities of Met3 and Met14 are expressed on a single dual-functional enzyme called PAPS synthetase (27,28) (Fig. 1B).…”

Section: ј-Nucleotidase and Lithium Toxicitymentioning

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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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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“…Sequence alignment of various monofunctional sulfurylase and kinase enzymes from lower organisms and plants, and bifunctional enzymes from animals reveal the presence of several highly conserved regions (1). Many of these conserved residues are present in motifs that have been implicated in ATP binding (P-loop) (13), phosphoryl transfer (FISP) (14), phosphodiester-cleavage (15), and pyrophosphate binding (PPloop) (16).…”

mentioning

confidence: 99%

Chemical Modification and Site-directed Mutagenesis of Conserved HXXH and PP-loop Motif Arginines and Histidines in the Murine Bifunctional ATP Sulfurylase/Adenosine 5′-Phosphosulfate Kinase

Deyrup

Singh

Krishnan

et al. 1999

Journal of Biological Chemistry

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The sulfurylase domain of the mouse bifunctional enzyme ATP sulfurylase/adenosine 5 -phosphosulfate (APS) kinase contains HXXH and PP-loop motifs. To elucidate the functional importance of these motifs and of conserved arginines and histidines, chemical modification and site-directed mutagenesis studies were performed. Chemical modification of arginines and histidines with phenylglyoxal and diethyl pyrocarbonate, respectively, renders the enzyme inactive in sulfurylase, kinase, and overall assays. Data base searches and sequence comparison of bifunctional ATP sulfurylase/APS kinase and monofunctional ATP sulfurylases shows a limited number of highly conserved arginines and histidines within the sulfurylase domain. Of these conserved residues, His-425, His-428, and Arg-421 are present within or near the HXXH motif whereas His-506, Arg-510, and Arg-522 residues are present in and around the PP-loop. The functional role of these conserved residues was further studied by site-directed mutagenesis. In the HXXH motif, none of the alanine mutants (H425A, H428A, and R421A) had sulfurylase or overall activity, whereas they all exhibited normal kinase activity. A slight improvement in reverse sulfurylase activity (<10% residual activity) and complete restoration of forward sulfurylase was observed with R421K. Mutants designed to probe the PP-loop requirements included H506A, R510A, R522A, R522K, and D523A. Of these, R510A exhibited normal sulfurylase and kinase activity, R522A and R522K showed no sulfurylase activity, and H506A had normal sulfurylase activity but produced an effect on kinase activity (<10% residual activity). The single aspartate, D523A, which is part of the highly conserved GRD sequence of the PP-loop, affected both sulfurylase and kinase activity. This mutational analysis indicates that the HXXH motif plays a role only in the sulfurylase activity, whereas the PP-loop is involved in both sulfurylase and kinase activities. Residues specific for sulfurylase activity have also been distinguished from those involved in kinase activity.Recently there has been increased interest in the sulfateactivating bifunctional enzyme, ATP sulfurylase/APS 1 kinase (PAPS synthetase). With the recent cloning of two isoforms of sulfurylase/kinase (SK) from both mouse, MSK1 (1) and MSK2 (2), and human, HSK1 (3, 4) and HSK2 (3), increased efforts are directed toward understanding the structure-function relationship of the bifunctional enzyme. This enzyme was initially identified by Sugahara and Schwartz (5-7) as the site of the brachymorphic defect in mice. The enzyme was subsequently purified to homogeneity and complete kinetic, functional, and structural analyses of the two-step pathway revealed that both activities reside on a single bifunctional protein that uses a channeling mechanism to efficiently produce PAPS (8 -12). We have also reported the cloning of two mouse bifunctional enzyme isoforms, MSK1 (1) and MSK2 (2), and have shown that a point mutation in the kinase portion of MSK2 renders the enzyme inactive, causing ...

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The Isolation and Characterization of cDNA Encoding the Mouse Bifunctional ATP Sulfurylase-Adenosine 5′-Phosphosulfate Kinase

Cited by 89 publications

References 42 publications

Characterization and expression of human bifunctional 3′-phosphoadenosine 5′-phosphosulphate synthase isoforms

Characterization and expression of human bifunctional 3′-phosphoadenosine 5′-phosphosulphate synthase isoforms

Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Chemical Modification and Site-directed Mutagenesis of Conserved HXXH and PP-loop Motif Arginines and Histidines in the Murine Bifunctional ATP Sulfurylase/Adenosine 5′-Phosphosulfate Kinase

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