Crystal structure of ATP sulfurylase from Saccharomyces cerevisiae, a key enzyme in sulfate activation

Ullrich, Tobias

doi:10.1093/emboj/20.3.316

Cited by 104 publications

(124 citation statements)

References 45 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…Humans express at least two isoforms of PAPS synthetase, hPAPSS1 and hPAPSS2 (29), which show Ͼ80% amino acid sequence similarity. The amino-terminal domain of hPAPSS2 has APS kinase activity and shares similarity with S. cerevisiae Met14 (28), whereas the carboxyl terminus of hPAPSS2 has ATP sulfurylase activity and shares similarity with Met3, including its strict conservation of active site residues (22,30). Because of its commercial availability, hPAPSS2 was subcloned via PCR from the IMAGE Consortium expressed sequence tag clone AL540583 into a galactose-inducible yeast expression vector and transformed into wild-type yeast or homozygous diploid met3⌬ or met14⌬ strains.…”

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

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…These studies also reveal the versatility of the ATP sulfurylase fold as sequence variations that alter the oligomerization interface lead to a range of architectures for this enzyme (Figs. 3 and 4) (43)(44)(45)(47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

“…Substrate recognition in ATP sulfurylases requires several regions around the active site for nucleotide and sulfate/PP i binding and reduced solvent access (Fig. 5C) (43)(44)(45)(47)(48)(49)(50). Localized structural changes were observed in the apoenzyme structure of the Riftia symbiont ATP sulfurylase, which showed residues corresponding to the ␤2c-␣9 loop of GmATPS rotated away from the active site (43).…”

Section: Journal Of Biological Chemistry 10925mentioning

confidence: 99%

“…In other prokaryotes, including the thermophiles Aquifex aeolicus and Thermus thermophilus, the purple sulfur bacterium Allochromatium vinosum, and a bacterial symbiont of the vent tubeworm Riftia pachyptila, ATP sulfurylase functions either as a monofunctional homodimeric enzyme or a bi-functional homodimeric ATP sulfurylase/APS kinase, also known as PAPS synthetase (43)(44)(45)(46). In fungi, such as Saccharomyces cerevisiae and Penicillium chrysogenum, ATP sulfurylase is a homohexamer in which each monomer contains an N-terminal ATP sulfurylase domain and a C-terminal APS kinase-like domain (47)(48)(49). The APS kinase-like domain can also function as an allosteric regulatory region in response to PAPS, as shown for the P. chrysogenum enzyme (50).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structure and Mechanism of Soybean ATP Sulfurylase and the Committed Step in Plant Sulfur Assimilation

Herrmann

Ravilious

McKinney

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: ATP sulfurylase catalyzes the energetically unfavorable formation of adenosine 5Ј-phosphosulfate in plant sulfur assimilation. Results: Structural and kinetic analyses identifies key active site residues. Conclusion: A reaction mechanism involving distortion of nucleotide conformation and stabilizing interactions is proposed. Significance: These results provide the first molecular insights on a plant ATP sulfurylase and the committed step of plant sulfur assimilation.

show abstract

“…Along the activation pathway, APS-kinase (K) phosphorylates APS and produces PAPS, which is the universal sulfate donor compound for all sulfotransferase enzymes (T). In the reductive branch of the pathway, APS-reductase (R) generates sulfite, which is eventually reduced to sulfide and incorporated into sulfur containing molecules J Mol Evol et al 2002;MacRae et al 1998), the budding yeast Saccharomyces cerevisiae (Ullrich et al 2001), and the aproteobacterium Rhodobacter sphaeroides (Sun and Leyh 2006). The K domain of the SK fusion is not well conserved, and a range of functions has been attributed to the K domain in different organisms.…”

Section: Introductionmentioning

confidence: 99%

Sulfate Activation Enzymes: Phylogeny and Association with Pyrophosphatase

Bradley

Rest

et al. 2008

J Mol Evol

View full text Add to dashboard Cite

The enzymes catalyzing the first two reactions in the sulfate activation pathway, ATP-sulfurylase (S) and APS-kinase (K), are fused as 'KS' in animals but are fused as 'SK' in select bacteria and fungi. We have discovered a novel triple fusion protein of K, S, and pyrophosphatase (P) in several protozoan genomes within the Stramenopile lineage. These triple domain fusion proteins led us to hypothesize that pyrophosphatase enzymes and sulfate activation enzymes physically interact to impact the thermodynamics of the sulfate activation pathway. In support of this hypothesis, we demonstrate through biochemical assays that separately encoded KS and P proteins physically interact and that KS/P complexes activate more sulfate than KS alone. We also conclude on the basis of phylogenetic analyses that all known KS fusions originate from a single fusion event early in the eukaryotic lineage. Strikingly, our analyses support the same conclusion for all known SK fusions. These observations indicate that the patchwork of fused and nonfused S and K genes observed in modern-day eukaryotes and prokaryotes are the result of the two ancestral fusion genes evolving by an assortment of gene fissions, duplications, deletions, and horizontal transfers in different lineages. Our integrative use of genomics, phylogenetics, and biochemistry to characterize pyrophosphatase as a new member of the sulfate activation pathway should be effective at identifying new protein members and connections in other molecular pathways.

show abstract

Crystal structure of ATP sulfurylase from Saccharomyces cerevisiae, a key enzyme in sulfate activation

Cited by 104 publications

References 45 publications

Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism

Structure and Mechanism of Soybean ATP Sulfurylase and the Committed Step in Plant Sulfur Assimilation

Sulfate Activation Enzymes: Phylogeny and Association with Pyrophosphatase

Contact Info

Product

Resources

About