PAPSS1 is a cytosolic and nuclear bifunctional enzyme that synthesizes PAPS (3'-phosphoadenosine 5'-phosphosulfate), the universal activated sulfate donor used by all cytosolic and Golgi sulfotransferases. It carries two catalytic activities fused into a single polypeptide: a C-terminal ATP sulfurylase (sulfate adenylyltransferase, EC 2.7.7.4) domain that produces adenosine 5'-phosphosulfate (APS) from ATP and inorganic sulfate, and an N-terminal APS kinase (adenylyl-sulfate kinase, EC 2.7.1.25) domain that phosphorylates APS on its 3'-hydroxyl to yield PAPS. The enzyme is a homodimer and consumes ATP in both reactions. In mammals PAPS is the sole physiological sulfonate donor, and APS is only an intermediate; PAPSS1-generated PAPS feeds sulfation of glycosaminoglycans and proteoglycans, sulfomucins (including selectin ligands), steroids, tyrosine residues, neurotransmitters, hormones, drugs and xenobiotics. PAPSS1 is broadly expressed and can shuttle between cytoplasm and nucleus, indicating that sulfate activation can occur in either compartment.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004020 adenylylsulfate kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: APS kinase activity is a core, experimentally established catalytic function of the N-terminal domain of PAPSS1. Phylogenetic (IBA) inference agrees with direct enzyme assays and structural work. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Bifunctional enzyme with both ATP sulfurylase and APS kinase |
| GO:0000103 sulfate assimilation | IBA GO_REF:0000033 | ACCEPT | Summary: Sulfate assimilation (activation of inorganic sulfate to PAPS) is the core biological process of PAPSS1. Matches the UniProt PATHWAY assignment and is supported experimentally. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Sulfur metabolism; sulfate assimilation. |
| GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAPS biosynthesis is precisely what the bifunctional enzyme does; this is a core BP. IBA agrees with direct evidence. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt In mammals, PAPS is the sole source of sulfate; APS appears to be only an |
| GO:0000103 sulfate assimilation | IEA GO_REF:0000120 | ACCEPT | Summary: Redundant electronic annotation to the gene's own correct core biological process. Accept (not over-annotation of the gene's own function). Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Sulfur metabolism; sulfate assimilation. |
| GO:0004020 adenylylsulfate kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Redundant electronic annotation (ARBA/InterPro/RHEA/EC 2.7.1.25) to the gene's own experimentally verified core MF. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=adenosine 5'-phosphosulfate + ATP = 3'-phosphoadenylyl sulfate |
| GO:0004781 sulfate adenylyltransferase (ATP) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Redundant electronic annotation (ARBA/InterPro/RHEA/EC 2.7.7.4) to the gene's own experimentally verified core MF. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=sulfate + ATP + H(+) = adenosine 5'-phosphosulfate + |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP is a substrate of both catalytic reactions and UniProt records two distinct ATP-binding sites (labels 1 and 2). ATP binding is a correct, supporting molecular function. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=adenosine 5'-phosphosulfate + ATP = 3'-phosphoadenylyl sulfate |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | MODIFY | Summary: Correct but less specific than the experimentally supported cytosol (GO:0005829) annotation. Generalized cytoplasm term; MODIFY to cytosol. Proposed replacements: cytosol Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt human PAPS synthetase 1 (PAPSS1), a bifunctional ATP sulfurylase/adenosine |
| GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: Redundant electronic annotation to the gene's own correct core BP. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt In mammals, PAPS is the sole source of sulfate; APS appears to be only an |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a high-throughput AP-MS interactome study (BioPlex 3.0); the with/from partner is the paralog PAPSS2 (O95340), consistent with the recorded PAPSS1-PAPSS2 interaction in UniProt. This term is uninformative about molecular function. Per policy, an IPI protein binding annotation is marked over-annotated rather than removed. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. |
| GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process | TAS Reactome:R-HSA-174389 | ACCEPT | Summary: Reactome reaction "PAPSS1,2 transfer PO4(2-) group from ATP to APS to form PAPS" (the APS kinase step of PAPS biosynthesis). Correct core BP. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt In mammals, PAPS is the sole source of sulfate; APS appears to be only an |
| GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process | TAS Reactome:R-HSA-174392 | ACCEPT | Summary: Reactome reaction "PAPSS1,2 transfer SO4(2-) group to ATP to form APS" (the ATP sulfurylase step, producing the APS intermediate en route to PAPS). Correct core BP. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=sulfate + ATP + H(+) = adenosine 5'-phosphosulfate + |
| GO:0004020 adenylylsulfate kinase activity | TAS Reactome:R-HSA-174389 | ACCEPT | Summary: Reactome captures the APS kinase reaction; core MF. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=adenosine 5'-phosphosulfate + ATP = 3'-phosphoadenylyl sulfate |
| GO:0004781 sulfate adenylyltransferase (ATP) activity | TAS Reactome:R-HSA-174392 | ACCEPT | Summary: Reactome captures the ATP sulfurylase reaction; core MF. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=sulfate + ATP + H(+) = adenosine 5'-phosphosulfate + |
| GO:0005634 nucleus | IDA PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzym... | ACCEPT | Summary: Experimental (IDA) evidence that PAPSS1 is active in the nucleus; PAPS synthases shuttle between nucleus and cytoplasm, consistent with the demonstrated nuclear accumulation of PAPSS1. Core CC. Accept. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0005829 cytosol | IDA PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzym... | ACCEPT | Summary: Experimental (IDA) evidence that PAPSS1 is active in the cytosol, the classical site of sulfate activation. Core CC. Accept. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0004020 adenylylsulfate kinase activity | EXP PMID:17276460 Elucidation of the active conformation of the APS-kinase dom... | ACCEPT | Summary: Direct experimental/structural characterization of the APS kinase domain (Michaelis complex with ADP-Mg and PAPS). Core MF. Accept. Supporting Evidence: PMID:17276460 the latter by the APS-kinase domain |
| GO:0004020 adenylylsulfate kinase activity | EXP PMID:17540769 Structural mechanism for substrate inhibition of the adenosi... | ACCEPT | Summary: APS kinase activity demonstrated experimentally, including its substrate-inhibition kinetics by APS. Core MF. Accept. Supporting Evidence: PMID:17540769 The APS kinase domain of PAPS synthetase catalyzes the second step |
| GO:0004020 adenylylsulfate kinase activity | EXP PMID:9576487 Sulfation in high endothelial venules: cloning and expressio... | ACCEPT | Summary: PAPS synthesis (requiring APS kinase activity) demonstrated on the cloned human enzyme. Core MF. Accept. Supporting Evidence: PMID:9576487 a multifunctional enzyme containing domains for both ATP sulfurylase and adenosine-5'-phosphosulfate kinase |
| GO:0004020 adenylylsulfate kinase activity | EXP PMID:9648242 cDNA cloning, expression, and characterization of the human ... | ACCEPT | Summary: Recombinant APS kinase domain expressed, purified and shown to carry its enzymatic activity. Core MF. Accept. Supporting Evidence: PMID:9648242 The enzyme contains an APS kinase domain in its N-terminal portion |
| GO:0004020 adenylylsulfate kinase activity | EXP PMID:9668121 Molecular cloning, expression, and characterization of human... | ACCEPT | Summary: The 1-268 fragment expressed APS kinase activity with defined kinetics. Core MF. Accept. Supporting Evidence: PMID:9668121 A 1-268-amino acid fragment expressed APS kinase activity |
| GO:0004781 sulfate adenylyltransferase (ATP) activity | EXP PMID:9576487 Sulfation in high endothelial venules: cloning and expressio... | ACCEPT | Summary: ATP sulfurylase activity demonstrated for the cloned human enzyme (PAPS synthesis abolished by the sulfation inhibitor chlorate). Core MF. Accept. Supporting Evidence: PMID:9576487 a multifunctional enzyme containing domains for both ATP sulfurylase |
| GO:0004781 sulfate adenylyltransferase (ATP) activity | EXP PMID:9648242 cDNA cloning, expression, and characterization of the human ... | ACCEPT | Summary: Recombinant ATP sulfurylase domain expressed, purified and shown to carry its enzymatic activity. Core MF. Accept. Supporting Evidence: PMID:9648242 an ATP sulfurylase domain in its C-terminal portion |
| GO:0004781 sulfate adenylyltransferase (ATP) activity | EXP PMID:9668121 Molecular cloning, expression, and characterization of human... | ACCEPT | Summary: The 220-623 fragment showed ATP sulfurylase (sulfate adenylyltransferase) activity. Core MF. Accept. Supporting Evidence: PMID:9668121 a 220-623 fragment evinced ATP sulfurylase activity |
| GO:0005634 nucleus | IDA PMID:10657990 Nuclear localization of PAPS synthetase 1: a sulfate activat... | ACCEPT | Summary: Direct experimental demonstration that PAPSS1 accumulates in the nucleus, with nuclear targeting mediated by the APS kinase domain and an N-terminal sequence. Core CC. Accept. Supporting Evidence: PMID:10657990 accumulates in the nucleus of mammalian cells |
| GO:0005634 nucleus | IDA PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzym... | ACCEPT | Summary: Second IDA supporting nuclear localization of PAPSS1. Core CC. Accept. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0005829 cytosol | IDA PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzym... | ACCEPT | Summary: IDA supporting cytosolic localization of PAPSS1, the canonical site of sulfate activation. Core CC. Accept. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6802927 | ACCEPT | Summary: Cytosol is a correct core location for PAPSS1, but this particular annotation is attached to a "Signaling by BRAF and RAF1 fusions" Reactome reaction with which PAPSS1 has no functional relationship; the pathway context is spurious co-occurrence. The location itself is correct and experimentally supported. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6802932 | ACCEPT | Summary: Cytosol location correct (experimentally supported) though attached to a BRAF/RAF-fusion signaling reaction unrelated to PAPSS1 function. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6802933 | ACCEPT | Summary: Cytosol location correct (experimentally supported) though attached to a BRAF/RAF-fusion signaling reaction unrelated to PAPSS1 function. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6802934 | ACCEPT | Summary: Cytosol location correct (experimentally supported) though attached to a BRAF/RAF-fusion signaling reaction unrelated to PAPSS1 function. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6802935 | ACCEPT | Summary: Cytosol location correct (experimentally supported) though attached to a BRAF/RAF-fusion signaling reaction unrelated to PAPSS1 function. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0000103 sulfate assimilation | IDA PMID:14747722 Expression, purification and crystallization of human 3'-pho... | ACCEPT | Summary: Direct demonstration that the purified full-length human enzyme forms PAPS (sulfate activation). Core BP. Accept. Supporting Evidence: PMID:14747722 forming 25 nmol PAPS per minute per milligram |
| GO:0004020 adenylylsulfate kinase activity | IDA PMID:14747722 Expression, purification and crystallization of human 3'-pho... | ACCEPT | Summary: The purified enzyme completes both steps to form PAPS, requiring APS kinase activity. Core MF. Accept. Supporting Evidence: PMID:14747722 The APS kinase domain then adds a phosphate group to the 3'-ribose and releases |
| GO:0004781 sulfate adenylyltransferase (ATP) activity | IDA PMID:14747722 Expression, purification and crystallization of human 3'-pho... | ACCEPT | Summary: The ATP sulfurylase domain forms the APS intermediate; verified for the purified human enzyme. Core MF. Accept. Supporting Evidence: PMID:14747722 The ATP sulfurylase domain catalyzes the formation of the intermediate |
| GO:0042803 protein homodimerization activity | IPI PMID:14747722 Expression, purification and crystallization of human 3'-pho... | KEEP AS NON CORE | Summary: PAPSS1 is a homodimer, shown by gel-filtration and crystallography; this is a real structural property (the homodimer is the biological unit). Retained as a non-core molecular function; the catalytic activities are the core functions. Supporting Evidence: PMID:14747722 The pure protein migrates as a dimer in gel-filtration chromatography. file:human/PAPSS1/PAPSS1-uniprot.txt Homodimer. |
| GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process | IDA PMID:14747722 Expression, purification and crystallization of human 3'-pho... | ACCEPT | Summary: Purified enzyme demonstrably synthesizes PAPS. Core BP. Accept. Supporting Evidence: PMID:14747722 forming 25 nmol PAPS per minute per milligram |
| GO:0004020 adenylylsulfate kinase activity | IDA PMID:23207770 Ethanol sulfation by the human cytosolic sulfotransferases: ... | ACCEPT | Summary: APS kinase activity is a correct, well-established core MF of PAPSS1. The cited reference (PMID:23207770) characterizes cytosolic sulfotransferases (SULTs) and [35S]sulfate metabolic labeling; its cached abstract does not directly assay the PAPSS1 APS-kinase reaction, so it is a weak/indirect source for this specific annotation (CAFA-assigned). The activity itself is strongly supported by other experimental references; retained as core. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=adenosine 5'-phosphosulfate + ATP = 3'-phosphoadenylyl sulfate |
| GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process | IDA PMID:23207770 Ethanol sulfation by the human cytosolic sulfotransferases: ... | ACCEPT | Summary: PAPS biosynthesis is a correct core BP for PAPSS1. The cited ethanol sulfation paper concerns SULT enzymes and 35S-sulfate metabolic labeling rather than direct PAPSS1 assays; the process is well supported by other references. Retained as core. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt In mammals, PAPS is the sole source of sulfate; APS appears to be only an |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174389 | ACCEPT | Summary: Cytosol localization supported by Reactome PAPS-biosynthesis reaction and by experimental IDA. Core CC. Accept. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174392 | ACCEPT | Summary: Cytosol localization supported by Reactome PAPS-biosynthesis reaction and by experimental IDA. Core CC. Accept. Supporting Evidence: PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm |
| GO:0004781 sulfate adenylyltransferase (ATP) activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the ATP sulfurylase activity, which is a correct experimentally validated core MF of PAPSS1. Accept. Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=sulfate + ATP + H(+) = adenosine 5'-phosphosulfate + |
| GO:0016779 nucleotidyltransferase activity | ISS GO_REF:0000024 | MODIFY | Summary: Nucleotidyltransferase activity is a correct but overly general parent of the specific sulfate adenylyltransferase (ATP) activity (GO:0004781). MODIFY to the specific term. Proposed replacements: sulfate adenylyltransferase (ATP) activity Supporting Evidence: file:human/PAPSS1/PAPSS1-uniprot.txt Reaction=sulfate + ATP + H(+) = adenosine 5'-phosphosulfate + |
| GO:0001501 skeletal system development | TAS PMID:9771708 Mutations in orthologous genes in human spondyloepimetaphyse... | MARK AS OVER ANNOTATED | Summary: This TAS annotation is mis-attributed. The cited paper (PMID:9771708) is about the paralog PAPSS2 / ATPSK2, the gene mutated in human spondyloepimetaphyseal dysplasia and in the brachymorphic mouse; the cartilage/skeletal phenotype is a PAPSS2-specific function. PAPSS1 is broadly expressed and this reference does not concern PAPSS1. Skeletal system development is not a core PAPSS1 function. Non-experimental (TAS) and the cited source is about a different gene; marked as over-annotated. Supporting Evidence: PMID:9771708 We identified two orthologous genes, ATPSK2 and Atpsk2, encoding novel ATP sulfurylase/APS kinase orthologues in the respective regions of the human and mouse genomes. |
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Download this section (compressed HTML)Q: Are the cytosolic and nuclear pools of PAPSS1 functionally distinct, and does nuclear PAPS synthesis supply a compartment-specific set of sulfotransferase reactions?
Q: What is the physiological non-redundancy between PAPSS1 and PAPSS2 in humans, given that PAPSS2 loss causes skeletal dysplasia while PAPSS1 is broadly expressed?
Experiment: Tissue- and compartment-resolved metabolomic quantification of APS and PAPS following selective PAPSS1 vs PAPSS2 knockdown, to define the relative contributions of the two paralogs to the cellular PAPS pool.
Experiment: Structure-guided mutagenesis of the interdomain interface to test the proposed communication mechanism whereby the ATP sulfurylase domain modulates APS-kinase substrate inhibition.
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