PAPSS2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004020 adenylylsulfate kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: APS kinase (adenylyl-sulfate kinase) is one of the two catalytic activities of this bifunctional PAPS synthase, carried by the N-terminal domain. This is a core molecular function and the phylogenetic inference is consistent with direct experimental and structural evidence. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt Bifunctional enzyme with both ATP sulfurylase and APS kinase
GO:0000103 sulfate assimilation	IBA GO_REF:0000033	ACCEPT	Summary: Sulfate assimilation is the UniProt-designated pathway for PAPSS2 and describes the overall process (sulfate to PAPS) that the enzyme executes. Core biological process. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt Sulfur metabolism; sulfate assimilation.
GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: PAPS biosynthesis is the direct end product of the two reactions PAPSS2 catalyzes. Core biological process, well supported experimentally in this and related studies. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt phosphoadenylylsulfate/PAPS, the activated sulfate donor used by
GO:0000103 sulfate assimilation	IEA GO_REF:0000120	ACCEPT	Summary: Redundant electronic annotation to the same core biological process supported by experimental and phylogenetic evidence. Retained as a correct core process. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt Sulfur metabolism; sulfate assimilation.
GO:0004020 adenylylsulfate kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (InterPro/RHEA/EC 2.7.1.25) to one of the two core catalytic activities of PAPSS2. Correct core molecular function; retained. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt EC=2.7.1.25
GO:0004781 sulfate adenylyltransferase (ATP) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (InterPro/RHEA/EC 2.7.7.4) to the ATP sulfurylase activity, the second core catalytic function of PAPSS2. Correct core molecular function; retained. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt EC=2.7.7.4
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: ATP is a co-substrate of both PAPSS2 reactions (ATP sulfurylase and APS kinase), and UniProt documents multiple ATP-binding sites in the crystal structure. Correct supporting molecular function; retained. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt The first step is the transfer of a sulfate group to ATP to yield
GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation to the core PAPS biosynthetic process. Redundant with the experimental IMP and phylogenetic IBA annotations to the same term; correct core process. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt phosphoadenylylsulfate/PAPS, the activated sulfate donor used by
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a large-scale binary (Y2H) interactome screen (partners include HSF2BP and CEP19, listed in the UniProt INTERACTION block). Uninformative for molecular function; marked as over-annotated rather than removed (experimental IPI). Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt O95340; O75031: HSF2BP; NbExp=3; IntAct=EBI-1053912, EBI-7116203;
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a neurodegenerative-disease interactome mapping screen (partner OPTN, listed in the UniProt INTERACTION block). Uninformative for molecular function; marked as over-annotated rather than removed (experimental IPI). Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt O95340; Q96CV9: OPTN; NbExp=3; IntAct=EBI-1053912, EBI-748974;
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from the BioPlex AP-MS interactome; the recorded partner is the paralog PAPSS1 (O43252), consistent with the known PAPSS1/PAPSS2 heterodimer. Biologically plausible but uninformative as a molecular function; marked as over-annotated, not removed. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt O95340; O43252: PAPSS1; NbExp=2; IntAct=EBI-1053912, EBI-713760;
GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process	TAS Reactome:R-HSA-174389	ACCEPT	Summary: Reactome reaction for the APS kinase step (APS -> PAPS) that PAPSS2 catalyzes, part of PAPS biosynthesis. Correct core process.
GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process	TAS Reactome:R-HSA-174392	ACCEPT	Summary: Reactome reaction for the ATP sulfurylase step (sulfate + ATP -> APS), the first step of PAPS biosynthesis catalyzed by PAPSS2. Correct core process.
GO:0004020 adenylylsulfate kinase activity	TAS Reactome:R-HSA-174389	ACCEPT	Summary: Reactome curation of the APS kinase (adenylyl-sulfate kinase) activity, a core catalytic function of PAPSS2. Retained.
GO:0004020 adenylylsulfate kinase activity	TAS Reactome:R-HSA-3560785	ACCEPT	Summary: Reactome "Defective PAPSS2" disease reaction annotating the same core APS kinase activity (the activity lost in SEMD-PA). Molecular function is correct; retained.
GO:0004781 sulfate adenylyltransferase (ATP) activity	TAS Reactome:R-HSA-174392	ACCEPT	Summary: Reactome curation of the ATP sulfurylase (sulfate adenylyltransferase (ATP)) activity, the second core catalytic function of PAPSS2. Retained.
GO:0004781 sulfate adenylyltransferase (ATP) activity	TAS Reactome:R-HSA-3560794	ACCEPT	Summary: Reactome "Defective PAPSS2" disease reaction annotating the same core ATP sulfurylase activity (the activity lost in SEMD-PA). Molecular function is correct; retained.
GO:0005829 cytosol	TAS Reactome:R-HSA-3560785	ACCEPT	Summary: Cytosol is the predominant subcellular location of PAPSS2, consistent with experimental localization data. Correct core location.
GO:0005829 cytosol	TAS Reactome:R-HSA-3560794	ACCEPT	Summary: Duplicate Reactome cytosol annotation on the ATP sulfurylase reaction; consistent with the predominant cytosolic localization of PAPSS2. Correct core location.
GO:0005634 nucleus	IDA PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzym...	KEEP AS NON CORE	Summary: PAPSS2 can shuttle into the nucleus; the study shows both PAPS synthase isoforms access the nucleus and cytoplasm via a conserved N-terminal KKxK NLS, although PAPSS2 is predominantly cytosolic. Nuclear function is genuine but secondary/context-dependent, so kept as a non-core location. Supporting Evidence: PMID:22242175 mobile enzymes capable of executing their function in the cytoplasm as well as in the nucleus
GO:0005829 cytosol	IDA PMID:22242175 Human PAPS synthase isoforms are dynamically regulated enzym...	ACCEPT	Summary: Direct imaging shows PAPSS2 localizes mainly to the cytoplasm/cytosol. This is the predominant, core subcellular location of the enzyme. Supporting Evidence: PMID:22242175 PAPSS1 was predominantly nuclear, whereas PAPSS2 localised mainly within the cytoplasm.
GO:0005634 nucleus	IGI PMID:10657990 Nuclear localization of PAPS synthetase 1: a sulfate activat...	KEEP AS NON CORE	Summary: Genetic-interaction inference (with/from PAPSS1, O43252): ectopically expressed PAPSS2 is cytoplasmic but relocates to the nucleus when co-expressed with PAPSS1. Supports a conditional nuclear localization dependent on the paralog rather than a native core location for PAPSS2; kept as non-core. Supporting Evidence: PMID:10657990 is relocated to the nucleus when coexpressed with PAPSS1
GO:0005829 cytosol	IDA PMID:10657990 Nuclear localization of PAPS synthetase 1: a sulfate activat...	ACCEPT	Summary: Ectopically expressed PAPSS2 localizes to the cytoplasm, consistent with cytosol as the predominant core location. Supporting Evidence: PMID:10657990 PAPSS2, which localizes to the cytoplasm when ectopically expressed in mammalian cells
GO:0004020 adenylylsulfate kinase activity	IC PMID:23824674 Clinical and radiographic features of the autosomal recessiv...	ACCEPT	Summary: Curator inference (from GO:0050428) of the APS kinase activity, supported by in vitro enzyme assays showing that PAPSS2 missense disease mutations abolish PAPS synthesis. Core catalytic function; retained. Supporting Evidence: PMID:23824674 In vitro enzyme assays showed that the missense mutations were also loss-of-function mutations.
GO:0004781 sulfate adenylyltransferase (ATP) activity	IC PMID:23824674 Clinical and radiographic features of the autosomal recessiv...	ACCEPT	Summary: Curator inference (from GO:0050428) of the ATP sulfurylase activity, supported by in vitro enzyme assays on PAPSS2 disease variants. Core catalytic function; retained. Supporting Evidence: PMID:23824674 In vitro enzyme assays showed that the missense mutations were also loss-of-function mutations.
GO:0042445 hormone metabolic process	IMP PMID:19474428 Inactivating PAPSS2 mutations in a patient with premature pu...	KEEP AS NON CORE	Summary: PAPSS2 supplies PAPS to the DHEA sulfotransferase SULT2A1; loss-of-function mutations cause androgen excess via impaired DHEA sulfation. This is a genuine but downstream/indirect role (steroid/hormone metabolism depends on PAPSS2-produced PAPS), not a direct molecular function of the enzyme. Kept as a non-core process. Supporting Evidence: PMID:19474428 PAPSS2 deficiency is a monogenic adrenocortical cause of androgen excess
GO:0050428 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process	IMP PMID:23824674 Clinical and radiographic features of the autosomal recessiv...	ACCEPT	Summary: Experimental (IMP) support that PAPSS2 loss-of-function mutations impair PAPS synthesis, directly implicating PAPSS2 in the PAPS biosynthetic process. Core biological process. Supporting Evidence: PMID:23824674 loss-of-function mutations of PAPSS2, the gene encoding PAPS (3'-phosphoadenosine 5'-phosphosulfate) synthase 2
GO:0000103 sulfate assimilation	IMP PMID:19474428 Inactivating PAPSS2 mutations in a patient with premature pu...	ACCEPT	Summary: Experimental (IMP) support that PAPSS2 mutations impair the sulfate activation pathway (very low DHEAS from failed PAPS-dependent sulfation). Core biological process. Supporting Evidence: PMID:19474428 SULT2A1 requires 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for catalytic activity
GO:0005829 cytosol	TAS Reactome:R-HSA-174389	ACCEPT	Summary: Reactome cytosol annotation on the APS kinase reaction; consistent with the predominant cytosolic localization of PAPSS2. Correct core location.
GO:0005829 cytosol	TAS Reactome:R-HSA-174392	ACCEPT	Summary: Reactome cytosol annotation on the ATP sulfurylase reaction; consistent with the predominant cytosolic localization of PAPSS2. Correct core location.
GO:0004781 sulfate adenylyltransferase (ATP) activity	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of the ATP sulfurylase activity, one of the two core catalytic functions of PAPSS2. Correct and redundant with experimental/structural evidence; retained. Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt In the C-terminal section; belongs to the sulfate
GO:0016779 nucleotidyltransferase activity	ISS GO_REF:0000024	MODIFY	Summary: This is a correct-branch but overly general parent of the specific ATP sulfurylase (sulfate adenylyltransferase (ATP)) activity that PAPSS2 has. The more informative, already-annotated GO:0004781 should be used instead. Proposed replacements: sulfate adenylyltransferase (ATP) activity Supporting Evidence: file:human/PAPSS2/PAPSS2-uniprot.txt In the C-terminal section; belongs to the sulfate

Gene Description

Existing Annotations Review

Core Functions

ATP sulfurylase activity: catalyzes the first step of the sulfate activation pathway, condensing inorganic sulfate with ATP to form adenosine 5'-phosphosulfate (APS) and pyrophosphate (C-terminal domain).

APS kinase activity: catalyzes the second step of the sulfate activation pathway, phosphorylating APS with ATP to produce 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the universal sulfonate donor (N-terminal domain).

ATP binding: both catalytic steps use ATP as a co-substrate (as the sulfate/phosphate acceptor and phosphate donor respectively); the crystal structure resolves multiple ATP-binding sites.

References

📚 Additional Documentation

Notes

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