PAICS

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004639 phosphoribosylaminoimidazolesuccinocarboxamide synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: SAICAR synthetase (EC 6.3.2.6) is one of the two catalytic activities of this bifunctional enzyme and is a core molecular function. The phylogenetic (IBA) inference is fully consistent with direct experimental and structural evidence. Reason: Core enzymatic function directly supported by biochemistry and crystallography (PMID:17224163) and by the disease study (PMID:31600779). The IBA is at the correct level of specificity for this well-conserved family. Supporting Evidence: PMID:17224163 Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase (SAICARs) activities.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: PAICS is a soluble cytosolic enzyme that acts in the cytoplasm as part of the de novo purine synthesis pathway and the purinosome. The IBA localization is corroborated by Reactome TAS annotations to cytosol. Reason: Correct site of action for this cytosolic metabolic enzyme, consistent with purinosome biology (PMID:31600779) and independent Reactome curation. Supporting Evidence: PMID:31600779 Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by
GO:0006189 'de novo' IMP biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: PAICS catalyzes two consecutive steps of the ten-reaction de novo pathway that builds IMP, making 'de novo' IMP biosynthetic process the correct core biological process. Reason: Correct pathway assignment for both catalytic activities; the IBA inference matches direct experimental evidence (PMID:27590927, PMID:31600779) and UniProt pathway annotation. Supporting Evidence: PMID:27590927 DNPS includes ten reactions catalysed by six enzymes.
GO:0004638 phosphoribosylaminoimidazole carboxylase activity	IEA GO_REF:0000120	ACCEPT	Summary: AIR carboxylase (EC 4.1.1.21) is one of the two core catalytic activities. This IEA (RHEA/EC mapping) is correct and redundant with the experimental EXP/IDA/IMP annotations for the same term. Reason: Accurate EC/RHEA-based mapping to a directly demonstrated enzymatic activity (PMID:17224163). Supporting Evidence: PMID:17224163 Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase (SAICARs) activities.
GO:0004639 phosphoribosylaminoimidazolesuccinocarboxamide synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: SAICAR synthetase (EC 6.3.2.6) core catalytic activity; IEA EC/RHEA mapping is correct and redundant with the experimental annotations for the same term. Reason: Accurate EC/RHEA-based mapping to a directly demonstrated enzymatic activity (PMID:17224163). Supporting Evidence: PMID:17224163 Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase (SAICARs) activities.
GO:0006164 purine nucleotide biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: Correct but general parent process. PAICS acts in de novo purine nucleotide biosynthesis; the more specific 'de novo' IMP biosynthetic process (GO:0006189) is also annotated and better captures the enzyme's role. Reason: Biologically accurate broad process term from InterPro2GO; kept because IEAs may legitimately be broader than the more specific experimental terms. Not marked core because the more specific GO:0006189 is the core process. Supporting Evidence: PMID:31600779 We report for the first time an autosomal recessive inborn error of de novo
GO:0006189 'de novo' IMP biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Correct core biological process, redundant with the IBA and experimental annotations to the same term. Reason: Accurate UniPathway/InterPro-based mapping to the de novo IMP biosynthesis pathway in which PAICS acts. Supporting Evidence: PMID:27590927 DNPS includes ten reactions catalysed by six enzymes.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a large-scale interactome dataset. Uninformative about molecular function and does not represent a core function. Reason: Bare 'protein binding' conveys no specific molecular function and derives from high-throughput interactome screening. Per curation guidelines this term should be avoided in favor of informative MF terms; retained per policy (do not remove IPIs) but flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:19060904 An empirical framework for binary interactome mapping.	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a binary interactome mapping study; uninformative about molecular function. Reason: Bare 'protein binding' from a high-throughput binary interactome dataset does not describe a specific molecular function; over-annotated.
GO:0005515 protein binding	IPI PMID:21653829 Protein interactome reveals converging molecular pathways am...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from an autism-focused interactome study; uninformative about molecular function. Reason: Bare 'protein binding' from high-throughput interactome data; not an informative molecular function and not core.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a proteome-scale interactome map; uninformative about molecular function. Reason: Bare 'protein binding' from a high-throughput interactome dataset; over-annotated.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from an alternative-splicing interactome study; uninformative about molecular function. Reason: Bare 'protein binding' from high-throughput interactome mapping; not informative and not core.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a reference binary interactome map; uninformative about molecular function. Reason: Bare 'protein binding' from a high-throughput binary interactome dataset; over-annotated.
GO:0042802 identical protein binding	IPI PMID:16169070 A human protein-protein interaction network: a resource for ...	KEEP AS NON CORE	Summary: Self-association is biologically real for PAICS, which forms a homooctamer. However, this is a structural/oligomerization property rather than a core enzymatic function, and the supporting datasets are high-throughput interactome screens. Reason: PAICS is a homooctamer (PMID:17224163), so identical-protein-binding is genuine and the octameric quaternary structure is functionally important for the carboxylase active sites. Kept as a valid but non-core annotation (self-assembly rather than catalytic function). The IPI evidence itself comes from a Y2H interactome screen. Supporting Evidence: PMID:17224163 eight PAICS subunits, each composed of distinct AIRc and SAICARs domains, assemble a compact homo-octamer with an octameric-carboxylase core and four symmetric periphery dimers formed by synthetase domains PMID:16169070 a protein matrix of 4456 baits and 5632 preys was screened by automated yeast two-hybrid (Y2H) interaction mating
GO:0042802 identical protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	KEEP AS NON CORE	Summary: Self-association consistent with the homooctamer; valid but non-core (structural oligomerization rather than catalytic function). Reason: Corroborated by the crystal structure showing a homooctamer (PMID:17224163); retained as a genuine but non-core property. Supporting Evidence: PMID:17224163 eight PAICS subunits, each composed of distinct AIRc and SAICARs domains, assemble a compact homo-octamer with an octameric-carboxylase core and four symmetric periphery dimers formed by synthetase domains
GO:0042802 identical protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	KEEP AS NON CORE	Summary: Self-association consistent with the homooctamer; valid but non-core. Reason: PAICS homooctamerization is documented structurally (PMID:17224163); retained as a real but non-core oligomerization property. Supporting Evidence: PMID:17224163 eight PAICS subunits, each composed of distinct AIRc and SAICARs domains, assemble a compact homo-octamer with an octameric-carboxylase core and four symmetric periphery dimers formed by synthetase domains
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Self-association consistent with the homooctamer; valid but non-core. Reason: Consistent with the octameric quaternary structure (PMID:17224163); retained as a genuine but non-core property. Supporting Evidence: PMID:17224163 eight PAICS subunits, each composed of distinct AIRc and SAICARs domains, assemble a compact homo-octamer with an octameric-carboxylase core and four symmetric periphery dimers formed by synthetase domains
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Self-association consistent with the homooctamer; valid but non-core. Reason: Consistent with the homooctamer (PMID:17224163); retained as a real but non-core oligomerization property. Supporting Evidence: PMID:17224163 eight PAICS subunits, each composed of distinct AIRc and SAICARs domains, assemble a compact homo-octamer with an octameric-carboxylase core and four symmetric periphery dimers formed by synthetase domains
GO:0004638 phosphoribosylaminoimidazole carboxylase activity	EXP PMID:17224163 Octameric structure of the human bifunctional enzyme PAICS i...	ACCEPT	Summary: AIR carboxylase (EC 4.1.1.21) core catalytic activity, directly demonstrated by biochemistry, crystallography (PDB 2H31) and active-site mutagenesis (His-303, Ser-332, Gly-334 loss-of-function). Reason: Directly experimentally supported core molecular function; the structural study identified the carboxylase active site and confirmed catalytic activity. Supporting Evidence: PMID:17224163 Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase (SAICARs) activities.
GO:0004639 phosphoribosylaminoimidazolesuccinocarboxamide synthase activity	EXP PMID:17224163 Octameric structure of the human bifunctional enzyme PAICS i...	ACCEPT	Summary: SAICAR synthetase (EC 6.3.2.6) core catalytic activity, directly demonstrated by biochemistry and crystallography. Reason: Directly experimentally supported core molecular function. Supporting Evidence: PMID:17224163 Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase (SAICARs) activities.
GO:0004638 phosphoribosylaminoimidazole carboxylase activity	IMP PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	ACCEPT	Summary: CRISPR-Cas9 knockout of PAICS in HeLa cells caused accumulation of its substrate, confirming the AIR carboxylase activity in vivo. Core molecular function. Reason: In vivo genetic (IMP) evidence via substrate accumulation upon knockout; supports the core carboxylase activity. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0006177 GMP biosynthetic process	IMP PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	KEEP AS NON CORE	Summary: PAICS acts upstream of IMP, which is the branch-point precursor for both AMP and GMP synthesis. GMP biosynthesis is therefore a downstream consequence, captured appropriately with the acts_upstream_of_or_within qualifier, but it is not PAICS's direct pathway step. Reason: Correct but downstream and indirect; PAICS makes an IMP precursor and GMP synthesis occurs downstream of IMP. The acts_upstream_of_or_within qualifier is appropriate. Not a core process for PAICS, whose direct role is IMP biosynthesis. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0006189 'de novo' IMP biosynthetic process	IMP PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	ACCEPT	Summary: Core biological process. PAICS knockout with substrate accumulation confirms its role in de novo IMP biosynthesis. Reason: Direct genetic evidence for the core pathway; the direct role of PAICS is in de novo IMP biosynthesis. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0044208 'de novo' AMP biosynthetic process	IMP PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	KEEP AS NON CORE	Summary: AMP biosynthesis occurs downstream of IMP; PAICS contributes indirectly by producing the IMP precursor. Appropriately captured with acts_upstream_of_or_within, but not PAICS's direct step. Reason: Correct but downstream and indirect; PAICS's direct role is IMP biosynthesis and AMP is made from IMP. Retained as non-core with the upstream qualifier. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0097294 'de novo' XMP biosynthetic process	IMP PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	KEEP AS NON CORE	Summary: XMP biosynthesis is downstream of IMP (IMP to XMP to GMP); PAICS contributes indirectly via the IMP precursor. Appropriately captured with acts_upstream_of_or_within, but not PAICS's direct step. Reason: Correct but downstream and indirect; PAICS's direct role is de novo IMP biosynthesis. Retained as non-core with the upstream qualifier. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0004638 phosphoribosylaminoimidazole carboxylase activity	IMP PMID:31600779 PAICS deficiency, a new defect of de novo purine synthesis r...	ACCEPT	Summary: The disease mutation p.Lys53Arg reduced both catalytic activities of PAICS, providing genetic evidence for the AIR carboxylase (EC 4.1.1.21) activity. Core molecular function. Reason: Genetic (IMP) evidence from a human loss-of-function disease variant that reduced the carboxylase activity; core enzymatic function. Supporting Evidence: PMID:31600779 The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively.
GO:0004639 phosphoribosylaminoimidazolesuccinocarboxamide synthase activity	IMP PMID:31600779 PAICS deficiency, a new defect of de novo purine synthesis r...	ACCEPT	Summary: The disease mutation reduced both catalytic activities, providing genetic evidence for the SAICAR synthetase (EC 6.3.2.6) activity. Core molecular function. Reason: Genetic (IMP) evidence from a human loss-of-function disease variant affecting the bifunctional enzyme's catalytic activity; core enzymatic function. Supporting Evidence: PMID:31600779 that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole
GO:0009113 purine nucleobase biosynthetic process	IDA PMID:31600779 PAICS deficiency, a new defect of de novo purine synthesis r...	KEEP AS NON CORE	Summary: PAICS participates in de novo purine synthesis, which ultimately produces purine nucleotides. This is a broadly correct process term; the more specific 'de novo' IMP biosynthetic process better captures the direct role. Reason: Correct but general. The core process term for PAICS is 'de novo' IMP biosynthetic process (GO:0006189); this broader purine nucleobase term is retained as non-core. Supporting Evidence: PMID:31600779 We report for the first time an autosomal recessive inborn error of de novo
GO:0097294 'de novo' XMP biosynthetic process	IDA PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	KEEP AS NON CORE	Summary: XMP biosynthesis is downstream of the IMP that PAICS helps produce. PAICS does not itself act in XMP synthesis, so this is a downstream/indirect involvement. Reason: PAICS's direct catalytic role is in de novo IMP biosynthesis; XMP is made downstream (IMP to XMP). Retained as a genuine but non-core downstream association. Action kept consistent with the acts_upstream_of_or_within annotation to the same term. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0004638 phosphoribosylaminoimidazole carboxylase activity	IDA PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	ACCEPT	Summary: AIR carboxylase core catalytic activity, supported by direct assay of the recombinant enzyme and substrate accumulation on knockout. Reason: Directly experimentally supported core molecular function (recombinant enzyme prepared and characterized; substrate accumulates when the gene is knocked out). Supporting Evidence: PMID:27590927 we prepared specific recombinant DNPS enzymes
GO:0006177 GMP biosynthetic process	IDA PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	KEEP AS NON CORE	Summary: GMP synthesis is downstream of the IMP branch point; PAICS acts upstream of IMP and does not itself catalyze a GMP-synthesis step. Reason: PAICS's direct pathway step is de novo IMP biosynthesis; GMP is synthesized downstream of IMP. Retained as a genuine but non-core downstream association. Action kept consistent with the acts_upstream_of_or_within annotation to the same term. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0006189 'de novo' IMP biosynthetic process	IDA PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	ACCEPT	Summary: Core biological process directly supported; PAICS is a de novo purine synthesis enzyme whose knockout causes substrate accumulation within the pathway. Reason: Direct experimental support for the core pathway in which PAICS acts. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0004639 phosphoribosylaminoimidazolesuccinocarboxamide synthase activity	IDA PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	ACCEPT	Summary: SAICAR synthetase core catalytic activity, supported by direct assay of the recombinant enzyme and substrate accumulation on knockout. Reason: Directly experimentally supported core molecular function. Supporting Evidence: PMID:27590927 we prepared specific recombinant DNPS enzymes
GO:0044208 'de novo' AMP biosynthetic process	IDA PMID:27590927 CRISPR-Cas9 induced mutations along de novo purine synthesis...	KEEP AS NON CORE	Summary: AMP synthesis is downstream of the IMP that PAICS helps make. PAICS does not itself catalyze an AMP-synthesis step, so this is a downstream/indirect involvement. Reason: PAICS's direct pathway step is de novo IMP biosynthesis; AMP is made downstream of IMP. Retained as a genuine but non-core downstream association. Action kept consistent with the acts_upstream_of_or_within annotation to the same term. Supporting Evidence: PMID:27590927 an accumulation of the substrate(s) for the knocked out enzyme was identified
GO:0045296 cadherin binding	HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by...	MARK AS OVER ANNOTATED	Summary: This annotation derives from a BioID proximity-biotinylation screen of the E-cadherin cytoplasmic tail, in which PAICS was one of ~561 vicinal proteins. It reflects spatial proximity in a high-throughput screen, not a genuine cadherin-binding molecular function of this cytosolic metabolic enzyme. Reason: The source study identified hundreds of proximal proteins by promiscuous biotin ligase labeling; the authors themselves note many proximal proteins do not localize to junctions. PAICS is a cytosolic purine-synthesis enzyme with no evidence of a true cadherin-binding function. Over-annotation. Supporting Evidence: PMID:25468996 We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin.
GO:0005737 cytoplasm	IDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by...	ACCEPT	Summary: Cytoplasmic localization is correct for this soluble cytosolic enzyme, though the more specific cytosol (GO:0005829) is also annotated and preferred. Reason: Consistent with PAICS being a cytosolic enzyme; a valid, if general, localization. The more specific cytosol annotation captures the same information. Supporting Evidence: PMID:25468996 We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: Detection in a shotgun proteomic survey of urinary prostatic-secretion exosomes (~900 proteins) reflects the abundance of this cytosolic enzyme in bulk proteomes rather than a functional extracellular/exosomal localization. Reason: PAICS is an abundant cytosolic metabolic enzyme commonly detected as a co-purifying species in large exosome/proteome datasets; there is no evidence of a functional role in the extracellular exosome. Over-annotation from high-throughput mass spectrometry. Supporting Evidence: PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Detection in an NK-cell membrane-proteome preparation (1843 proteins, ~40% predicted membrane) reflects co-isolation of an abundant soluble enzyme with membrane fractions, not integral/peripheral membrane localization. PAICS has no transmembrane domain or lipid anchor. Reason: The study itself notes many identified proteins are cellular-process proteins only transiently or non-specifically associated with membranes. PAICS is a cytosolic enzyme lacking membrane-targeting features. Over-annotation from a membrane-enriched proteome. Supporting Evidence: PMID:19946888 Mass spectrometric analysis identified 1843 proteins with high confidence scores.
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	MARK AS OVER ANNOTATED	Summary: Detection in a B-cell exosome proteome (539 proteins) reflects the abundance of this cytosolic enzyme in bulk proteomes, not a functional exosomal localization. Reason: High-throughput exosome proteomics routinely detects abundant cytosolic enzymes; PAICS is not functionally an extracellular exosome protein. Over-annotation. Supporting Evidence: PMID:20458337 we first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-73805	ACCEPT	Summary: Cytosolic localization curated by Reactome for the SAICAR synthetase reaction (CAIR + Aspartate + ATP to SAICAR + ADP + Pi). Correct core localization. Reason: Authoritative pathway (Reactome) assignment consistent with all other evidence that PAICS is a cytosolic enzyme.
GO:0005829 cytosol	TAS Reactome:R-HSA-73806	ACCEPT	Summary: Cytosolic localization curated by Reactome for the AIR carboxylase reaction (AIR + CO2 to CAIR). Correct core localization. Reason: Authoritative pathway (Reactome) assignment consistent with all other evidence that PAICS is a cytosolic enzyme.
GO:0004639 phosphoribosylaminoimidazolesuccinocarboxamide synthase activity	TAS PMID:2253271 Cloning and sequencing of a human cDNA coding for a multifun...	ACCEPT	Summary: Original cloning of the human cDNA identified the SAICAR synthetase (EC 6.3.2.6) activity from sequence homology and yeast complementation. Core molecular function; TAS supported by the primary literature. Reason: Foundational evidence for the SAICAR synthetase activity; the 5' half of the cDNA is homologous to bacterial SAICAR synthetase and complements yeast ade1. Supporting Evidence: PMID:2253271 Its 5' half is homologous to Bacillus subtilis SAICAR synthetase PMID:2253271 pADE2H1 clones complement both ade1 and ade2 mutants of S. cerevisiae
GO:0009113 purine nucleobase biosynthetic process	TAS PMID:2253271 Cloning and sequencing of a human cDNA coding for a multifun...	KEEP AS NON CORE	Summary: The cloning study established PAICS as a de novo purine pathway enzyme. Broadly correct process; the more specific 'de novo' IMP biosynthetic process is preferred as core. Reason: Correct but general. The specific core process is 'de novo' IMP biosynthetic process (GO:0006189); retained as non-core. Supporting Evidence: PMID:2253271 coding for a multifunctional polypeptide of the purine pathway

📄 View Raw YAML

id: P22234
gene_symbol: PAICS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Bifunctional enzyme of the de novo purine biosynthesis pathway that catalyzes
  two consecutive reactions. Its phosphoribosylaminoimidazole carboxylase (AIR carboxylase,
  AIRC; EC 4.1.1.21) activity carboxylates 5-aminoimidazole ribonucleotide (AIR) to
  4-carboxy-AIR (CAIR) using CO2/bicarbonate; its phosphoribosylaminoimidazolesuccinocarboxamide
  synthetase (SAICAR synthetase, SAICARS; EC 6.3.2.6) activity then condenses CAIR
  with L-aspartate in an ATP-dependent reaction to form SAICAR, the substrate that
  adenylosuccinate lyase (ADSL) subsequently cleaves to AICAR. The two catalytic activities
  reside in distinct domains of a single polypeptide (an N-terminal SAICAR synthetase
  domain and a C-terminal AIR carboxylase domain), and the protein assembles into a
  homooctamer whose quaternary structure builds the carboxylase active sites and provides
  intersubunit tunnels for substrate channeling between the two active sites. PAICS
  is a cytosolic enzyme and a component of the purinosome, the reversible multi-enzyme
  assembly of de novo purine synthesis. Loss-of-function causes an autosomal recessive
  inborn error of purine metabolism with multiple congenital anomalies and neonatal
  lethality.
alternative_products:
- name: '1'
  id: P22234-1
- name: '2'
  id: P22234-2
  sequence_note: VSP_041265
existing_annotations:
- term:
    id: GO:0004639
    label: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: SAICAR synthetase (EC 6.3.2.6) is one of the two catalytic activities of
      this bifunctional enzyme and is a core molecular function. The phylogenetic (IBA)
      inference is fully consistent with direct experimental and structural evidence.
    action: ACCEPT
    reason: Core enzymatic function directly supported by biochemistry and crystallography
      (PMID:17224163) and by the disease study (PMID:31600779). The IBA is at the correct
      level of specificity for this well-conserved family.
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole
        succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de
        novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide
        carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide
        synthetase (SAICARs) activities.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: PAICS is a soluble cytosolic enzyme that acts in the cytoplasm as part of
      the de novo purine synthesis pathway and the purinosome. The IBA localization is
      corroborated by Reactome TAS annotations to cytosol.
    action: ACCEPT
    reason: Correct site of action for this cytosolic metabolic enzyme, consistent with
      purinosome biology (PMID:31600779) and independent Reactome curation.
    supported_by:
    - reference_id: PMID:31600779
      supporting_text: Similar to other two known DNPS defects-adenylosuccinate lyase
        deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome
        formation in the patient's skin fibroblasts, and this phenotype was corrected by
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PAICS catalyzes two consecutive steps of the ten-reaction de novo pathway
      that builds IMP, making 'de novo' IMP biosynthetic process the correct core
      biological process.
    action: ACCEPT
    reason: Correct pathway assignment for both catalytic activities; the IBA inference
      matches direct experimental evidence (PMID:27590927, PMID:31600779) and UniProt
      pathway annotation.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: DNPS includes ten reactions catalysed by six enzymes.
- term:
    id: GO:0004638
    label: phosphoribosylaminoimidazole carboxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: AIR carboxylase (EC 4.1.1.21) is one of the two core catalytic activities.
      This IEA (RHEA/EC mapping) is correct and redundant with the experimental
      EXP/IDA/IMP annotations for the same term.
    action: ACCEPT
    reason: Accurate EC/RHEA-based mapping to a directly demonstrated enzymatic activity
      (PMID:17224163).
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole
        succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de
        novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide
        carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide
        synthetase (SAICARs) activities.
- term:
    id: GO:0004639
    label: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: SAICAR synthetase (EC 6.3.2.6) core catalytic activity; IEA EC/RHEA mapping
      is correct and redundant with the experimental annotations for the same term.
    action: ACCEPT
    reason: Accurate EC/RHEA-based mapping to a directly demonstrated enzymatic activity
      (PMID:17224163).
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole
        succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de
        novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide
        carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide
        synthetase (SAICARs) activities.
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Correct but general parent process. PAICS acts in de novo purine nucleotide
      biosynthesis; the more specific 'de novo' IMP biosynthetic process (GO:0006189)
      is also annotated and better captures the enzyme's role.
    action: ACCEPT
    reason: Biologically accurate broad process term from InterPro2GO; kept because IEAs
      may legitimately be broader than the more specific experimental terms. Not marked
      core because the more specific GO:0006189 is the core process.
    supported_by:
    - reference_id: PMID:31600779
      supporting_text: We report for the first time an autosomal recessive inborn error
        of de novo
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Correct core biological process, redundant with the IBA and experimental
      annotations to the same term.
    action: ACCEPT
    reason: Accurate UniPathway/InterPro-based mapping to the de novo IMP biosynthesis
      pathway in which PAICS acts.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: DNPS includes ten reactions catalysed by six enzymes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a large-scale interactome dataset.
      Uninformative about molecular function and does not represent a core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' conveys no specific molecular function and derives from
      high-throughput interactome screening. Per curation guidelines this term should be
      avoided in favor of informative MF terms; retained per policy (do not remove IPIs)
      but flagged as over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19060904
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a binary interactome mapping study;
      uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' from a high-throughput binary interactome dataset does
      not describe a specific molecular function; over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21653829
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from an autism-focused interactome study;
      uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' from high-throughput interactome data; not an
      informative molecular function and not core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale interactome map;
      uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' from a high-throughput interactome dataset;
      over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from an alternative-splicing interactome
      study; uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' from high-throughput interactome mapping; not
      informative and not core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a reference binary interactome map;
      uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' from a high-throughput binary interactome dataset;
      over-annotated.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16169070
  qualifier: enables
  review:
    summary: Self-association is biologically real for PAICS, which forms a homooctamer.
      However, this is a structural/oligomerization property rather than a core enzymatic
      function, and the supporting datasets are high-throughput interactome screens.
    action: KEEP_AS_NON_CORE
    reason: PAICS is a homooctamer (PMID:17224163), so identical-protein-binding is
      genuine and the octameric quaternary structure is functionally important for the
      carboxylase active sites. Kept as a valid but non-core annotation (self-assembly
      rather than catalytic function). The IPI evidence itself comes from a Y2H
      interactome screen.
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: eight PAICS subunits, each composed of distinct AIRc and SAICARs
        domains, assemble a compact homo-octamer with an octameric-carboxylase core and
        four symmetric periphery dimers formed by synthetase domains
    - reference_id: PMID:16169070
      supporting_text: a protein matrix of 4456 baits and 5632 preys was screened by
        automated yeast two-hybrid (Y2H) interaction mating
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Self-association consistent with the homooctamer; valid but non-core
      (structural oligomerization rather than catalytic function).
    action: KEEP_AS_NON_CORE
    reason: Corroborated by the crystal structure showing a homooctamer (PMID:17224163);
      retained as a genuine but non-core property.
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: eight PAICS subunits, each composed of distinct AIRc and SAICARs
        domains, assemble a compact homo-octamer with an octameric-carboxylase core and
        four symmetric periphery dimers formed by synthetase domains
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: Self-association consistent with the homooctamer; valid but non-core.
    action: KEEP_AS_NON_CORE
    reason: PAICS homooctamerization is documented structurally (PMID:17224163); retained
      as a real but non-core oligomerization property.
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: eight PAICS subunits, each composed of distinct AIRc and SAICARs
        domains, assemble a compact homo-octamer with an octameric-carboxylase core and
        four symmetric periphery dimers formed by synthetase domains
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Self-association consistent with the homooctamer; valid but non-core.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the octameric quaternary structure (PMID:17224163); retained
      as a genuine but non-core property.
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: eight PAICS subunits, each composed of distinct AIRc and SAICARs
        domains, assemble a compact homo-octamer with an octameric-carboxylase core and
        four symmetric periphery dimers formed by synthetase domains
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Self-association consistent with the homooctamer; valid but non-core.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the homooctamer (PMID:17224163); retained as a real but
      non-core oligomerization property.
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: eight PAICS subunits, each composed of distinct AIRc and SAICARs
        domains, assemble a compact homo-octamer with an octameric-carboxylase core and
        four symmetric periphery dimers formed by synthetase domains
- term:
    id: GO:0004638
    label: phosphoribosylaminoimidazole carboxylase activity
  evidence_type: EXP
  original_reference_id: PMID:17224163
  qualifier: enables
  review:
    summary: AIR carboxylase (EC 4.1.1.21) core catalytic activity, directly demonstrated
      by biochemistry, crystallography (PDB 2H31) and active-site mutagenesis (His-303,
      Ser-332, Gly-334 loss-of-function).
    action: ACCEPT
    reason: Directly experimentally supported core molecular function; the structural
      study identified the carboxylase active site and confirmed catalytic activity.
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole
        succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de
        novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide
        carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide
        synthetase (SAICARs) activities.
- term:
    id: GO:0004639
    label: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
  evidence_type: EXP
  original_reference_id: PMID:17224163
  qualifier: enables
  review:
    summary: SAICAR synthetase (EC 6.3.2.6) core catalytic activity, directly demonstrated
      by biochemistry and crystallography.
    action: ACCEPT
    reason: Directly experimentally supported core molecular function.
    supported_by:
    - reference_id: PMID:17224163
      supporting_text: Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole
        succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de
        novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide
        carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide
        synthetase (SAICARs) activities.
- term:
    id: GO:0004638
    label: phosphoribosylaminoimidazole carboxylase activity
  evidence_type: IMP
  original_reference_id: PMID:27590927
  qualifier: enables
  review:
    summary: CRISPR-Cas9 knockout of PAICS in HeLa cells caused accumulation of its
      substrate, confirming the AIR carboxylase activity in vivo. Core molecular function.
    action: ACCEPT
    reason: In vivo genetic (IMP) evidence via substrate accumulation upon knockout;
      supports the core carboxylase activity.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:27590927
  qualifier: acts_upstream_of_or_within
  review:
    summary: PAICS acts upstream of IMP, which is the branch-point precursor for both AMP
      and GMP synthesis. GMP biosynthesis is therefore a downstream consequence, captured
      appropriately with the acts_upstream_of_or_within qualifier, but it is not PAICS's
      direct pathway step.
    action: KEEP_AS_NON_CORE
    reason: Correct but downstream and indirect; PAICS makes an IMP precursor and GMP
      synthesis occurs downstream of IMP. The acts_upstream_of_or_within qualifier is
      appropriate. Not a core process for PAICS, whose direct role is IMP biosynthesis.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IMP
  original_reference_id: PMID:27590927
  qualifier: acts_upstream_of_or_within
  review:
    summary: Core biological process. PAICS knockout with substrate accumulation confirms
      its role in de novo IMP biosynthesis.
    action: ACCEPT
    reason: Direct genetic evidence for the core pathway; the direct role of PAICS is in
      de novo IMP biosynthesis.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0044208
    label: '''de novo'' AMP biosynthetic process'
  evidence_type: IMP
  original_reference_id: PMID:27590927
  qualifier: acts_upstream_of_or_within
  review:
    summary: AMP biosynthesis occurs downstream of IMP; PAICS contributes indirectly by
      producing the IMP precursor. Appropriately captured with acts_upstream_of_or_within,
      but not PAICS's direct step.
    action: KEEP_AS_NON_CORE
    reason: Correct but downstream and indirect; PAICS's direct role is IMP biosynthesis
      and AMP is made from IMP. Retained as non-core with the upstream qualifier.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0097294
    label: '''de novo'' XMP biosynthetic process'
  evidence_type: IMP
  original_reference_id: PMID:27590927
  qualifier: acts_upstream_of_or_within
  review:
    summary: XMP biosynthesis is downstream of IMP (IMP to XMP to GMP); PAICS contributes
      indirectly via the IMP precursor. Appropriately captured with
      acts_upstream_of_or_within, but not PAICS's direct step.
    action: KEEP_AS_NON_CORE
    reason: Correct but downstream and indirect; PAICS's direct role is de novo IMP
      biosynthesis. Retained as non-core with the upstream qualifier.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0004638
    label: phosphoribosylaminoimidazole carboxylase activity
  evidence_type: IMP
  original_reference_id: PMID:31600779
  qualifier: enables
  review:
    summary: The disease mutation p.Lys53Arg reduced both catalytic activities of PAICS,
      providing genetic evidence for the AIR carboxylase (EC 4.1.1.21) activity. Core
      molecular function.
    action: ACCEPT
    reason: Genetic (IMP) evidence from a human loss-of-function disease variant that
      reduced the carboxylase activity; core enzymatic function.
    supported_by:
    - reference_id: PMID:31600779
      supporting_text: The mutation reduced the catalytic activity of PAICS in
        heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of
        control levels, respectively.
- term:
    id: GO:0004639
    label: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
  evidence_type: IMP
  original_reference_id: PMID:31600779
  qualifier: enables
  review:
    summary: The disease mutation reduced both catalytic activities, providing genetic
      evidence for the SAICAR synthetase (EC 6.3.2.6) activity. Core molecular function.
    action: ACCEPT
    reason: Genetic (IMP) evidence from a human loss-of-function disease variant affecting
      the bifunctional enzyme's catalytic activity; core enzymatic function.
    supported_by:
    - reference_id: PMID:31600779
      supporting_text: that affects the structure of the catalytic site of the bifunctional
        enzyme phosphoribosylaminoimidazole
- term:
    id: GO:0009113
    label: purine nucleobase biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:31600779
  qualifier: involved_in
  review:
    summary: PAICS participates in de novo purine synthesis, which ultimately produces
      purine nucleotides. This is a broadly correct process term; the more specific
      'de novo' IMP biosynthetic process better captures the direct role.
    action: KEEP_AS_NON_CORE
    reason: Correct but general. The core process term for PAICS is 'de novo' IMP
      biosynthetic process (GO:0006189); this broader purine nucleobase term is retained
      as non-core.
    supported_by:
    - reference_id: PMID:31600779
      supporting_text: We report for the first time an autosomal recessive inborn error
        of de novo
- term:
    id: GO:0097294
    label: '''de novo'' XMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:27590927
  qualifier: involved_in
  review:
    summary: XMP biosynthesis is downstream of the IMP that PAICS helps produce. PAICS
      does not itself act in XMP synthesis, so this is a downstream/indirect involvement.
    action: KEEP_AS_NON_CORE
    reason: PAICS's direct catalytic role is in de novo IMP biosynthesis; XMP is made
      downstream (IMP to XMP). Retained as a genuine but non-core downstream association.
      Action kept consistent with the acts_upstream_of_or_within annotation to the same
      term.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0004638
    label: phosphoribosylaminoimidazole carboxylase activity
  evidence_type: IDA
  original_reference_id: PMID:27590927
  qualifier: enables
  review:
    summary: AIR carboxylase core catalytic activity, supported by direct assay of the
      recombinant enzyme and substrate accumulation on knockout.
    action: ACCEPT
    reason: Directly experimentally supported core molecular function (recombinant enzyme
      prepared and characterized; substrate accumulates when the gene is knocked out).
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: we prepared specific recombinant DNPS enzymes
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:27590927
  qualifier: involved_in
  review:
    summary: GMP synthesis is downstream of the IMP branch point; PAICS acts upstream of
      IMP and does not itself catalyze a GMP-synthesis step.
    action: KEEP_AS_NON_CORE
    reason: PAICS's direct pathway step is de novo IMP biosynthesis; GMP is synthesized
      downstream of IMP. Retained as a genuine but non-core downstream association. Action
      kept consistent with the acts_upstream_of_or_within annotation to the same term.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:27590927
  qualifier: involved_in
  review:
    summary: Core biological process directly supported; PAICS is a de novo purine
      synthesis enzyme whose knockout causes substrate accumulation within the pathway.
    action: ACCEPT
    reason: Direct experimental support for the core pathway in which PAICS acts.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0004639
    label: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
  evidence_type: IDA
  original_reference_id: PMID:27590927
  qualifier: enables
  review:
    summary: SAICAR synthetase core catalytic activity, supported by direct assay of the
      recombinant enzyme and substrate accumulation on knockout.
    action: ACCEPT
    reason: Directly experimentally supported core molecular function.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: we prepared specific recombinant DNPS enzymes
- term:
    id: GO:0044208
    label: '''de novo'' AMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:27590927
  qualifier: involved_in
  review:
    summary: AMP synthesis is downstream of the IMP that PAICS helps make. PAICS does not
      itself catalyze an AMP-synthesis step, so this is a downstream/indirect involvement.
    action: KEEP_AS_NON_CORE
    reason: PAICS's direct pathway step is de novo IMP biosynthesis; AMP is made
      downstream of IMP. Retained as a genuine but non-core downstream association. Action
      kept consistent with the acts_upstream_of_or_within annotation to the same term.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme was
        identified
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: This annotation derives from a BioID proximity-biotinylation screen of the
      E-cadherin cytoplasmic tail, in which PAICS was one of ~561 vicinal proteins. It
      reflects spatial proximity in a high-throughput screen, not a genuine
      cadherin-binding molecular function of this cytosolic metabolic enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: The source study identified hundreds of proximal proteins by promiscuous
      biotin ligase labeling; the authors themselves note many proximal proteins do not
      localize to junctions. PAICS is a cytosolic purine-synthesis enzyme with no evidence
      of a true cadherin-binding function. Over-annotation.
    supported_by:
    - reference_id: PMID:25468996
      supporting_text: We used proximity biotinylation and quantitative proteomics to
        identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:25468996
  qualifier: located_in
  review:
    summary: Cytoplasmic localization is correct for this soluble cytosolic enzyme, though
      the more specific cytosol (GO:0005829) is also annotated and preferred.
    action: ACCEPT
    reason: Consistent with PAICS being a cytosolic enzyme; a valid, if general,
      localization. The more specific cytosol annotation captures the same information.
    supported_by:
    - reference_id: PMID:25468996
      supporting_text: We used proximity biotinylation and quantitative proteomics to
        identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: Detection in a shotgun proteomic survey of urinary prostatic-secretion
      exosomes (~900 proteins) reflects the abundance of this cytosolic enzyme in bulk
      proteomes rather than a functional extracellular/exosomal localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: PAICS is an abundant cytosolic metabolic enzyme commonly detected as a
      co-purifying species in large exosome/proteome datasets; there is no evidence of a
      functional role in the extracellular exosome. Over-annotation from high-throughput
      mass spectrometry.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: In pooled EPS-urine exosome samples, ~900 proteins were detected.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: Detection in an NK-cell membrane-proteome preparation (1843 proteins, ~40%
      predicted membrane) reflects co-isolation of an abundant soluble enzyme with
      membrane fractions, not integral/peripheral membrane localization. PAICS has no
      transmembrane domain or lipid anchor.
    action: MARK_AS_OVER_ANNOTATED
    reason: The study itself notes many identified proteins are cellular-process proteins
      only transiently or non-specifically associated with membranes. PAICS is a cytosolic
      enzyme lacking membrane-targeting features. Over-annotation from a membrane-enriched
      proteome.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: Mass spectrometric analysis identified 1843 proteins with high
        confidence scores.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: Detection in a B-cell exosome proteome (539 proteins) reflects the abundance
      of this cytosolic enzyme in bulk proteomes, not a functional exosomal localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput exosome proteomics routinely detects abundant cytosolic
      enzymes; PAICS is not functionally an extracellular exosome protein. Over-annotation.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: we first analyzed the total proteome of highly purified B
        cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and
        identified 539 proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73805
  qualifier: located_in
  review:
    summary: Cytosolic localization curated by Reactome for the SAICAR synthetase reaction
      (CAIR + Aspartate + ATP to SAICAR + ADP + Pi). Correct core localization.
    action: ACCEPT
    reason: Authoritative pathway (Reactome) assignment consistent with all other evidence
      that PAICS is a cytosolic enzyme.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73806
  qualifier: located_in
  review:
    summary: Cytosolic localization curated by Reactome for the AIR carboxylase reaction
      (AIR + CO2 to CAIR). Correct core localization.
    action: ACCEPT
    reason: Authoritative pathway (Reactome) assignment consistent with all other evidence
      that PAICS is a cytosolic enzyme.
- term:
    id: GO:0004639
    label: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
  evidence_type: TAS
  original_reference_id: PMID:2253271
  qualifier: enables
  review:
    summary: Original cloning of the human cDNA identified the SAICAR synthetase (EC
      6.3.2.6) activity from sequence homology and yeast complementation. Core molecular
      function; TAS supported by the primary literature.
    action: ACCEPT
    reason: Foundational evidence for the SAICAR synthetase activity; the 5' half of the
      cDNA is homologous to bacterial SAICAR synthetase and complements yeast ade1.
    supported_by:
    - reference_id: PMID:2253271
      supporting_text: Its 5' half is homologous to Bacillus subtilis SAICAR synthetase
    - reference_id: PMID:2253271
      supporting_text: pADE2H1 clones complement both ade1 and ade2 mutants of S.
        cerevisiae
- term:
    id: GO:0009113
    label: purine nucleobase biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:2253271
  qualifier: involved_in
  review:
    summary: The cloning study established PAICS as a de novo purine pathway enzyme.
      Broadly correct process; the more specific 'de novo' IMP biosynthetic process is
      preferred as core.
    action: KEEP_AS_NON_CORE
    reason: Correct but general. The specific core process is 'de novo' IMP biosynthetic
      process (GO:0006189); retained as non-core.
    supported_by:
    - reference_id: PMID:2253271
      supporting_text: coding for a multifunctional polypeptide of the purine pathway
core_functions:
- description: Phosphoribosylaminoimidazole carboxylase (AIR carboxylase) activity;
    carboxylates AIR to CAIR (EC 4.1.1.21) as the first of two consecutive de novo
    purine synthesis steps catalyzed by PAICS.
  molecular_function:
    id: GO:0004638
    label: phosphoribosylaminoimidazole carboxylase activity
  directly_involved_in:
  - id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:17224163
    supporting_text: Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole
      succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de
      novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide
      carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide
      synthetase (SAICARs) activities.
- description: Phosphoribosylaminoimidazolesuccinocarboxamide synthetase (SAICAR
    synthetase) activity; ATP-dependent condensation of CAIR with L-aspartate to form
    SAICAR (EC 6.3.2.6), the second consecutive de novo purine synthesis step catalyzed
    by PAICS.
  molecular_function:
    id: GO:0004639
    label: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
  directly_involved_in:
  - id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:17224163
    supporting_text: Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole
      succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de
      novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide
      carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide
      synthetase (SAICARs) activities.
  - reference_id: PMID:31600779
    supporting_text: The mutation reduced the catalytic activity of PAICS in
      heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of
      control levels, respectively.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16169070
  title: 'A human protein-protein interaction network: a resource for annotating the
    proteome.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale Y2H interactome; supports identical protein binding only
      as a high-throughput self-interaction, not a specific molecular function.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome dataset; source of generic protein-binding
      and identical-protein-binding annotations.
- id: PMID:17224163
  title: Octameric structure of the human bifunctional enzyme PAICS in purine biosynthesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Crystal structure (PDB 2H31); establishes both catalytic activities,
      the homooctamer, active-site residues, and substrate-channeling tunnels.
- id: PMID:19060904
  title: An empirical framework for binary interactome mapping.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput binary interactome dataset; source of a generic
      protein-binding annotation.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Membrane-enriched proteome; PAICS detected as an abundant soluble
      co-isolate, not a genuine membrane protein.
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteome; PAICS detected as an abundant cytosolic co-isolate,
      not a functional exosomal protein.
- id: PMID:21653829
  title: Protein interactome reveals converging molecular pathways among autism disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a generic protein-binding
      annotation.
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of an identical-protein-binding
      annotation, consistent with homooctamerization.
- id: PMID:2253271
  title: Cloning and sequencing of a human cDNA coding for a multifunctional polypeptide
    of the purine pathway by complementation of the ade2-101 mutant in Saccharomyces
    cerevisiae.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original cloning of human PAICS (ADE2); establishes both SAICARS and
      AIRC activities by homology and yeast complementation.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteomics; PAICS detected among ~900 proteins as an abundant
      co-isolate.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of protein-binding and
      identical-protein-binding annotations.
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative
    proteomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioID proximity-biotinylation of E-cadherin tail identifying ~561
      vicinal proteins; PAICS proximity is not a genuine cadherin-binding function.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a generic protein-binding
      annotation.
- id: PMID:27590927
  title: CRISPR-Cas9 induced mutations along de novo purine synthesis in HeLa cells
    result in accumulation of individual enzyme substrates and affect purinosome formation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: CRISPR knockouts of DNPS enzymes with substrate accumulation and
      reduced purinosome assembly; basis for the MGI experimental MF/BP annotations.
- id: PMID:31600779
  title: PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple
    congenital anomalies and fatal outcome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Human loss-of-function disease (PAICSD); p.Lys53Arg reduces both
      catalytic activities and prevents purinosome formation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput binary interactome; source of multiple protein-binding
      and identical-protein-binding annotations.
- id: Reactome:R-HSA-73805
  title: CAIR + Aspartate + ATP => SAICAR + ADP + Pi
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for the SAICAR synthetase step; cytosolic localization.
- id: Reactome:R-HSA-73806
  title: AIR + CO2 => CAIR
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for the AIR carboxylase step; cytosolic localization.
suggested_questions:
- question: Does phosphorylation of PAICS (e.g. at Ser-27, Ser-107, Thr-238) regulate
    its catalytic activity or its recruitment into the purinosome?
- question: What is the molecular basis of PAICS upregulation in cancers, and does the
    substrate-channeling octamer offer a druggable target distinct from the salvage
    pathway?
suggested_experiments:
- description: Structure-guided design and testing of active-site-selective inhibitors
    targeting the AIRC versus SAICARS active sites, exploiting the intersubunit
    substrate-channeling tunnels revealed by the octameric structure.
  hypothesis: Selective inhibition of one PAICS active site can block de novo purine
    flux with a therapeutic window over the salvage pathway.
- description: Quantitative measurement of AIR/CAIR/SAICAR flux in PAICS-deficient
    versus wild-type cells to define the metabolic consequences and confirm the two
    consecutive steps in vivo.
  hypothesis: Loss of PAICS causes accumulation of its AIR substrate and depletion of
    SAICAR, consistent with a block at both consecutive de novo purine synthesis steps.

Gene Description

Existing Annotations Review

Core Functions

Phosphoribosylaminoimidazole carboxylase (AIR carboxylase) activity; carboxylates AIR to CAIR (EC 4.1.1.21) as the first of two consecutive de novo purine synthesis steps catalyzed by PAICS.

Phosphoribosylaminoimidazolesuccinocarboxamide synthetase (SAICAR synthetase) activity; ATP-dependent condensation of CAIR with L-aspartate to form SAICAR (EC 6.3.2.6), the second consecutive de novo purine synthesis step catalyzed by PAICS.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

PAICS (P22234, PUR6_HUMAN) review notes

Domain architecture (UniProt P22234)

Localization

Key experimental evidence

Over-annotations identified

Core functions (for core_functions block)

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