RPIA

UniProt ID: P49247
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

RPIA is ribose-5-phosphate isomerase (EC 5.3.1.6), a cytosolic enzyme of the non-oxidative branch of the pentose phosphate pathway. It catalyses the reversible aldose-ketose interconversion of D-ribose-5-phosphate and D-ribulose-5-phosphate. In the biosynthetic direction it supplies ribose-5-phosphate for nucleotide, nucleotide-cofactor and other precursor biosynthesis; in the regenerative direction it feeds ribulose-5-phosphate toward the transketolase/transaldolase reactions that reconnect the pathway to glycolysis. Loss-of-function causes ribose-5-phosphate isomerase deficiency, an extremely rare autosomal-recessive inborn error of metabolism presenting as a slowly progressive leukoencephalopathy with peripheral neuropathy and markedly elevated polyols (ribitol, D-arabitol) in brain and body fluids.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004751 ribose-5-phosphate isomerase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetically-inferred core molecular function; RPIA is the human member of the ribose-5-phosphate isomerase (RpiA) family and catalyses the R5P <-> Ru5P isomerisation. This is the correct, most specific MF term and is corroborated by direct experimental and NAS evidence.
Reason: IBA at the correct level of specificity, concordant with the experimentally-verified catalytic activity of the enzyme.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Catalyzes the reversible conversion of ribose-5-phosphate to
PMID:14988808
the reversible phase of the PPP
GO:0009052 pentose-phosphate shunt, non-oxidative branch
IBA
GO_REF:0000033 		ACCEPT
Summary: Core biological process. RPIA acts in the first step of the non-oxidative branch of the pentose phosphate pathway, isomerising ribulose-5-phosphate and ribose-5-phosphate.
Reason: Correct and specific BP term, consistent with the UniProt PATHWAY annotation (non-oxidative stage, step 1/1) and the enzyme's characterised reaction.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
pentose phosphate pathway; D-ribose
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: RPIA is a soluble cytoplasmic/cytosolic enzyme with no signal or transit peptide. Cytoplasm is correct, though the more specific cytosol term (GO:0005829) is also annotated and preferred for core representation.
Reason: Consistent with the cytosolic Reactome/UniProt localisation of this housekeeping metabolic enzyme.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Belongs to the ribose 5-phosphate isomerase family
GO:0006014 D-ribose metabolic process
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: RPIA interconverts D-ribose-5-phosphate and D-ribulose-5-phosphate, so it participates in ribose-phosphate (D-ribose) metabolism. This is a correct but broader process term relative to the pentose-phosphate-shunt terms.
Reason: True but less specific than the pentose-phosphate-shunt, non-oxidative branch term; retained as supporting rather than core process.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Catalyzes the reversible conversion of ribose-5-phosphate to
GO:0004751 ribose-5-phosphate isomerase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of the core isomerase activity, backed by RHEA:14657 (aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate), EC 5.3.1.6 and the RpiA InterPro signatures. Fully consistent with experimental evidence.
Reason: Correct EC/RHEA/InterPro-to-GO mapping for the family; matches the experimentally-verified catalytic activity.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
GO:0009052 pentose-phosphate shunt, non-oxidative branch
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of the correct, specific non-oxidative PPP branch process, concordant with the IBA annotation.
Reason: Correct and specific BP term for a ribose-5-phosphate isomerase.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
pentose phosphate pathway; D-ribose
GO:0005515 protein binding
IPI
PMID:16189514
Towards a proteome-scale map of the human protein-protein in... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from a high-throughput proteome-scale yeast two-hybrid interactome map (CCSB-HI1). Uninformative for RPIA's molecular function.
Reason: Generic protein binding derived from a large-scale binary interactome screen; per curation guidance this uninformative term should not be treated as representing RPIA function. Retained (not removed) as an experimental IPI.
Supporting Evidence:
PMID:16189514
an initial version of a proteome-scale map
GO:0005515 protein binding
IPI
PMID:21516116
Next-generation sequencing to generate interactome datasets. 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from a high-throughput interactome-mapping pipeline (Stitch-seq). Uninformative for RPIA's molecular function.
Reason: Generic protein binding from a large-scale interactome dataset; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:21516116
Next-generation sequencing to generate interactome datasets.
GO:0005515 protein binding
IPI
PMID:24722188
Protein interaction network of alternatively spliced isoform... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from a brain alternatively-spliced-isoform interactome screen. Uninformative for RPIA's molecular function.
Reason: Generic protein binding from a large-scale interactome dataset; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:24722188
Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from a proteome-scale human interactome map (HI-II-14). Uninformative for RPIA's molecular function.
Reason: Generic protein binding from a large-scale binary interactome screen; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network
GO:0005515 protein binding
IPI
PMID:25910212
Widespread macromolecular interaction perturbations in human... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from an interactome-perturbation study of human genetic disorders. Uninformative for RPIA's molecular function.
Reason: Generic protein binding from a large-scale interactome dataset; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:25910212
Widespread macromolecular interaction perturbations in human genetic disorders.
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from a large-scale affinity-purification/interactome community-network study. Uninformative for RPIA's molecular function.
Reason: Generic protein binding from a large-scale interactome dataset; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding
IPI
PMID:29892012
An interactome perturbation framework prioritizes damaging m... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from an interactome-perturbation framework for developmental-disorder missense variants. Uninformative for RPIA function.
Reason: Generic protein binding from a large-scale interactome dataset; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:29892012
An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.
GO:0005515 protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from a large-scale study of interaction disruption by human genetic variants. Uninformative for RPIA's molecular function.
Reason: Generic protein binding from a large-scale interactome dataset; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
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 the HuRI reference binary interactome map. Uninformative for RPIA's molecular function.
Reason: Generic protein binding from a large-scale binary interactome screen; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:32296183
A reference map of the human binary protein interactome
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 dual proteome-scale (BioPlex) affinity-capture interactome study. Uninformative for RPIA's molecular function.
Reason: Generic protein binding from a large-scale interactome dataset; not informative of molecular function. Retained as an experimental IPI.
Supporting Evidence:
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
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-interaction (P49247 with P49247) detected in a high-throughput binary interactome map. Ribose-5-phosphate isomerase A enzymes are characteristically homodimeric, so self-association is biologically plausible, but this remains a screen-derived binding term rather than a core catalytic function.
Reason: Homodimerisation is consistent with RpiA family architecture; kept as a non-core structural property rather than a core molecular function.
Supporting Evidence:
PMID:16189514
an initial version of a proteome-scale map
GO:0042802 identical protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: Self-interaction (P49247 with P49247) detected in the HuRI reference binary interactome map, consistent with the homodimeric architecture of RpiA-family isomerases.
Reason: Homodimerisation is consistent with RpiA family architecture; kept as a non-core structural property rather than a core molecular function.
Supporting Evidence:
PMID:32296183
A reference map of the human binary protein interactome
GO:0005829 cytosol
IEA
GO_REF:0000120 		ACCEPT
Summary: Cytosol is the correct subcellular location for this soluble PPP enzyme, consistent with the Reactome TAS cytosol annotations and the absence of any signal/transit peptide.
Reason: Correct, specific cellular-component term for the active enzyme.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Belongs to the ribose 5-phosphate isomerase family
GO:0006098 pentose-phosphate shunt
IEA
GO_REF:0000120 		ACCEPT
Summary: RPIA participates in the pentose phosphate pathway; this is the correct but broader parent of the non-oxidative-branch term.
Reason: Correct process term; a more specific non-oxidative-branch annotation (GO:0009052) is also present and preferred for the core representation.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
pentose phosphate pathway; D-ribose
GO:0030246 carbohydrate binding
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Electronic transfer (Ensembl Compara, from the rat ortholog) of a generic carbohydrate-binding term. RPIA binds its phosphorylated pentose substrate at the active site as part of catalysis; a standalone lectin-like carbohydrate-binding function is not supported and this term is uninformative/over-general.
Reason: Over-general electronic mapping; substrate binding is already captured by the isomerase activity term and there is no evidence of a distinct carbohydrate-binding role.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
GO:0048029 monosaccharide binding
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Electronic transfer (Ensembl Compara, from the rat ortholog) of a generic monosaccharide-binding term. As with carbohydrate binding, RPIA's binding of its phosphorylated pentose substrate is part of catalysis, not a distinct sugar-binding function.
Reason: Over-general electronic mapping subsumed by the isomerase activity term; no evidence of a distinct monosaccharide-binding role.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
GO:0006098 pentose-phosphate shunt
TAS
Reactome:R-HSA-71336 		ACCEPT
Summary: Reactome traceable-author annotation placing RPIA in the pentose phosphate pathway. Correct; the broader parent of the non-oxidative-branch term.
Reason: Correct process term supported by curated Reactome pathway knowledge.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
pentose phosphate pathway; D-ribose
GO:0004751 ribose-5-phosphate isomerase activity
EXP
PMID:14988808
Ribose-5-phosphate isomerase deficiency: new inborn error in... 		ACCEPT
Summary: Direct experimental evidence: RPI enzyme activity (EC 5.3.1.6) was measured and found deficient in patient fibroblasts, establishing the human protein as a functional ribose-5-phosphate isomerase. This is the definitive core molecular function.
Reason: Experimentally verified catalytic activity of the human enzyme; assay of RPI activity in patient fibroblasts and disease-causing loss of function.
Supporting Evidence:
PMID:14988808
pentose-phosphate-pathway (PPP) enzymes, was demonstrated in fibroblasts
GO:0004751 ribose-5-phosphate isomerase activity
TAS
Reactome:R-HSA-5660013 		ACCEPT
Summary: Reactome traceable-author annotation of the core isomerase activity (in the context of a reaction whose defective form underlies RPIA deficiency). Correct core molecular function.
Reason: Correct MF term from curated Reactome knowledge, concordant with experimental evidence.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
GO:0004751 ribose-5-phosphate isomerase activity
TAS
Reactome:R-HSA-5660015 		ACCEPT
Summary: Reactome traceable-author annotation of the core isomerase activity. Correct core molecular function.
Reason: Correct MF term from curated Reactome knowledge, concordant with experimental evidence.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		MARK AS OVER ANNOTATED
Summary: RPIA appears in a large-scale high-throughput mitochondrial proteome (MitoCoP) dataset. RPIA is a soluble cytosolic housekeeping enzyme with no mitochondrial transit peptide, and its established site of action is the cytosol; the mitochondrial signal most likely reflects co-purification in the proteomic preparation rather than a genuine mitochondrial pool.
Reason: Isolated HTP proteomics hit that conflicts with the well-established cytosolic localisation and the lack of any targeting sequence; treated as an over-annotation rather than removed, as it is an experimental (high-throughput) dataset whose full detail is not verifiable here.
Supporting Evidence:
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
file:human/RPIA/RPIA-uniprot.txt
Belongs to the ribose 5-phosphate isomerase family
GO:0005829 cytosol
TAS
Reactome:R-HSA-177784 		ACCEPT
Summary: Reactome traceable-author localisation of RPIA to the cytosol, consistent with its role as a soluble PPP enzyme. Core location.
Reason: Correct, specific cytosolic localisation from curated Reactome knowledge.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Belongs to the ribose 5-phosphate isomerase family
GO:0005829 cytosol
TAS
Reactome:R-HSA-71306 		ACCEPT
Summary: Reactome traceable-author localisation of RPIA to the cytosol. Core location, concordant with the other cytosol annotations.
Reason: Correct, specific cytosolic localisation from curated Reactome knowledge.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Belongs to the ribose 5-phosphate isomerase family
GO:0005829 cytosol
TAS
Reactome:R-HSA-5660013 		ACCEPT
Summary: Reactome traceable-author localisation of RPIA to the cytosol. Core location.
Reason: Correct, specific cytosolic localisation from curated Reactome knowledge.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Belongs to the ribose 5-phosphate isomerase family
GO:0005829 cytosol
TAS
Reactome:R-HSA-5660015 		ACCEPT
Summary: Reactome traceable-author localisation of RPIA to the cytosol. Core location.
Reason: Correct, specific cytosolic localisation from curated Reactome knowledge.
Supporting Evidence:
file:human/RPIA/RPIA-uniprot.txt
Belongs to the ribose 5-phosphate isomerase family
GO:0004751 ribose-5-phosphate isomerase activity
NAS
PMID:7758956
The ribose 5-phosphate isomerase-encoding gene is located im... 		ACCEPT
Summary: Non-traceable author statement assigning ribose-5-phosphate isomerase activity, based on cloning of the mouse/human RPI gene and demonstration that a recombinant GST-RPI fusion has enzymatic activity. Supports the core molecular function.
Reason: Correct core MF term; the underlying study cloned the RPI gene and showed a recombinant fusion protein is enzymatically active, corroborating the human enzyme's identity.
Supporting Evidence:
PMID:7758956
protein has enzymatic activity and that an anti-mRPI antibody detects a protein
PMID:7758956
the RPI gene is evolutionarily conserved

Core Functions

Ribose-5-phosphate isomerase catalysing the reversible aldose-ketose interconversion of D-ribose-5-phosphate and D-ribulose-5-phosphate in the non-oxidative branch of the pentose phosphate pathway, in the cytosol.

Molecular Function:
ribose-5-phosphate isomerase activity
Directly Involved In:
pentose-phosphate shunt, non-oxidative branch
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:14988808
    pentose-phosphate-pathway (PPP) enzymes, was demonstrated in fibroblasts
  • file:human/RPIA/RPIA-uniprot.txt
    Catalyzes the reversible conversion of ribose-5-phosphate to

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
file:human/RPIA/RPIA-uniprot.txt
UniProtKB entry P49247 (RPIA_HUMAN)
PMID:14988808
Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy.
PMID:16189514
Towards a proteome-scale map of the human protein-protein interaction network.
PMID:21516116
Next-generation sequencing to generate interactome datasets.
PMID:24722188
Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:25910212
Widespread macromolecular interaction perturbations in human genetic disorders.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:29892012
An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
PMID:7758956
The ribose 5-phosphate isomerase-encoding gene is located immediately downstream from that encoding murine immunoglobulin kappa.
Reactome:R-HSA-177784
RPIA isomerizes ribose 5-phosphate to D-ribulose 5-phosphate
Reactome:R-HSA-5660013
Defective RPIA does not isomerize RU5P to R5P
Reactome:R-HSA-5660015
Defective RPIA does not isomerize R5P to RU5P
Reactome:R-HSA-71306
RPIA isomerizes D-ribulose 5-phosphate to ribose 5-phosphate
Reactome:R-HSA-71336
Pentose phosphate pathway

Suggested Questions for Experts

Q: Does RPIA have any moonlighting or non-catalytic role that could explain the neurological phenotype of RPIA deficiency beyond simple pentose-phosphate flux disruption?

Q: Is the polyol accumulation (ribitol, D-arabitol) in RPIA deficiency directly neurotoxic, or is the phenotype driven by ribose-5-phosphate / nucleotide precursor shortage in the developing brain?

Suggested Experiments

Experiment: Kinetic characterisation of the human recombinant enzyme (wild-type versus disease variants such as p.Ala135Val) to quantify catalytic impairment in both reaction directions.

Type: enzyme kinetics

Experiment: Subcellular fractionation and imaging to test whether a genuine mitochondrial pool of RPIA exists or whether the high-throughput mitochondrial-proteome signal reflects co-purification of a cytosolic enzyme.

Type: cell biology / localisation

📚 Additional Documentation

Notes

(RPIA-notes.md)

RPIA (Ribose-5-phosphate isomerase A) — review notes

UniProtKB: P49247 (RPIA_HUMAN). HGNC:10297. EC 5.3.1.6. 311 aa, cytosolic.

Core biology

RPIA is ribose-5-phosphate isomerase, the enzyme of the non-oxidative branch of the
pentose phosphate pathway (PPP) that catalyses the reversible aldose–ketose
interconversion of D-ribose-5-phosphate and D-ribulose-5-phosphate.

  • UniProt FUNCTION: "Catalyzes the reversible conversion of ribose-5-phosphate to
    ribulose 5-phosphate and participates in the first step of the non-oxidative branch of
    the pentose phosphate pathway." [file:human/RPIA/RPIA-uniprot.txt]
  • Rhea RHEA:14657: aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate; EC=5.3.1.6.
  • PATHWAY: pentose phosphate pathway; D-ribose 5-phosphate from D-ribulose 5-phosphate
    (non-oxidative stage): step 1/1. [file:human/RPIA/RPIA-uniprot.txt]
  • Family: ribose 5-phosphate isomerase (type A / RpiA). InterPro IPR004788, IPR020672;
    Pfam PF06026; CDD cd01398 RPI_A; PANTHER PTHR11934.

Directionally, RPIA supplies ribose-5-phosphate for nucleotide, nucleotide-cofactor
(NAD, FAD, CoA) and histidine/aromatic precursor biosynthesis; in the regenerative
direction it feeds ribulose-5-phosphate (and downstream via the epimerase into the
transketolase/transaldolase reactions) back toward glycolytic intermediates.

Disease

Ribose-5-phosphate isomerase deficiency (RPIAD; MIM:608611). Autosomal recessive; one of
the rarest known inborn errors of metabolism (single/very few patients described). Slowly
progressive leukoencephalopathy with peripheral neuropathy; highly elevated polyols
(ribitol, D-arabitol) in brain (MRS) and body fluids.
[PMID:14988808 "the first patient with a deficiency of ribose-5-phosphate isomerase (RPI)
(Enzyme Commission number 5.3.1.6) who presented with leukoencephalopathy and peripheral
neuropathy"; "highly elevated levels of the polyols ribitol and D-arabitol"]
- p.Ala135Val (VAR_019122) plus a frameshift; deficient RPI activity in fibroblasts.
[file:human/RPIA/RPIA-uniprot.txt VARIANT 135; PMID:14988808]

Annotation assessment summary

  • MF GO:0004751 ribose-5-phosphate isomerase activity: core. EXP (PMID:14988808), IBA, IEA
    (RHEA:14657, EC:5.3.1.6), NAS (PMID:7758956). All ACCEPT.
  • BP GO:0009052 pentose-phosphate shunt, non-oxidative branch: core (IBA, IEA). ACCEPT.
  • BP GO:0006098 pentose-phosphate shunt (parent), GO:0006014 D-ribose metabolic process:
    correct but less specific / non-core supporting; ACCEPT / KEEP_AS_NON_CORE.
  • CC cytosol GO:0005829 / cytoplasm GO:0005737: core location (IBA, IEA, TAS). ACCEPT.
  • CC mitochondrion GO:0005739 (HTP, PMID:34800366): RPIA is a soluble cytosolic enzyme
    with no transit/signal peptide; appears only in a large-scale MitoCoP mass-spec dataset.
    Treat as over-annotation (MARK_AS_OVER_ANNOTATED) — do NOT REMOVE an HTP experimental
    annotation whose full text/supp is unverified.
  • MF GO:0005515 protein binding (IPI): all from high-throughput interactome maps (Y2H /
    AP-MS: Rual 2005, Rolland 2014, Luck 2020, Yu 2011, etc.). Uninformative bare protein
    binding → MARK_AS_OVER_ANNOTATED (not REMOVE, per policy).
  • MF GO:0042802 identical protein binding (IPI, self EBI-744831–EBI-744831): RpiA is a
    homodimer in the family; self-interaction plausible but still an interactome-map bare
    binding term → KEEP_AS_NON_CORE (real homodimerization) but not a core catalytic MF.
  • MF GO:0030246 carbohydrate binding / GO:0048029 monosaccharide binding (IEA, Ensembl
    Compara from rat ortholog): over-general electronic mappings; the substrate is a
    phosphorylated pentose bound as the isomerase substrate, not lectin-type sugar binding.
    MARK_AS_OVER_ANNOTATED.

References

  • PMID:14988808 — abstract-only cache (full_text_available: false) but abstract itself
    establishes RPI deficiency, EC 5.3.1.6, catalytic deficiency, disease. HIGH.
  • PMID:7758956 — mouse/human RPI gene cloning; GST-mRPI fusion has enzymatic activity.
    Basis for NAS MF annotation. MEDIUM/HIGH.
  • Interactome papers (16189514, 21516116, 24722188, 25416956, 25910212, 28514442,
    29892012, 31515488, 32296183, 33961781): high-throughput binary/AP-MS maps; LOW
    relevance to RPIA molecular function.
  • PMID:34800366 — MitoCoP mitochondrial proteome; RPIA an HTP hit only; LOW relevance
    (localization likely a co-purification artifact for a cytosolic enzyme).

📄 View Raw YAML

 
id: P49247
gene_symbol: RPIA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RPIA is ribose-5-phosphate isomerase (EC 5.3.1.6), a cytosolic enzyme of the
  non-oxidative branch of the pentose phosphate pathway. It catalyses the
  reversible aldose-ketose interconversion of D-ribose-5-phosphate and
  D-ribulose-5-phosphate. In the biosynthetic direction it supplies
  ribose-5-phosphate for nucleotide, nucleotide-cofactor and other precursor
  biosynthesis; in the regenerative direction it feeds ribulose-5-phosphate
  toward the transketolase/transaldolase reactions that reconnect the pathway to
  glycolysis. Loss-of-function causes ribose-5-phosphate isomerase deficiency, an
  extremely rare autosomal-recessive inborn error of metabolism presenting as a
  slowly progressive leukoencephalopathy with peripheral neuropathy and markedly
  elevated polyols (ribitol, D-arabitol) in brain and body fluids.
existing_annotations:
- term:
    id: GO:0004751
    label: ribose-5-phosphate isomerase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically-inferred core molecular function; RPIA is the human member
      of the ribose-5-phosphate isomerase (RpiA) family and catalyses the R5P
      <-> Ru5P isomerisation. This is the correct, most specific MF term and is
      corroborated by direct experimental and NAS evidence.
    action: ACCEPT
    reason: >-
      IBA at the correct level of specificity, concordant with the
      experimentally-verified catalytic activity of the enzyme.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Catalyzes the reversible conversion of ribose-5-phosphate to
    - reference_id: PMID:14988808
      supporting_text: the reversible phase of the PPP
- term:
    id: GO:0009052
    label: pentose-phosphate shunt, non-oxidative branch
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. RPIA acts in the first step of the non-oxidative
      branch of the pentose phosphate pathway, isomerising ribulose-5-phosphate
      and ribose-5-phosphate.
    action: ACCEPT
    reason: >-
      Correct and specific BP term, consistent with the UniProt PATHWAY
      annotation (non-oxidative stage, step 1/1) and the enzyme's characterised
      reaction.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: pentose phosphate pathway; D-ribose
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      RPIA is a soluble cytoplasmic/cytosolic enzyme with no signal or transit
      peptide. Cytoplasm is correct, though the more specific cytosol term
      (GO:0005829) is also annotated and preferred for core representation.
    action: ACCEPT
    reason: >-
      Consistent with the cytosolic Reactome/UniProt localisation of this
      housekeeping metabolic enzyme.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Belongs to the ribose 5-phosphate isomerase family
- term:
    id: GO:0006014
    label: D-ribose metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      RPIA interconverts D-ribose-5-phosphate and D-ribulose-5-phosphate, so it
      participates in ribose-phosphate (D-ribose) metabolism. This is a correct
      but broader process term relative to the pentose-phosphate-shunt terms.
    action: KEEP_AS_NON_CORE
    reason: >-
      True but less specific than the pentose-phosphate-shunt, non-oxidative
      branch term; retained as supporting rather than core process.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Catalyzes the reversible conversion of ribose-5-phosphate to
- term:
    id: GO:0004751
    label: ribose-5-phosphate isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core isomerase activity, backed by RHEA:14657
      (aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate), EC 5.3.1.6 and
      the RpiA InterPro signatures. Fully consistent with experimental evidence.
    action: ACCEPT
    reason: >-
      Correct EC/RHEA/InterPro-to-GO mapping for the family; matches the
      experimentally-verified catalytic activity.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
- term:
    id: GO:0009052
    label: pentose-phosphate shunt, non-oxidative branch
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment of the correct, specific non-oxidative PPP branch
      process, concordant with the IBA annotation.
    action: ACCEPT
    reason: >-
      Correct and specific BP term for a ribose-5-phosphate isomerase.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: pentose phosphate pathway; D-ribose
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a high-throughput proteome-scale yeast two-hybrid
      interactome map (CCSB-HI1). Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding derived from a large-scale binary interactome
      screen; per curation guidance this uninformative term should not be treated
      as representing RPIA function. Retained (not removed) as an experimental IPI.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: an initial version of a proteome-scale map
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a high-throughput interactome-mapping pipeline
      (Stitch-seq). Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale interactome dataset; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: Next-generation sequencing to generate interactome datasets.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24722188
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a brain alternatively-spliced-isoform interactome
      screen. Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale interactome dataset; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:24722188
      supporting_text: Protein interaction network of alternatively spliced isoforms
        from brain links genetic risk factors for autism.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a proteome-scale human interactome map
      (HI-II-14). Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale binary interactome screen; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from an interactome-perturbation study of human genetic
      disorders. Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale interactome dataset; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:25910212
      supporting_text: Widespread macromolecular interaction perturbations in human
        genetic disorders.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a large-scale affinity-purification/interactome
      community-network study. Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale interactome dataset; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities
        and disease networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29892012
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from an interactome-perturbation framework for
      developmental-disorder missense variants. Uninformative for RPIA function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale interactome dataset; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:29892012
      supporting_text: An interactome perturbation framework prioritizes damaging
        missense mutations for developmental disorders.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a large-scale study of interaction disruption by
      human genetic variants. Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale interactome dataset; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants
        across the allele frequency spectrum in human populations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from the HuRI reference binary interactome map.
      Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale binary interactome screen; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a dual proteome-scale (BioPlex) affinity-capture
      interactome study. Uninformative for RPIA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale interactome dataset; not
      informative of molecular function. Retained as an experimental IPI.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling
        of the human interactome.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Self-interaction (P49247 with P49247) detected in a high-throughput binary
      interactome map. Ribose-5-phosphate isomerase A enzymes are characteristically
      homodimeric, so self-association is biologically plausible, but this remains
      a screen-derived binding term rather than a core catalytic function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Homodimerisation is consistent with RpiA family architecture; kept as a
      non-core structural property rather than a core molecular function.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: an initial version of a proteome-scale map
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Self-interaction (P49247 with P49247) detected in the HuRI reference binary
      interactome map, consistent with the homodimeric architecture of RpiA-family
      isomerases.
    action: KEEP_AS_NON_CORE
    reason: >-
      Homodimerisation is consistent with RpiA family architecture; kept as a
      non-core structural property rather than a core molecular function.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: is_active_in
  review:
    summary: >-
      Cytosol is the correct subcellular location for this soluble PPP enzyme,
      consistent with the Reactome TAS cytosol annotations and the absence of any
      signal/transit peptide.
    action: ACCEPT
    reason: >-
      Correct, specific cellular-component term for the active enzyme.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Belongs to the ribose 5-phosphate isomerase family
- term:
    id: GO:0006098
    label: pentose-phosphate shunt
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      RPIA participates in the pentose phosphate pathway; this is the correct but
      broader parent of the non-oxidative-branch term.
    action: ACCEPT
    reason: >-
      Correct process term; a more specific non-oxidative-branch annotation
      (GO:0009052) is also present and preferred for the core representation.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: pentose phosphate pathway; D-ribose
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from the rat ortholog) of a generic
      carbohydrate-binding term. RPIA binds its phosphorylated pentose substrate
      at the active site as part of catalysis; a standalone lectin-like
      carbohydrate-binding function is not supported and this term is
      uninformative/over-general.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-general electronic mapping; substrate binding is already captured by
      the isomerase activity term and there is no evidence of a distinct
      carbohydrate-binding role.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
- term:
    id: GO:0048029
    label: monosaccharide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from the rat ortholog) of a generic
      monosaccharide-binding term. As with carbohydrate binding, RPIA's binding of
      its phosphorylated pentose substrate is part of catalysis, not a distinct
      sugar-binding function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-general electronic mapping subsumed by the isomerase activity term; no
      evidence of a distinct monosaccharide-binding role.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
- term:
    id: GO:0006098
    label: pentose-phosphate shunt
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71336
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author annotation placing RPIA in the pentose phosphate
      pathway. Correct; the broader parent of the non-oxidative-branch term.
    action: ACCEPT
    reason: >-
      Correct process term supported by curated Reactome pathway knowledge.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: pentose phosphate pathway; D-ribose
- term:
    id: GO:0004751
    label: ribose-5-phosphate isomerase activity
  evidence_type: EXP
  original_reference_id: PMID:14988808
  qualifier: enables
  review:
    summary: >-
      Direct experimental evidence: RPI enzyme activity (EC 5.3.1.6) was measured
      and found deficient in patient fibroblasts, establishing the human protein
      as a functional ribose-5-phosphate isomerase. This is the definitive core
      molecular function.
    action: ACCEPT
    reason: >-
      Experimentally verified catalytic activity of the human enzyme; assay of
      RPI activity in patient fibroblasts and disease-causing loss of function.
    supported_by:
    - reference_id: PMID:14988808
      supporting_text: pentose-phosphate-pathway (PPP) enzymes, was demonstrated in
        fibroblasts
- term:
    id: GO:0004751
    label: ribose-5-phosphate isomerase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5660013
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author annotation of the core isomerase activity (in the
      context of a reaction whose defective form underlies RPIA deficiency).
      Correct core molecular function.
    action: ACCEPT
    reason: >-
      Correct MF term from curated Reactome knowledge, concordant with
      experimental evidence.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
- term:
    id: GO:0004751
    label: ribose-5-phosphate isomerase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5660015
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author annotation of the core isomerase activity.
      Correct core molecular function.
    action: ACCEPT
    reason: >-
      Correct MF term from curated Reactome knowledge, concordant with
      experimental evidence.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Reaction=aldehydo-D-ribose 5-phosphate = D-ribulose 5-phosphate
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      RPIA appears in a large-scale high-throughput mitochondrial proteome
      (MitoCoP) dataset. RPIA is a soluble cytosolic housekeeping enzyme with no
      mitochondrial transit peptide, and its established site of action is the
      cytosol; the mitochondrial signal most likely reflects co-purification in
      the proteomic preparation rather than a genuine mitochondrial pool.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Isolated HTP proteomics hit that conflicts with the well-established
      cytosolic localisation and the lack of any targeting sequence; treated as an
      over-annotation rather than removed, as it is an experimental
      (high-throughput) dataset whose full detail is not verifiable here.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome and
        its dynamics in cellular context.
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Belongs to the ribose 5-phosphate isomerase family
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-177784
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localisation of RPIA to the cytosol, consistent
      with its role as a soluble PPP enzyme. Core location.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localisation from curated Reactome knowledge.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Belongs to the ribose 5-phosphate isomerase family
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71306
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localisation of RPIA to the cytosol. Core
      location, concordant with the other cytosol annotations.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localisation from curated Reactome knowledge.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Belongs to the ribose 5-phosphate isomerase family
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5660013
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localisation of RPIA to the cytosol. Core
      location.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localisation from curated Reactome knowledge.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Belongs to the ribose 5-phosphate isomerase family
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5660015
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localisation of RPIA to the cytosol. Core
      location.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localisation from curated Reactome knowledge.
    supported_by:
    - reference_id: file:human/RPIA/RPIA-uniprot.txt
      supporting_text: Belongs to the ribose 5-phosphate isomerase family
- term:
    id: GO:0004751
    label: ribose-5-phosphate isomerase activity
  evidence_type: NAS
  original_reference_id: PMID:7758956
  qualifier: enables
  review:
    summary: >-
      Non-traceable author statement assigning ribose-5-phosphate isomerase
      activity, based on cloning of the mouse/human RPI gene and demonstration
      that a recombinant GST-RPI fusion has enzymatic activity. Supports the core
      molecular function.
    action: ACCEPT
    reason: >-
      Correct core MF term; the underlying study cloned the RPI gene and showed a
      recombinant fusion protein is enzymatically active, corroborating the human
      enzyme's identity.
    supported_by:
    - reference_id: PMID:7758956
      supporting_text: protein has enzymatic activity and that an anti-mRPI antibody
        detects a protein
    - reference_id: PMID:7758956
      supporting_text: the RPI gene is evolutionarily conserved
core_functions:
- description: >-
    Ribose-5-phosphate isomerase catalysing the reversible aldose-ketose
    interconversion of D-ribose-5-phosphate and D-ribulose-5-phosphate in the
    non-oxidative branch of the pentose phosphate pathway, in the cytosol.
  molecular_function:
    id: GO:0004751
    label: ribose-5-phosphate isomerase activity
  directly_involved_in:
  - id: GO:0009052
    label: pentose-phosphate shunt, non-oxidative branch
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:14988808
    supporting_text: pentose-phosphate-pathway (PPP) enzymes, was demonstrated in fibroblasts
  - reference_id: file:human/RPIA/RPIA-uniprot.txt
    supporting_text: Catalyzes the reversible conversion of ribose-5-phosphate to
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/RPIA/RPIA-uniprot.txt
  title: UniProtKB entry P49247 (RPIA_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Swiss-Prot record; establishes EC 5.3.1.6, the RHEA:14657 reaction, the
      non-oxidative PPP pathway step, cytosolic family membership, and RPIA
      deficiency (MIM:608611).
- id: PMID:14988808
  title: 'Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose
    phosphate pathway associated with a slowly progressive leukoencephalopathy.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      First described patient with RPI deficiency; measured deficient RPI activity
      (EC 5.3.1.6) in fibroblasts, elevated ribitol/D-arabitol, and identified
      causative RPIA variants. Cached entry is abstract-only but the abstract itself
      establishes the enzyme activity and disease.
- 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 yeast two-hybrid interactome map (CCSB-HI1); source of a bare
      protein-binding IPI, uninformative for RPIA molecular function.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome-mapping methodology (Stitch-seq); source of a bare
      protein-binding IPI.
- id: PMID:24722188
  title: Protein interaction network of alternatively spliced isoforms from brain
    links genetic risk factors for autism.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale isoform interactome screen; source of a bare protein-binding IPI.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale binary interactome map (HI-II-14); source of bare
      protein-binding IPIs.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Interactome-perturbation study; source of a bare protein-binding IPI.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale interactome community-network study; source of a bare
      protein-binding IPI.
- id: PMID:29892012
  title: An interactome perturbation framework prioritizes damaging missense mutations
    for developmental disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Interactome-perturbation framework; source of bare protein-binding IPIs.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Variant-interaction disruption study; source of a bare protein-binding IPI.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI reference binary interactome; source of bare protein-binding and
      identical-protein-binding (self) IPIs.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex dual proteome-scale affinity-capture networks; source of a bare
      protein-binding IPI.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      MitoCoP high-throughput mitochondrial proteome; RPIA is an HTP hit only. Given
      the cytosolic localisation and absence of a transit peptide, the mitochondrial
      signal likely reflects co-purification rather than a genuine mitochondrial pool.
- id: PMID:7758956
  title: The ribose 5-phosphate isomerase-encoding gene is located immediately downstream
    from that encoding murine immunoglobulin kappa.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Cloned the mouse/human RPI gene and showed a recombinant GST-RPI fusion is
      enzymatically active; basis for the NAS molecular-function annotation.
- id: Reactome:R-HSA-177784
  title: RPIA isomerizes ribose 5-phosphate to D-ribulose 5-phosphate
  findings: []
- id: Reactome:R-HSA-5660013
  title: Defective RPIA does not isomerize RU5P to R5P
  findings: []
- id: Reactome:R-HSA-5660015
  title: Defective RPIA does not isomerize R5P to RU5P
  findings: []
- id: Reactome:R-HSA-71306
  title: RPIA isomerizes D-ribulose 5-phosphate to ribose 5-phosphate
  findings: []
- id: Reactome:R-HSA-71336
  title: Pentose phosphate pathway
  findings: []
suggested_questions:
- question: >-
    Does RPIA have any moonlighting or non-catalytic role that could explain the
    neurological phenotype of RPIA deficiency beyond simple pentose-phosphate flux
    disruption?
- question: >-
    Is the polyol accumulation (ribitol, D-arabitol) in RPIA deficiency directly
    neurotoxic, or is the phenotype driven by ribose-5-phosphate / nucleotide
    precursor shortage in the developing brain?
suggested_experiments:
- description: >-
    Kinetic characterisation of the human recombinant enzyme (wild-type versus
    disease variants such as p.Ala135Val) to quantify catalytic impairment in
    both reaction directions.
  experiment_type: enzyme kinetics
- description: >-
    Subcellular fractionation and imaging to test whether a genuine mitochondrial
    pool of RPIA exists or whether the high-throughput mitochondrial-proteome
    signal reflects co-purification of a cytosolic enzyme.
  experiment_type: cell biology / localisation