PGLS

UniProt ID: O95336
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

PGLS is 6-phosphogluconolactonase (EC 3.1.1.31), the second enzyme of the oxidative branch of the pentose phosphate pathway. It hydrolyses 6-phospho-D-glucono-1,5-lactone, the product of glucose-6-phosphate dehydrogenase (G6PD), to 6-phospho-D-gluconate, the substrate of 6-phosphogluconate dehydrogenase (PGD). By accelerating hydrolysis of the reactive delta-lactone it both drives flux through the oxidative branch and prevents accumulation of the electrophilic lactone (and its dead-end gamma-isomer), which can react with cellular nucleophiles. The enzyme is cytosolic, belongs to the glucosamine/galactosamine-6-phosphate isomerase family (6-phosphogluconolactonase subfamily), and is ubiquitously expressed.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005829 cytosol
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetically inferred cytosolic localization, consistent with the curated cytosolic/cytoplasmic location of PGLS and its role as a soluble oxidative-PPP enzyme. This represents the core subcellular location and is corroborated by HPA IDA (cytosol) and Reactome.
Supporting Evidence:
Reactome:R-HSA-71296
Cytosolic 6-phosphogluconolactonase (PGLS) catalyzes the hydrolysis of D-glucono-1,5-lactone 6-phosphate to form 6-phospho-D-gluconate
file:human/PGLS/PGLS-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0009051 pentose-phosphate shunt, oxidative branch
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetically inferred involvement in the oxidative branch of the pentose phosphate pathway. This is the core biological process for PGLS, which catalyses step 2 of the oxidative branch, and is well supported by direct biochemical characterisation of the human enzyme.
Supporting Evidence:
PMID:11457850
6-Phosphogluconolactonase is the second enzyme of the oxidative branch and
GO:0017057 6-phosphogluconolactonase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetically inferred 6-phosphogluconolactonase activity. This is the core molecular function of PGLS and is directly demonstrated for the human enzyme (EC 3.1.1.31; RHEA:12556).
Supporting Evidence:
PMID:10518023
shown to be 6-phosphogluconolactonase, the enzyme catalyzing the second step of the pentose phosphate pathway
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Electronic annotation from the UniProt Subcellular Location mapping (Cytoplasm). This is a correct but broad parent of the more precise cytosol location; keep as a non-core, less-specific localization.
Reason: Correct localization but less specific than GO:0005829 (cytosol), which is supported by IBA and HPA IDA and better captures the location of this soluble enzyme.
Supporting Evidence:
file:human/PGLS/PGLS-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005975 carbohydrate metabolic process
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro2GO electronic annotation. Correct but very general; PGLS acts in carbohydrate metabolism, but the specific and informative process term is the oxidative pentose-phosphate branch. Keep as a non-core, high-level annotation.
Reason: Broad parent process. The precise process (GO:0009051, pentose-phosphate shunt, oxidative branch) is annotated separately and is preferred as core.
GO:0006098 pentose-phosphate shunt
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic annotation to the overall pentose-phosphate shunt. Correct; PGLS participates in the pentose phosphate pathway. This is a valid parent of the more specific oxidative-branch term and is also supported experimentally (PMID:10518023) and by Reactome.
Supporting Evidence:
file:human/PGLS/PGLS-uniprot.txt
PATHWAY: Carbohydrate degradation; pentose phosphate pathway; D-
GO:0009051 pentose-phosphate shunt, oxidative branch
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA electronic annotation to the oxidative branch of the pentose phosphate pathway, consistent with the IBA and experimental evidence. Core biological process.
Supporting Evidence:
PMID:11457850
6-Phosphogluconolactonase is the second enzyme of the oxidative branch and
GO:0017057 6-phosphogluconolactonase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic annotation (ARBA/InterPro/RHEA:12556/EC:3.1.1.31) to the core molecular function. Correct and directly supported by experimental characterisation of the human enzyme.
Supporting Evidence:
file:human/PGLS/PGLS-uniprot.txt
EC=3.1.1.31 {ECO:0000269|PubMed:10518023}
GO:0005515 protein binding
IPI
PMID:21044950
Genome-wide YFP fluorescence complementation screen identifi... 		MARK AS OVER ANNOTATED
Summary: Interaction reported from a genome-wide split-YFP (BiFC) complementation screen for regulators of telomere signaling (PGLS scored against a core telomeric protein; IntAct with UniProtKB:Q9NYB0/TERF2IP). This is a high-throughput binary-interaction dataset in which most hits had no prior functional link to the process, and no PGLS-specific functional characterization was performed. The bare term "protein binding" is uninformative about molecular function.
Reason: High-throughput interactome hit captured only as the uninformative parent term GO:0005515. Retained (a genuine curated IPI), but not a core molecular function and not indicative of a specific binding role for PGLS.
Supporting Evidence:
PMID:21044950
we identified over 300 proteins that associated with the six core telomeric proteins
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: Binary interaction from the HuRI human all-by-all reference interactome (PGLS-BLMH; IntAct with UniProtKB:Q13867). A systematic proteome-scale Y2H dataset with no PGLS-specific functional follow-up; the bare term "protein binding" is uninformative.
Reason: Systematic interactome hit captured only as the uninformative parent term GO:0005515. Retained as a real curated IPI but not a core molecular function.
Supporting Evidence:
PMID:32296183
reference interactome map of human binary protein interactions
GO:0006098 pentose-phosphate shunt
TAS
Reactome:R-HSA-71336 		ACCEPT
Summary: Reactome traceable-author-statement annotation placing PGLS in the pentose phosphate pathway. Correct; PGLS catalyses step 2 (conversion of D-glucono-1,5-lactone 6-phosphate to 6-phospho-D-gluconate) of the pathway.
Supporting Evidence:
Reactome:R-HSA-71336
Conversion of D-glucono-1,5-lactone 6-phosphate to 6-phospho-D-gluconate
GO:0017057 6-phosphogluconolactonase activity
EXP
PMID:10518023
Identification of the cDNA encoding human 6-phosphogluconola... 		ACCEPT
Summary: Experimental demonstration that the human protein, expressed in E. coli and purified, is 6-phosphogluconolactonase. Direct evidence for the core molecular function.
Supporting Evidence:
PMID:10518023
The protein was expressed in Escherichia coli, purified and shown to be 6-phosphogluconolactonase, the enzyme catalyzing the second step of the pentose phosphate pathway
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: HPA immunofluorescence detected PGLS in the nucleoplasm in addition to the cytosol. Small soluble metabolic enzymes are frequently detected in the nucleoplasm by immunofluorescence, and no nuclear function of PGLS is described. Keep as a non-core localization.
Reason: Immunofluorescence-based localization with no associated nuclear function; the core location is the cytosol. Not removed, as it is a valid curated IDA.
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: HPA immunofluorescence localizes PGLS to the cytosol, consistent with the IBA, Reactome, and UniProt cytoplasm annotations. Core subcellular location.
Supporting Evidence:
Reactome:R-HSA-71296
Cytosolic 6-phosphogluconolactonase (PGLS) catalyzes the hydrolysis of D-glucono-1,5-lactone 6-phosphate to form 6-phospho-D-gluconate
GO:0009051 pentose-phosphate shunt, oxidative branch
IMP
PMID:31586547
γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pent... 		ACCEPT
Summary: Genetic perturbation (knockdown/knockout) of PGLS in human cancer cells reduces oxidative-PPP flux, decreases 6-phosphogluconate, and causes accumulation of 6-phosphogluconolactone, confirming that PGLS acts within the oxidative branch of the pentose phosphate pathway. The paper's downstream signaling findings (gamma-6PGL to Src/PP2A/AMPK) are consequences of altered oxiPPP metabolite levels, and the annotation correctly uses the metabolic-branch process term.
Supporting Evidence:
PMID:31586547
The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to
PMID:31586547
stable knockdown of PGLS in Group I H1299 and K562 cells as well
GO:0017057 6-phosphogluconolactonase activity
IDA
PMID:11457850
NMR spectroscopic analysis of the first two steps of the pen... 		ACCEPT
Summary: NMR-based kinetic characterization directly demonstrating 6-phosphogluconolactonase activity of the human enzyme, acting on the delta form of 6-phosphogluconolactone. Direct evidence for the core molecular function.
Supporting Evidence:
PMID:11457850
6-phosphogluconolactonase activity accelerates hydrolysis of the delta form
GO:0070062 extracellular exosome
HDA
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expres... 		MARK AS OVER ANNOTATED
Summary: High-throughput mass-spectrometry detection of PGLS in exosomes from expressed prostatic secretions in urine (~900 proteins detected). Abundant cytosolic enzymes are routinely detected in exosome proteomes; this does not indicate a functional extracellular localization.
Reason: Bulk proteomic detection in secreted vesicles; not a functional or core localization for a cytosolic metabolic enzyme. Retained as a curated HDA observation.
Supporting Evidence:
PMID:23533145
In pooled EPS-urine exosome samples, ~900 proteins were detected
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		MARK AS OVER ANNOTATED
Summary: High-throughput mass-spectrometry detection of PGLS in human urinary exosomes. As above, abundant cytosolic enzymes commonly appear in exosome proteomes; not a functional localization.
Reason: Bulk proteomic detection in secreted vesicles; not a core localization for this cytosolic enzyme.
Supporting Evidence:
PMID:19056867
we used LC-MS/MS to profile the proteome of human urinary exosomes
GO:0005829 cytosol
TAS
Reactome:R-HSA-71296 		ACCEPT
Summary: Reactome traceable-author-statement localizing PGLS to the cytosol, where it catalyses the hydrolysis of D-glucono-1,5-lactone 6-phosphate. Core subcellular location.
Supporting Evidence:
Reactome:R-HSA-71296
Cytosolic 6-phosphogluconolactonase (PGLS) catalyzes the hydrolysis of D-glucono-1,5-lactone 6-phosphate to form 6-phospho-D-gluconate
GO:0006098 pentose-phosphate shunt
IDA
PMID:10518023
Identification of the cDNA encoding human 6-phosphogluconola... 		ACCEPT
Summary: Direct evidence placing PGLS in the pentose phosphate pathway as the enzyme catalysing its second step. Correct; a valid parent of the oxidative-branch term.
Supporting Evidence:
PMID:10518023
shown to be 6-phosphogluconolactonase, the enzyme catalyzing the second step of the pentose phosphate pathway
GO:0017057 6-phosphogluconolactonase activity
IDA
PMID:10518023
Identification of the cDNA encoding human 6-phosphogluconola... 		ACCEPT
Summary: Direct biochemical demonstration that purified human PGLS has 6-phosphogluconolactonase activity. Core molecular function.
Supporting Evidence:
PMID:10518023
shown to be 6-phosphogluconolactonase, the enzyme catalyzing the second step of the pentose phosphate pathway

Core Functions

Hydrolysis of 6-phospho-D-glucono-1,5-lactone to 6-phospho-D-gluconate, the second reaction of the oxidative branch of the pentose phosphate pathway, acting downstream of G6PD and upstream of PGD/6PGD.

Molecular Function:
6-phosphogluconolactonase activity
Directly Involved In:
pentose-phosphate shunt, oxidative branch
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:10518023
    shown to be 6-phosphogluconolactonase, the enzyme catalyzing the second step of the pentose phosphate pathway
  • PMID:11457850
    6-Phosphogluconolactonase is the second enzyme of the oxidative branch and

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10518023
Identification of the cDNA encoding human 6-phosphogluconolactonase, the enzyme catalyzing the second step of the pentose phosphate pathway(1).
PMID:11457850
NMR spectroscopic analysis of the first two steps of the pentose-phosphate pathway elucidates the role of 6-phosphogluconolactonase.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:21044950
Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
PMID:31586547
γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pentose Phosphate Pathway, Contributes to AMPK Activation through Inhibition of PP2A.
PMID:32296183
A reference map of the human binary protein interactome.
Reactome:R-HSA-71296
PGLS hydrolyzes D-glucono-1,5-lactone 6-phosphate
Reactome:R-HSA-71336
Pentose phosphate pathway
file:human/PGLS/PGLS-uniprot.txt
UniProtKB entry O95336 (6PGL_HUMAN)

📚 Additional Documentation

Notes

(PGLS-notes.md)

PGLS (human) — 6-phosphogluconolactonase — review notes

UniProt: O95336 (6PGL_HUMAN); HGNC:8903; EC 3.1.1.31; 258 aa; chr19.
Family: glucosamine/galactosamine-6-phosphate isomerase family, 6-phosphogluconolactonase subfamily.
InterPro: IPR005900 (6PGL_DevB), IPR039104 (6PGL), IPR006148 (Glc/Gal-6P isomerase). CDD cd01400 (6PGL). PANTHER PTHR11054.

Core biology

PGLS is the second enzyme of the oxidative branch of the pentose phosphate pathway
(oxiPPP). It hydrolyses 6-phospho-D-glucono-1,5-lactone (the product of G6PD,
the first oxiPPP enzyme) to 6-phospho-D-gluconate (the substrate of the third
enzyme, 6PGD/PGD). RHEA:12556; EC 3.1.1.31.

  • UniProt FUNCTION: "Hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate."
    [file:human/PGLS/PGLS-uniprot.txt]
  • UniProt PATHWAY: pentose phosphate pathway; D-ribulose 5-phosphate from
    D-glucose 6-phosphate (oxidative stage): step 2/3. [ECO:0000269|PubMed:10518023]

Identification / catalytic activity (PMID:10518023, Collard et al. 1999)

Human cDNA cloned; protein expressed in E. coli, purified, and "shown to be
6-phosphogluconolactonase, the enzyme catalyzing the second step of the pentose
phosphate pathway." Homologous to bacterial devB and to the C-terminal part of
human hexose-6-phosphate dehydrogenase; related to glucosamine-6-phosphate
isomerases. This is the source of the EXP/IDA MF and pentose-phosphate-shunt BP
annotations. full_text_available: false (abstract only).

Enzymatic role clarified by NMR (PMID:11457850, Miclet et al. 2001)

"6-Phosphogluconolactonase is the second enzyme of the oxidative branch and
catalyzes the hydrolysis of 6-phosphogluconolactones, the products of glucose
6-phosphate oxidation by glucose-6-phosphate dehydrogenase." Key point: the
δ-form (1→5) is the only G6PD product and the only PGLS substrate; it can undergo
slow spontaneous hydrolysis but can also rearrange to the γ-form (1→4), a "dead
end." PGLS "activity accelerates hydrolysis of the delta form, thus preventing its
conversion into the gamma form" and "guards against the accumulation of
delta-6-phosphogluconolactone, which may be toxic through its reaction with
endogenous cellular nucleophiles." IDA MF (PMID:11457850). full_text_available: false.

PGLS in oxiPPP / signaling (PMID:31586547, Gao et al. 2019, Mol Cell)

Full text available. Confirms PGLS as "the second oxiPPP enzyme" that "converts 6PGL
to 6-phosphogluconate (6PG)." Knockdown of PGLS reduces oxiPPP flux, decreases 6PG,
accumulates 6PGL (δ and γ), increases ROS, and activates AMPK via decreased PP2A
activity; reduces cell proliferation/tumor growth in xenografts. This is the basis
for the IMP acts_upstream_of_or_within GO:0009051 annotation — genetic perturbation
of PGLS alters oxiPPP output. The paper's headline mechanistic finding (γ-6PGL → Src →
PP2A → AMPK) is a downstream signaling consequence, not a molecular function of PGLS
itself; the annotation appropriately uses the metabolic-branch BP term.

Localization

  • Cytosolic. UniProt SUBCELLULAR LOCATION: Cytoplasm (ECO:0000250). Reactome
    R-HSA-71296 states "Cytosolic 6-phosphogluconolactonase (PGLS)". HPA IDA cytosol +
    IBA cytosol. This is the core/consensus location.
  • HPA IDA nucleoplasm (GO:0005654): HPA immunofluorescence also scores nucleoplasm.
    Small soluble metabolic enzymes are commonly detected in the nucleoplasm by IF;
    no described nuclear function. Keep as non-core.
  • Extracellular exosome (GO:0070062), two HDA proteomics datasets (PMID:23533145
    prostatic-secretion/urine exosomes; PMID:19056867 urinary exosomes). Bulk
    MS detection in secreted vesicles; abundant cytosolic enzymes routinely appear in
    exosome proteomes. Non-core; over-annotation from high-throughput MS.
  • IEA cytoplasm (GO:0005737, UniProt SubCell mapping): broad-but-correct parent of
    cytosol. Accept.

protein binding (IPI, GO:0005515) — two annotations

  • PMID:21044950 (Lee et al. 2011, Mol Cell Proteomics): genome-wide split-YFP (BiFC)
    complementation screen for telomere signaling regulators; PGLS (with TERF2IP/
    RAP1, IntAct with UniProtKB:Q9NYB0) is one of >300 hits, "the majority ... have not
    been previously linked to telomere biology." High-throughput, uncharacterized;
    bare protein binding is uninformative. MARK_AS_OVER_ANNOTATED (do not REMOVE per
    policy; it is a real IPI, not clearly wrong).
  • PMID:32296183 (Luck et al. 2020, HuRI): human all-by-all binary interactome
    (Y2H-based); PGLS–BLMH (UniProtKB:Q13867). Systematic, no PGLS-specific functional
    follow-up. Bare protein binding uninformative. MARK_AS_OVER_ANNOTATED.
  • Both interactions are also recorded in the UniProt INTERACTION block (BLMH Q13867;
    TERF2IP Q9NYB0), i.e. IntAct-curated but with no functional interpretation for PGLS.

Disease

No well-established Mendelian disease associated with PGLS (unlike G6PD). MIM 604951
is the gene entry. Reviewed here as the middle step of the oxidative PPP.

Reference reliability

  • PMID:10518023, 11457850, 31586547: HIGH relevance, VERIFIED (directly establish the
    enzyme's identity/activity/pathway role).
  • PMID:21044950, 32296183: interactome screens, LOW relevance to PGLS function; the
    citations are correct (VERIFIED) but only support a bare interaction.
  • PMID:23533145, 19056867: exosome proteomics, LOW relevance; VERIFIED as MS detection.
  • Reactome R-HSA-71296 / R-HSA-71336: HIGH relevance, VERIFIED.

Core functions (author-supplied, strictly validated)

  • MF: GO:0017057 6-phosphogluconolactonase activity (confirmed current label, MF).
  • BP: GO:0009051 pentose-phosphate shunt, oxidative branch (confirmed current label, BP).
  • CC: GO:0005829 cytosol (confirmed current label, CC).

📄 View Raw YAML

 
id: O95336
gene_symbol: PGLS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PGLS is 6-phosphogluconolactonase (EC 3.1.1.31), the second enzyme of
  the oxidative branch of the pentose phosphate pathway. It hydrolyses 6-phospho-D-glucono-1,5-lactone,
  the product of glucose-6-phosphate dehydrogenase (G6PD), to 6-phospho-D-gluconate,
  the substrate of 6-phosphogluconate dehydrogenase (PGD). By accelerating hydrolysis
  of the reactive delta-lactone it both drives flux through the oxidative branch and
  prevents accumulation of the electrophilic lactone (and its dead-end gamma-isomer),
  which can react with cellular nucleophiles. The enzyme is cytosolic, belongs to
  the glucosamine/galactosamine-6-phosphate isomerase family (6-phosphogluconolactonase
  subfamily), and is ubiquitously expressed.
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically inferred cytosolic localization, consistent with the
      curated cytosolic/cytoplasmic location of PGLS and its role as a soluble oxidative-PPP
      enzyme. This represents the core subcellular location and is corroborated by
      HPA IDA (cytosol) and Reactome.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-71296
      supporting_text: Cytosolic 6-phosphogluconolactonase (PGLS) catalyzes the hydrolysis
        of D-glucono-1,5-lactone 6-phosphate to form 6-phospho-D-gluconate
    - reference_id: file:human/PGLS/PGLS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0009051
    label: pentose-phosphate shunt, oxidative branch
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred involvement in the oxidative branch of the
      pentose phosphate pathway. This is the core biological process for PGLS, which
      catalyses step 2 of the oxidative branch, and is well supported by direct biochemical
      characterisation of the human enzyme.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11457850
      supporting_text: 6-Phosphogluconolactonase is the second enzyme of the oxidative
        branch and
- term:
    id: GO:0017057
    label: 6-phosphogluconolactonase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred 6-phosphogluconolactonase activity. This is
      the core molecular function of PGLS and is directly demonstrated for the human
      enzyme (EC 3.1.1.31; RHEA:12556).
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10518023
      supporting_text: shown to be 6-phosphogluconolactonase, the enzyme catalyzing
        the second step of the pentose phosphate pathway
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation from the UniProt Subcellular Location mapping (Cytoplasm).
      This is a correct but broad parent of the more precise cytosol location; keep
      as a non-core, less-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but less specific than GO:0005829 (cytosol), which
      is supported by IBA and HPA IDA and better captures the location of this soluble
      enzyme.
    supported_by:
    - reference_id: file:human/PGLS/PGLS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO electronic annotation. Correct but very general; PGLS acts
      in carbohydrate metabolism, but the specific and informative process term is
      the oxidative pentose-phosphate branch. Keep as a non-core, high-level annotation.
    action: KEEP_AS_NON_CORE
    reason: Broad parent process. The precise process (GO:0009051, pentose-phosphate
      shunt, oxidative branch) is annotated separately and is preferred as core.
- term:
    id: GO:0006098
    label: pentose-phosphate shunt
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation to the overall pentose-phosphate shunt. Correct;
      PGLS participates in the pentose phosphate pathway. This is a valid parent of
      the more specific oxidative-branch term and is also supported experimentally
      (PMID:10518023) and by Reactome.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/PGLS/PGLS-uniprot.txt
      supporting_text: 'PATHWAY: Carbohydrate degradation; pentose phosphate pathway;
        D-'
- term:
    id: GO:0009051
    label: pentose-phosphate shunt, oxidative branch
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA electronic annotation to the oxidative branch of the pentose phosphate
      pathway, consistent with the IBA and experimental evidence. Core biological
      process.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11457850
      supporting_text: 6-Phosphogluconolactonase is the second enzyme of the oxidative
        branch and
- term:
    id: GO:0017057
    label: 6-phosphogluconolactonase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation (ARBA/InterPro/RHEA:12556/EC:3.1.1.31) to the core
      molecular function. Correct and directly supported by experimental characterisation
      of the human enzyme.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/PGLS/PGLS-uniprot.txt
      supporting_text: EC=3.1.1.31 {ECO:0000269|PubMed:10518023}
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  qualifier: enables
  review:
    summary: 'Interaction reported from a genome-wide split-YFP (BiFC) complementation
      screen for regulators of telomere signaling (PGLS scored against a core telomeric
      protein; IntAct with UniProtKB:Q9NYB0/TERF2IP). This is a high-throughput binary-interaction
      dataset in which most hits had no prior functional link to the process, and
      no PGLS-specific functional characterization was performed. The bare term "protein
      binding" is uninformative about molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome hit captured only as the uninformative parent
      term GO:0005515. Retained (a genuine curated IPI), but not a core molecular
      function and not indicative of a specific binding role for PGLS.
    supported_by:
    - reference_id: PMID:21044950
      supporting_text: we identified over 300 proteins that associated with the six
        core telomeric proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: 'Binary interaction from the HuRI human all-by-all reference interactome
      (PGLS-BLMH; IntAct with UniProtKB:Q13867). A systematic proteome-scale Y2H dataset
      with no PGLS-specific functional follow-up; the bare term "protein binding"
      is uninformative.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Systematic interactome hit captured only as the uninformative parent term
      GO:0005515. Retained as a real curated IPI but not a core molecular function.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions
- 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-statement annotation placing PGLS in the pentose
      phosphate pathway. Correct; PGLS catalyses step 2 (conversion of D-glucono-1,5-lactone
      6-phosphate to 6-phospho-D-gluconate) of the pathway.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-71336
      supporting_text: Conversion of D-glucono-1,5-lactone 6-phosphate to 6-phospho-D-gluconate
- term:
    id: GO:0017057
    label: 6-phosphogluconolactonase activity
  evidence_type: EXP
  original_reference_id: PMID:10518023
  qualifier: enables
  review:
    summary: Experimental demonstration that the human protein, expressed in E. coli
      and purified, is 6-phosphogluconolactonase. Direct evidence for the core molecular
      function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10518023
      supporting_text: The protein was expressed in Escherichia coli, purified and
        shown to be 6-phosphogluconolactonase, the enzyme catalyzing the second step
        of the pentose phosphate pathway
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence detected PGLS in the nucleoplasm in addition to
      the cytosol. Small soluble metabolic enzymes are frequently detected in the
      nucleoplasm by immunofluorescence, and no nuclear function of PGLS is described.
      Keep as a non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Immunofluorescence-based localization with no associated nuclear function;
      the core location is the cytosol. Not removed, as it is a valid curated IDA.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence localizes PGLS to the cytosol, consistent with
      the IBA, Reactome, and UniProt cytoplasm annotations. Core subcellular location.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-71296
      supporting_text: Cytosolic 6-phosphogluconolactonase (PGLS) catalyzes the hydrolysis
        of D-glucono-1,5-lactone 6-phosphate to form 6-phospho-D-gluconate
- term:
    id: GO:0009051
    label: pentose-phosphate shunt, oxidative branch
  evidence_type: IMP
  original_reference_id: PMID:31586547
  qualifier: acts_upstream_of_or_within
  review:
    summary: Genetic perturbation (knockdown/knockout) of PGLS in human cancer cells
      reduces oxidative-PPP flux, decreases 6-phosphogluconate, and causes accumulation
      of 6-phosphogluconolactone, confirming that PGLS acts within the oxidative branch
      of the pentose phosphate pathway. The paper's downstream signaling findings
      (gamma-6PGL to Src/PP2A/AMPK) are consequences of altered oxiPPP metabolite
      levels, and the annotation correctly uses the metabolic-branch process term.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:31586547
      supporting_text: The second enzyme in the oxiPPP, 6-phosphogluconolactonase
        (PGLS), converts 6PGL to
    - reference_id: PMID:31586547
      supporting_text: stable knockdown of PGLS in Group I H1299 and K562 cells as
        well
- term:
    id: GO:0017057
    label: 6-phosphogluconolactonase activity
  evidence_type: IDA
  original_reference_id: PMID:11457850
  qualifier: enables
  review:
    summary: NMR-based kinetic characterization directly demonstrating 6-phosphogluconolactonase
      activity of the human enzyme, acting on the delta form of 6-phosphogluconolactone.
      Direct evidence for the core molecular function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11457850
      supporting_text: 6-phosphogluconolactonase activity accelerates hydrolysis of
        the delta form
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: High-throughput mass-spectrometry detection of PGLS in exosomes from
      expressed prostatic secretions in urine (~900 proteins detected). Abundant cytosolic
      enzymes are routinely detected in exosome proteomes; this does not indicate
      a functional extracellular localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bulk proteomic detection in secreted vesicles; not a functional or core
      localization for a cytosolic metabolic enzyme. Retained as a curated HDA observation.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: In pooled EPS-urine exosome samples, ~900 proteins were detected
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput mass-spectrometry detection of PGLS in human urinary
      exosomes. As above, abundant cytosolic enzymes commonly appear in exosome proteomes;
      not a functional localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bulk proteomic detection in secreted vesicles; not a core localization
      for this cytosolic enzyme.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: we used LC-MS/MS to profile the proteome of human urinary exosomes
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71296
  qualifier: located_in
  review:
    summary: Reactome traceable-author-statement localizing PGLS to the cytosol, where
      it catalyses the hydrolysis of D-glucono-1,5-lactone 6-phosphate. Core subcellular
      location.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-71296
      supporting_text: Cytosolic 6-phosphogluconolactonase (PGLS) catalyzes the hydrolysis
        of D-glucono-1,5-lactone 6-phosphate to form 6-phospho-D-gluconate
- term:
    id: GO:0006098
    label: pentose-phosphate shunt
  evidence_type: IDA
  original_reference_id: PMID:10518023
  qualifier: involved_in
  review:
    summary: Direct evidence placing PGLS in the pentose phosphate pathway as the
      enzyme catalysing its second step. Correct; a valid parent of the oxidative-branch
      term.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10518023
      supporting_text: shown to be 6-phosphogluconolactonase, the enzyme catalyzing
        the second step of the pentose phosphate pathway
- term:
    id: GO:0017057
    label: 6-phosphogluconolactonase activity
  evidence_type: IDA
  original_reference_id: PMID:10518023
  qualifier: enables
  review:
    summary: Direct biochemical demonstration that purified human PGLS has 6-phosphogluconolactonase
      activity. Core molecular function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10518023
      supporting_text: shown to be 6-phosphogluconolactonase, the enzyme catalyzing
        the second step of the pentose phosphate pathway
core_functions:
- description: Hydrolysis of 6-phospho-D-glucono-1,5-lactone to 6-phospho-D-gluconate,
    the second reaction of the oxidative branch of the pentose phosphate pathway,
    acting downstream of G6PD and upstream of PGD/6PGD.
  molecular_function:
    id: GO:0017057
    label: 6-phosphogluconolactonase activity
  directly_involved_in:
  - id: GO:0009051
    label: pentose-phosphate shunt, oxidative branch
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:10518023
    supporting_text: shown to be 6-phosphogluconolactonase, the enzyme catalyzing
      the second step of the pentose phosphate pathway
  - reference_id: PMID:11457850
    supporting_text: 6-Phosphogluconolactonase is the second enzyme of the oxidative
      branch and
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10518023
  title: Identification of the cDNA encoding human 6-phosphogluconolactonase, the
    enzyme catalyzing the second step of the pentose phosphate pathway(1).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary identification and biochemical characterization of human
      PGLS; establishes EC 3.1.1.31 and the second-step-of-PPP role. Source of the
      EXP/IDA MF and pentose-phosphate-shunt BP annotations. Cached record is abstract-only.
- id: PMID:11457850
  title: NMR spectroscopic analysis of the first two steps of the pentose-phosphate
    pathway elucidates the role of 6-phosphogluconolactonase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: NMR characterization showing PGLS acts on the delta form of 6-phosphogluconolactone,
      accelerating its hydrolysis and preventing accumulation of the toxic/dead-end
      forms. Directly supports the MF and oxidative-branch role.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput MS detection of PGLS in urinary exosomes; supports
      only a bulk-proteomics observation, not a functional localization.
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators
    for telomere signaling in human cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BiFC interactome screen; PGLS is one of >300 telomere-associated
      hits with no prior functional link. Supports only a bare protein-binding IPI.
- 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: High-throughput MS detection of PGLS in prostatic-secretion/urine
      exosomes; supports only a bulk-proteomics observation.
- id: PMID:31586547
  title: γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pentose Phosphate
    Pathway, Contributes to AMPK Activation through Inhibition of PP2A.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text available. Confirms PGLS as the second oxiPPP enzyme;
      PGLS knockdown/knockout reduces oxiPPP flux and alters 6PGL/6PG levels. Basis
      for the IMP oxidative-branch annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI all-by-all binary interactome; PGLS-BLMH interaction. Supports
      only a bare protein-binding IPI, no PGLS-specific function.
- id: Reactome:R-HSA-71296
  title: PGLS hydrolyzes D-glucono-1,5-lactone 6-phosphate
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction describing the cytosolic PGLS-catalysed hydrolysis;
      supports the MF and cytosol location.
- id: Reactome:R-HSA-71336
  title: Pentose phosphate pathway
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome pathway; step 2 is the PGLS-catalysed conversion of D-glucono-1,5-lactone
      6-phosphate to 6-phospho-D-gluconate.
- id: file:human/PGLS/PGLS-uniprot.txt
  title: UniProtKB entry O95336 (6PGL_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: UniProt record for human PGLS; FUNCTION, CATALYTIC ACTIVITY (EC
      3.1.1.31, RHEA:12556), PATHWAY (oxidative-stage step 2/3), and cytoplasm localization.