id: Q9Y673
gene_symbol: ALG5
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ALG5 is the endoplasmic reticulum dolichyl-phosphate beta-glucosyltransferase
  (Dol-P-Glc synthase; EC 2.4.1.117), a single-pass type II ER membrane protein of the
  glycosyltransferase family 2 (CAZy GT2). Acting on the cytosolic face of the ER
  membrane, it transfers glucose from UDP-alpha-D-glucose onto dolichyl phosphate to
  form dolichyl beta-D-glucosyl phosphate (Dol-P-Glc). Dol-P-Glc is the lipid-linked
  glucose donor subsequently used by ALG6, ALG8 and ALG10 to add the three terminal
  glucose residues onto the Man(9)GlcNAc(2)-PP-dolichol structure, completing the
  dolichol-linked oligosaccharide (Glc(3)Man(9)GlcNAc(2)-PP-Dol) that is transferred to
  nascent proteins during asparagine (N)-linked glycosylation. Loss of ALG5 function
  causes a congenital disorder of glycosylation (ALG5-CDG); a specific truncating ALG5
  variant and missense variants also cause an autosomal-dominant polycystic kidney/liver
  disease (PKD7) by impairing N-glycosylation and maturation of polycystin-1 (PKD1).
alternative_products:
- name: '1'
  id: Q9Y673-1
- name: '2'
  id: Q9Y673-2
  sequence_note: VSP_041019
existing_annotations:
- term:
    id: GO:0004581
    label: dolichyl-phosphate beta-glucosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (PAN-GO) inference of the core catalytic molecular function.
      ALG5 is the dolichyl-phosphate beta-glucosyltransferase (Dol-P-Glc synthase,
      EC 2.4.1.117), the defining activity of this conserved GT2-family enzyme.
    action: ACCEPT
    reason: This is the well-established core molecular function of ALG5, supported
      by direct enzymatic/complementation characterization of the human protein and
      conserved across orthologs used in the IBA inference. It represents the core
      function of the gene.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "EC=2.4.1.117"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference that ALG5 acts in the ER membrane, consistent with
      its role in dolichol-linked oligosaccharide assembly on the ER membrane.
    action: ACCEPT
    reason: ALG5 is a single-pass ER membrane protein and its catalysis occurs at the
      ER membrane; this is the correct core cellular location.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference that ALG5 participates in dolichol-linked
      oligosaccharide (LLO) biosynthesis. ALG5 supplies Dol-P-Glc, the glucose donor
      used by ALG6/ALG8/ALG10 for the terminal glucosylation steps of the LLO.
    action: ACCEPT
    reason: This is the core biological process in which ALG5 acts and is well supported
      by the pathway context; represents a core function of the gene.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "glucose donor substrate used sequentially by ALG6, ALG8 and ALG10"
- term:
    id: GO:0004581
    label: dolichyl-phosphate beta-glucosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (RHEA/EC-based) assignment of the dolichyl-phosphate
      beta-glucosyltransferase activity from EC 2.4.1.117 / RHEA:15401. This matches
      the experimentally characterized catalytic activity of human ALG5.
    action: ACCEPT
    reason: The EC/RHEA-to-GO mapping is correct and specific; it captures the core
      catalytic activity. Duplicates the IBA/TAS MF annotations, which is acceptable.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "EC=2.4.1.117"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated assignment of ER membrane localization from the UniProt
      subcellular-location keyword mapping (SL-0097).
    action: ACCEPT
    reason: Consistent with the experimentally supported ER membrane localization of
      ALG5; correct and appropriately specific.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32353859
  qualifier: enables
  review:
    summary: IntAct IPI recording a physical interaction between ALG5 and the SARS-CoV-2
      accessory protein ORF3a (P0DTC3), detected in a proteome-wide virus-host
      interactome screen. This is a non-informative protein binding term that does
      not describe ALG5's endogenous molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput viral interactome captures a
      xenobiotic (virus-host) interaction, not an informative molecular function of
      ALG5. Retained but flagged as over-annotation per curation policy (not removed).
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "Q9Y673; P0DTC3: 3a; Xeno; NbExp=4"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32838362
  qualifier: enables
  review:
    summary: IntAct IPI recording the ALG5-SARS-CoV-2 ORF3a (P0DTC3) interaction from a
      virus-host interactome/proteomic survey. Non-informative protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput virus-host interaction; protein binding is uninformative
      about ALG5's biological function. Retained but flagged as over-annotation.
    supported_by:
    - reference_id: PMID:32838362
      supporting_text: "ORF3a"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33060197
  qualifier: enables
  review:
    summary: IntAct IPI recording the ALG5-SARS-CoV-2 ORF3a (P0DTC3) interaction from a
      comparative host-coronavirus interactome study. Non-informative protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput virus-host interaction; protein binding is uninformative
      about ALG5's endogenous molecular function. Retained but flagged as over-annotation.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "Q9Y673; P0DTC3: 3a; Xeno; NbExp=4"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36217030
  qualifier: enables
  review:
    summary: IntAct IPI recording the ALG5-SARS-CoV-2 ORF3a (P0DTC3) interaction from a
      comprehensive SARS-CoV-2-human interactome. Non-informative protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput virus-host interaction; protein binding is uninformative
      about ALG5's function. Retained but flagged as over-annotation.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "Q9Y673; P0DTC3: 3a; Xeno; NbExp=4"
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-480985
  qualifier: involved_in
  review:
    summary: Reactome-asserted involvement in protein N-linked glycosylation. ALG5 makes
      Dol-P-Glc, the glucose donor for the terminal LLO glucosylation steps that produce
      the fully assembled glycan precursor transferred to nascent proteins.
    action: ACCEPT
    reason: Correct and central to ALG5 biology; the LLO it helps complete is the donor
      substrate for N-glycosylation. Core biological process.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "the glycan precursors employed in protein asparagine (N)-glycosylation"
- term:
    id: GO:0004581
    label: dolichyl-phosphate beta-glucosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446214
  qualifier: enables
  review:
    summary: Reactome-asserted dolichyl-phosphate beta-glucosyltransferase activity.
      Reactome describes ALG5 catalyzing UDP-glucose + dolichyl phosphate to form
      Dol-P-Glc on the cytosolic face of the ER membrane.
    action: ACCEPT
    reason: Correctly captures the core catalytic function with an authoritative
      pathway-database traceable assertion.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "EC=2.4.1.117"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:10359825
  qualifier: located_in
  review:
    summary: Experimental localization of human ALG5 to the ER membrane (Imbach et al.
      1999), the study that cloned and functionally characterized the human ALG5 ortholog.
    action: ACCEPT
    reason: Experimental support for the correct core localization; consistent with the
      protein's single-pass ER membrane topology.
    supported_by:
    - reference_id: PMID:10359825
      supporting_text: "have cloned and analyzed the human orthologs to the ALG5 dolichyl phosphate"
- term:
    id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  evidence_type: IGI
  original_reference_id: PMID:10359825
  qualifier: is_active_in
  review:
    summary: ALG5 is active on the cytoplasmic (cytosolic) face of the ER membrane, where
      it synthesizes Dol-P-Glc from cytosolic UDP-glucose; supported by yeast genetic
      interaction / complementation data and the protein's topology (large cytoplasmic
      catalytic domain).
    action: ACCEPT
    reason: Correctly specifies the membrane face on which the catalytic domain acts,
      consistent with UniProt topology and Reactome. More informative than bare ER membrane.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "most probably active on the cytoplasmic side of the endoplasmic"
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: IMP
  original_reference_id: PMID:10359825
  qualifier: involved_in
  review:
    summary: ALG5's role in N-linked glycosylation demonstrated via functional
      characterization/complementation of the human ortholog (Imbach et al. 1999).
    action: ACCEPT
    reason: Experimental (mutant-phenotype/complementation) support for a core biological
      process of ALG5. Full text not in cache; deferring to curator per policy.
    supported_by:
    - reference_id: PMID:10359825
      supporting_text: "Expression of the human ALG5 and ALG6 cDNA could partially"
- term:
    id: GO:0004581
    label: dolichyl-phosphate beta-glucosyltransferase activity
  evidence_type: IGI
  original_reference_id: PMID:10359825
  qualifier: enables
  review:
    summary: Dolichyl-phosphate beta-glucosyltransferase activity of human ALG5 inferred
      from genetic interaction / complementation of the S. cerevisiae alg5 deficiency by
      the human ALG5 cDNA (Imbach et al. 1999).
    action: ACCEPT
    reason: Experimental support (functional complementation) for the core catalytic
      function. Core molecular function of the gene.
    supported_by:
    - reference_id: PMID:10359825
      supporting_text: "Expression of the human ALG5 and ALG6 cDNA could partially"
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:10359825
  qualifier: involved_in
  review:
    summary: ALG5's role in dolichol-linked oligosaccharide (LLO) biosynthesis supported
      by functional characterization of the human ortholog; ALG5 provides the Dol-P-Glc
      glucose donor for the terminal LLO glucosylation steps.
    action: ACCEPT
    reason: Experimental support for the core biological process of ALG5. Core function
      of the gene.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "glucose donor substrate used sequentially by ALG6, ALG8 and ALG10"
- term:
    id: GO:0098556
    label: cytoplasmic side of rough endoplasmic reticulum membrane
  evidence_type: IGI
  original_reference_id: PMID:10359825
  qualifier: is_active_in
  review:
    summary: A more granular restatement of the cytoplasmic-face ER-membrane location of
      active ALG5 (rough ER membrane, cytoplasmic side).
    action: ACCEPT
    reason: Consistent with the protein's topology and site of catalysis; slightly more
      specific granularity of GO:0098554. Retained.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "most probably active on the cytoplasmic side of the endoplasmic"
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput MS detection of ALG5 in a membrane-proteome preparation
      (NK-like cell line). Localizes the protein to bulk membrane without specifying the
      ER.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic membrane term is far less informative than the well-supported
      endoplasmic reticulum membrane term; this HDA localization is redundant with, and
      subsumed by, the specific ER membrane annotations. Flagged as over-annotation
      rather than removed (it is not incorrect, merely uninformative).
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: "identified 1843 proteins with high confidence scores"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446214
  qualifier: located_in
  review:
    summary: Reactome-asserted ER membrane localization of ALG5, consistent with the
      experimental and phylogenetic ER-membrane annotations.
    action: ACCEPT
    reason: Correct core localization from an authoritative pathway database; duplicates
      other ER membrane annotations, which is acceptable.
    supported_by:
    - reference_id: file:human/ALG5/ALG5-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
core_functions:
- description: Dolichyl-phosphate beta-glucosyltransferase (Dol-P-Glc synthase) that
    transfers glucose from UDP-alpha-D-glucose onto dolichyl phosphate to form dolichyl
    beta-D-glucosyl phosphate (Dol-P-Glc) on the cytosolic face of the ER membrane.
  molecular_function:
    id: GO:0004581
    label: dolichyl-phosphate beta-glucosyltransferase activity
  directly_involved_in:
  - id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/ALG5/ALG5-uniprot.txt
    supporting_text: "glucose donor substrate used sequentially by ALG6, ALG8 and ALG10"
- description: Supplies Dol-P-Glc, the lipid-linked glucose donor used by ALG6, ALG8 and
    ALG10 for the three terminal glucosylation steps of the dolichol-linked oligosaccharide,
    thereby contributing to protein N-linked glycosylation.
  molecular_function:
    id: GO:0004581
    label: dolichyl-phosphate beta-glucosyltransferase activity
  directly_involved_in:
  - id: GO:0006487
    label: protein N-linked glycosylation
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/ALG5/ALG5-uniprot.txt
    supporting_text: "the glycan precursors employed in protein asparagine (N)-glycosylation"
references:
- 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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/ALG5/ALG5-uniprot.txt
  title: UniProtKB entry Q9Y673 (ALG5_HUMAN)
  findings: []
- id: PMID:10359825
  title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene
    causes carbohydrate-deficient glycoprotein syndrome type-Ic.
  findings:
  - statement: The human ALG5 ortholog was cloned and functionally characterized; its
      cDNA partially complements the S. cerevisiae alg5 deficiency, and ALG5 encodes the
      dolichyl phosphate glucosyltransferase acting in LLO biosynthesis. ALG5 itself was
      not mutated in the CDGS-Ic patients (the causal gene was ALG6).
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only in cache (full_text_available false). Titled/framed around
      ALG6 causing CDGS-Ic, but the study also cloned and functionally characterized human
      ALG5 (Dol-P-Glc synthase; yeast alg5 complementation), which underpins the ALG5
      experimental annotations. Deferring to curator on the experimental annotations whose
      full text is not cached.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings:
  - statement: Large-scale MS characterization of the NK (YTS) cell membrane proteome
      identified ALG5 among 1843 proteins; supports bulk membrane localization only.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput membrane proteome; ALG5 detected but only supports the
      generic membrane term, less informative than ER membrane.
- id: PMID:32353859
  title: A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
  findings:
  - statement: Proteome-wide SARS-CoV-2-human interactome identified an ALG5-ORF3a
      (P0DTC3) physical interaction; source of an IntAct protein binding IPI.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Abstract-only in cache. Virus-host interactome; interaction is with the
      xenobiotic viral ORF3a, not informative of ALG5 endogenous function.
- id: PMID:32838362
  title: Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors
    Influencing SARS-CoV-2 Pathogenesis.
  findings:
  - statement: Virus-host interactome/proteomic survey reporting ALG5 interaction with
      SARS-CoV-2 ORF3a; source of an IntAct protein binding IPI.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Full text available in cache and mentions ORF3a; virus-host interaction,
      uninformative for ALG5 molecular function.
- id: PMID:33060197
  title: Comparative host-coronavirus protein interaction networks reveal pan-viral
    disease mechanisms.
  findings:
  - statement: Comparative host-coronavirus interactome reporting the ALG5-ORF3a
      interaction; source of an IntAct protein binding IPI.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Abstract-only in cache. Virus-host interactome; uninformative for ALG5
      endogenous function.
- id: PMID:36217030
  title: A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19
    pathobiology and potential host therapeutic targets.
  findings:
  - statement: Comprehensive SARS-CoV-2-human interactome reporting the ALG5-ORF3a
      interaction; source of an IntAct protein binding IPI.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Abstract-only in cache. Virus-host interactome; uninformative for ALG5
      endogenous function.
- id: Reactome:R-HSA-446214
  title: Synthesis of dolichyl-phosphate-glucose
  findings:
  - statement: Reactome reaction in which ALG5 (dolichyl-phosphate beta-glucosyltransferase)
      catalyzes UDP-glucose + dolichyl phosphate to form Dol-P-Glc on the cytosolic face
      of the ER membrane.
- id: Reactome:R-HSA-480985
  title: Synthesis of dolichyl-phosphate-glucose
  findings:
  - statement: Reactome pathway describing synthesis of Dol-P-Glc and its role as glucose
      donor in three steps of N-glycan precursor biosynthesis.
suggested_questions:
- question: Is the reduced N-glycosylation phenotype in ALG5-CDG and PKD7 driven
    predominantly by loss of the terminal glucosylation steps (ALG6/ALG8/ALG10) that
    depend on Dol-P-Glc, or does Dol-P-Glc have additional roles?
suggested_experiments:
- description: Reconstitute purified recombinant human ALG5 with dolichyl phosphate and
    UDP-glucose to measure Dol-P-Glc synthase kinetics, and test the PKD7 missense
    variants (R208H, R212H) for loss of catalytic activity.
  hypothesis: PKD7-associated ALG5 missense variants reduce or abolish Dol-P-Glc synthase
    activity, explaining the downstream N-glycosylation defect.