id: Q9Y672
gene_symbol: ALG6
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ALG6 (Dol-P-Glc:Man(9)GlcNAc(2)-PP-dolichol alpha-1,3-glucosyltransferase;
  EC 2.4.1.267) is a multi-pass endoplasmic reticulum membrane enzyme that catalyzes the first
  of the three glucosylation steps in the assembly of the dolichol-linked oligosaccharide (LLO),
  the N-glycan precursor. Acting on the lumenal face of the ER membrane, it transfers a glucose
  residue from the lipid donor dolichyl-phosphate-glucose (Dol-P-Glc, not UDP-glucose) onto
  Man9GlcNAc2-PP-dolichol to produce Glc1Man9GlcNAc2-PP-dolichol, which is then extended by ALG8
  and ALG10 to yield the mature Glc3Man9GlcNAc2-PP-dolichol. Glucosylation of the LLO is required
  for efficient transfer of the glycan onto nascent proteins by the oligosaccharyltransferase, so
  ALG6 activity supports protein N-linked glycosylation. It belongs to the ALG6/ALG8 glucosyltransferase
  family (CAZy GT57). Loss-of-function variants cause ALG6-congenital disorder of glycosylation
  (ALG6-CDG / CDG type Ic), one of the most common CDG-I subtypes, characterized by accumulation of
  Man9GlcNAc2-PP-dolichol and hypoglycosylation of serum glycoproteins, with a multisystem clinical
  presentation.
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) assertion that ALG6 is active in the ER membrane. This matches the
      experimentally supported subcellular location and the multi-pass ER membrane topology of the
      protein.
    action: ACCEPT
    reason: >-
      ALG6 is a multi-pass ER membrane protein whose glucosyltransferase active site faces the ER
      lumen; the ER membrane is its correct site of action.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "Multi-pass membrane protein"
- 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 (IBA) assertion that ALG6 participates in dolichol-linked oligosaccharide (LLO)
      biosynthesis. This is the core biological process of the enzyme: it adds the first glucose to the
      Man9GlcNAc2-PP-Dol intermediate during LLO assembly.
    action: ACCEPT
    reason: >-
      Directly supported: ALG6 catalyzes a defined step of LLO assembly, producing
      Glc1Man9GlcNAc2-PP-Dol from Man9GlcNAc2-PP-Dol. Loss of ALG6 causes accumulation of the
      Man9GlcNAc2-PP-Dol precursor. This is a core function.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: >-
        adds the first glucose residue from dolichyl phosphate glucose (Dol-P-
    - reference_id: PMID:25792706
      supporting_text: >-
        A defect in the assembly of the oligosaccharide donor
- term:
    id: GO:0042281
    label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assertion of the specific molecular function of ALG6: dolichyl pyrophosphate
      Man9GlcNAc2 alpha-1,3-glucosyltransferase activity (EC 2.4.1.267). This is the exact enzymatic
      activity supported by experimental and biochemical evidence and is the core molecular function.
    action: ACCEPT
    reason: >-
      This is the precise, correct molecular-function term for ALG6, consistent across IBA, IMP and
      IEA/EC evidence and the UniProt catalytic-activity record (RHEA:30635, EC 2.4.1.267).
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: >-
        adds the first glucose residue from dolichyl phosphate glucose (Dol-P-
    - reference_id: PMID:10924277
      supporting_text: >-
        encodes an alpha-1,3 glucosyltransferase
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic (IEA) subcellular-location mapping from UniProt Swiss-Prot keyword/SubCell vocabulary
      placing ALG6 in the ER membrane. Consistent with the experimentally curated location.
    action: ACCEPT
    reason: >-
      Correct localization, redundant with the IBA and TAS ER-membrane annotations and with the
      curated UniProt subcellular location.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0016758
    label: hexosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Electronic (IEA) InterPro2GO mapping (IPR004856, the ALG6/ALG8 glucosyltransferase domain) to the
      broad grouping term hexosyltransferase activity. This is correct but far less specific than the
      known activity.
    action: MODIFY
    reason: >-
      Hexosyltransferase activity is a high-level parent that is chemically correct but uninformative
      given the well-established, specific activity of ALG6. Replace with the specific
      alpha-1,3-glucosyltransferase term.
    proposed_replacement_terms:
    - id: GO:0042281
      label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "Belongs to the ALG6/ALG8 glucosyltransferase family"
- term:
    id: GO:0042281
    label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (IEA) annotation of the specific alpha-1,3-glucosyltransferase activity derived from the
      EC/RHEA mapping (RHEA:30635, EC 2.4.1.267). Fully consistent with the curated catalytic activity.
    action: ACCEPT
    reason: >-
      The EC 2.4.1.267 / RHEA:30635 mapping matches the experimentally curated reaction; this is the
      correct, specific molecular function.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "EC=2.4.1.267"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IPI annotation to the generic term protein binding, from a proteome-scale AP-MS interactome study
      (BioPlex). The interaction partner (UniProtKB:Q9BVK2 = ALG8) is biologically meaningful: ALG8 is
      the next enzyme in LLO glucosylation and acts on the ALG6 product. However, the term itself is
      uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding conveys no specific molecular function and is discouraged per curation
      guidelines. The underlying ALG6-ALG8 interaction is real and pathway-relevant (ALG8 extends the
      Glc1Man9GlcNAc2-PP-Dol product made by ALG6), but this should not be treated as a core function
      annotation. Retain as over-annotated rather than removed, since it is a valid experimental
      interaction.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "Q9Y672; Q9BVK2: ALG8"
    - reference_id: PMID:33961781
      supporting_text: >-
        affinity-purification mass spectrometry
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446193
  qualifier: involved_in
  review:
    summary: >-
      Traceable-author (Reactome) annotation to LLO biosynthesis, from the pathway "Biosynthesis of the
      N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein".
      Correct core biological process.
    action: ACCEPT
    reason: >-
      Redundant with the IBA/IMP LLO-biosynthesis annotations; correctly captures ALG6's role in LLO
      assembly.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: >-
        adds the first glucose residue from dolichyl phosphate glucose (Dol-P-
- term:
    id: GO:0098553
    label: lumenal side of endoplasmic reticulum membrane
  evidence_type: IC
  original_reference_id: PMID:10359825
  qualifier: is_active_in
  review:
    summary: >-
      Curator-inferred (IC) annotation that ALG6 is active on the lumenal side of the ER membrane. This
      reflects the enzyme mechanism: it uses the lumenal LLO intermediate Man9GlcNAc2-PP-Dol as acceptor,
      and the UniProt membrane topology places lumenal loops between transmembrane helices.
    action: ACCEPT
    reason: >-
      Correct and more precise than the generic ER membrane term. LLO glucosylation occurs in the ER
      lumen (the assembly begins on the cytosolic face and finishes in the lumen), consistent with a
      lumenal-side active site.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: >-
        adds the first glucose residue from dolichyl phosphate glucose (Dol-P-
    - reference_id: PMID:10359825
      supporting_text: >-
        in the endoplasmic reticulum
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: IMP
  original_reference_id: PMID:10359825
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to protein N-linked glycosylation based on mutant phenotype: patient/mutant ALG6
      fails to restore glycosylation in an alg6-deficient yeast strain, and ALG6 deficiency underlies
      CDG type Ic (defective N-glycosylation). ALG6 acts upstream, providing the glucosylated LLO used by
      the oligosaccharyltransferase.
    action: ACCEPT
    reason: >-
      ALG6 is genuinely required for normal protein N-linked glycosylation; loss-of-function produces
      hypoglycosylation. This is a bona fide, if upstream, involvement in N-glycosylation.
    supported_by:
    - reference_id: PMID:10359825
      supporting_text: >-
        the mutant ALG6 cDNA of CDGS patients failed to revert the hypoglycosylation
    - reference_id: PMID:10924277
      supporting_text: >-
        addition of the first glucose residue to the lipid-linked oligosaccharide
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: IMP
  original_reference_id: PMID:25792706
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to protein N-linked glycosylation from analysis of ALG6-deficient cell lines, which
      assemble Man9GlcNAc2-PP-Dol as the largest donor and show hypoglycosylation of oligosaccharyl-
      transferase substrate sites.
    action: ACCEPT
    reason: >-
      Directly demonstrates that ALG6 loss impairs protein N-linked glycosylation; supports involvement
      in the N-glycosylation process.
    supported_by:
    - reference_id: PMID:25792706
      supporting_text: >-
        A defect in the assembly of the oligosaccharide donor
    - reference_id: PMID:25792706
      supporting_text: >-
        assemble Dol-PP-GlcNAc(2)Man(9)
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:10359825
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to LLO biosynthesis: CDG-Ic patients accumulate dolichyl pyrophosphate-linked
      Man9GlcNAc2, and mutant ALG6 fails to complement the yeast alg6 glycosylation defect, demonstrating
      ALG6's role in LLO assembly.
    action: ACCEPT
    reason: >-
      Core process; strongly supported by the accumulation of the Man9GlcNAc2-PP-Dol intermediate on
      ALG6 loss and by yeast complementation.
    supported_by:
    - reference_id: PMID:10359825
      supporting_text: >-
        impaired biosynthesis of dolichyl pyrophosphate-linked
    - reference_id: PMID:10359825
      supporting_text: >-
        the mutant ALG6 cDNA of CDGS patients failed to revert the hypoglycosylation
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:25792706
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to LLO biosynthesis from ALG6-deficient cells, which stall LLO assembly at
      Man9GlcNAc2-PP-Dol (the largest donor they can make), confirming ALG6's role in extending the LLO.
    action: ACCEPT
    reason: >-
      Consistent with ALG6 being the enzyme that adds the first glucose during LLO biosynthesis; loss
      halts assembly at Man9GlcNAc2-PP-Dol.
    supported_by:
    - reference_id: PMID:25792706
      supporting_text: >-
        assemble Dol-PP-GlcNAc(2)Man(9)
- term:
    id: GO:0042281
    label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:25792706
  qualifier: enables
  review:
    summary: >-
      IMP annotation of the specific alpha-1,3-glucosyltransferase activity, inferred from the phenotype
      of ALG6-deficient cells that cannot add glucose beyond Man9GlcNAc2-PP-Dol. This is the core
      molecular function.
    action: ACCEPT
    reason: >-
      The mutant phenotype (accumulation of Man9GlcNAc2-PP-Dol; hypoglycosylation) directly attributes
      the alpha-1,3-glucosyltransferase activity to ALG6.
    supported_by:
    - reference_id: PMID:25792706
      supporting_text: >-
        assemble Dol-PP-GlcNAc(2)Man(9)
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "EC=2.4.1.267"
- term:
    id: GO:0042281
    label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
  evidence_type: IGI
  original_reference_id: PMID:10359825
  qualifier: enables
  review:
    summary: >-
      IGI annotation (genetic interaction with the ALG8 glucosyltransferase, UniProtKB:Q12001) supporting
      the alpha-1,3-glucosyltransferase activity of ALG6. Consistent with yeast complementation defining
      ALG6 as the first LLO glucosyltransferase acting upstream of ALG8.
    action: ACCEPT
    reason: >-
      The genetic relationship with the downstream glucosyltransferase (ALG8) plus yeast complementation
      supports ALG6 as the alpha-1,3-glucosyltransferase adding the first glucose; correct specific MF.
    supported_by:
    - reference_id: PMID:10359825
      supporting_text: >-
        ALG6 dolichyl pyrophosphate Man9GlcNAc2
- term:
    id: GO:0004583
    label: dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446202
  qualifier: enables
  review:
    summary: >-
      Reactome TAS annotation of a Dol-P-Glc-dependent glucosyltransferase activity for the reaction
      "Addition of the first glucose to the N-glycan precursor by ALG6". The chemistry (Dol-P-Glc donor)
      is correct, but this parent term is less precise than the specific ALG6 activity term.
    action: MODIFY
    reason: >-
      GO:0004583 correctly captures the Dol-P-Glc donor chemistry but is a broader grouping; the specific
      substrate-defined activity GO:0042281 (dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-
      glucosyltransferase activity, EC 2.4.1.267) is the accurate molecular function for ALG6.
    proposed_replacement_terms:
    - id: GO:0042281
      label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: >-
        adds the first glucose residue from dolichyl phosphate glucose (Dol-P-
- term:
    id: GO:0004583
    label: dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4724291
  qualifier: enables
  review:
    summary: >-
      Reactome TAS annotation of Dol-P-Glc-dependent glucosyltransferase activity from the CDG variant
      pathway ("Defective ALG6 does not add glucose to the N-glycan precursor"). Same as the R-HSA-446202
      annotation: correct chemistry, but a broader term than the specific ALG6 activity.
    action: MODIFY
    reason: >-
      As above, replace the broader Dol-P-Glc glucosyltransferase grouping with the specific
      GO:0042281 term that matches ALG6's defined substrate and product.
    proposed_replacement_terms:
    - id: GO:0042281
      label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: >-
        adds the first glucose residue from dolichyl phosphate glucose (Dol-P-
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4724291
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation placing ALG6 in the ER membrane. Consistent with the curated subcellular
      location and multi-pass ER membrane topology.
    action: ACCEPT
    reason: >-
      Correct localization, redundant with other ER-membrane annotations.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HDA) proteomics annotation to the generic term membrane, from a mass-spectrometry
      membrane-proteome survey of NK-like cells. This detects ALG6 in a membrane fraction but is not
      specific to the ER.
    action: MODIFY
    reason: >-
      The generic membrane term is uninformative given the well-established ER membrane localization.
      Replace with the specific ER membrane term. The proteomics detection is consistent with (though
      not diagnostic of) ER membrane residence.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        1843 proteins with high confidence scores
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446202
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation placing ALG6 in the ER membrane (from the "Addition of the first glucose"
      pathway). Correct localization.
    action: ACCEPT
    reason: >-
      Correct and redundant with the other ER-membrane annotations; consistent with the curated location.
    supported_by:
    - reference_id: file:human/ALG6/ALG6-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: IDA
  original_reference_id: PMID:10924277
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      IDA annotation (acts_upstream_of_or_within protein N-linked glycosylation) from biochemical/
      molecular analysis of a CDG-Ic patient with multiple hALG6 mutations. ALG6 adds the first glucose
      to the LLO precursor, an event required upstream of protein N-glycosylation.
    action: ACCEPT
    reason: >-
      Correctly captures ALG6's upstream role in N-linked glycosylation. The acts_upstream_of_or_within
      qualifier is appropriate because ALG6 provides the glucosylated LLO used by the
      oligosaccharyltransferase rather than performing the protein-transfer step itself.
    supported_by:
    - reference_id: PMID:10924277
      supporting_text: >-
        addition of the first glucose residue to the lipid-linked oligosaccharide
    - reference_id: PMID:10924277
      supporting_text: >-
        This enzyme is required for the
- term:
    id: GO:0046527
    label: glucosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:10359825
  qualifier: enables
  review:
    summary: >-
      IDA annotation to the grouping term glucosyltransferase activity, from the cloning/complementation
      study that identified human ALG6 as the alpha-1,3-glucosyltransferase adding the first glucose to
      the LLO. Correct chemistry but less specific than the defined ALG6 activity.
    action: MODIFY
    reason: >-
      Glucosyltransferase activity is a correct parent but under-specifies ALG6's function; the specific
      GO:0042281 term (matching the EC 2.4.1.267 reaction) is the accurate molecular function.
    proposed_replacement_terms:
    - id: GO:0042281
      label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
    supported_by:
    - reference_id: PMID:10359825
      supporting_text: >-
        ALG6 dolichyl pyrophosphate Man9GlcNAc2
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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  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: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Foundational paper cloning human ALG6 as the ortholog of yeast ALG6 dolichyl pyrophosphate
      Man9GlcNAc2 alpha-1,3-glucosyltransferase; defines CDG type Ic. Abstract-only in cache but
      directly supports the MF, LLO-biosynthesis, N-glycosylation, and ER localization annotations.
- id: PMID:10924277
  title: Analysis of multiple mutations in the hALG6 gene in a patient with congenital
    disorder of glycosylation Ic.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      States that hALG6 encodes an alpha-1,3 glucosyltransferase required for adding the first glucose
      to the LLO precursor for N-glycosylation; source of the IDA N-glycosylation annotation.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput NK-cell membrane proteome MS study; detects ALG6 in a membrane fraction (generic
      membrane annotation) but is not specific for the ER and does not address function.
- id: PMID:25792706
  title: Reduced expression of the oligosaccharyltransferase exacerbates protein hypoglycosylation
    in cells lacking the fully assembled oligosaccharide donor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Uses ALG6-deficient cell lines (assembling Man9GlcNAc2-PP-Dol as largest donor) to demonstrate
      hypoglycosylation; supports the MF, LLO-biosynthesis, and N-glycosylation annotations.
- 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: >-
      Proteome-scale AP-MS interactome (BioPlex 3.0); source of the ALG6-ALG8 protein-binding IPI. The
      ALG6-ALG8 interaction is pathway-relevant but the bare protein binding term is uninformative.
- id: Reactome:R-HSA-446193
  title: Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide,
    LLO) and transfer to a nascent protein
  findings: []
- id: Reactome:R-HSA-446202
  title: Addition of the first glucose to the N-glycan precursor by ALG6
  findings: []
- id: Reactome:R-HSA-4724291
  title: Defective ALG6 does not add glucose to the N-glycan precursor
  findings: []
- id: file:human/ALG6/ALG6-uniprot.txt
  title: UniProtKB Q9Y672 (ALG6_HUMAN) record
  findings: []
core_functions:
- description: >-
    ALG6 is the ER-lumenal alpha-1,3-glucosyltransferase that adds the first of the three glucoses to
    the dolichol-linked oligosaccharide precursor. Using dolichyl-phosphate-glucose (Dol-P-Glc) as
    donor, it converts Man9GlcNAc2-PP-dolichol to Glc1Man9GlcNAc2-PP-dolichol during dolichol-linked
    oligosaccharide biosynthesis, thereby supporting downstream protein N-linked glycosylation.
  molecular_function:
    id: GO:0042281
    label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
  directly_involved_in:
  - id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  - id: GO:0006487
    label: protein N-linked glycosylation
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/ALG6/ALG6-uniprot.txt
    supporting_text: >-
      adds the first glucose residue from dolichyl phosphate glucose (Dol-P-
  - reference_id: file:human/ALG6/ALG6-uniprot.txt
    supporting_text: >-
      substrate for ALG8, the following
  - reference_id: PMID:25792706
    supporting_text: >-
      A defect in the assembly of the oligosaccharide donor
  - reference_id: PMID:10924277
    supporting_text: >-
      addition of the first glucose residue to the lipid-linked oligosaccharide
proposed_new_terms: []
suggested_questions:
- question: >-
    What is the structural basis for ALG6 substrate recognition of Man9GlcNAc2-PP-dolichol, and how do
    the common CDG-Ic variants (e.g. A333V, S478P) reduce catalytic activity?
- question: >-
    Does ALG6 function as part of a stable multi-enzyme LLO-glucosylation module with ALG8 and ALG10, or
    is the ALG6-ALG8 interaction transient/substrate-channeling?
suggested_experiments:
- description: >-
    Reconstitute purified ALG6 with Dol-P-Glc and Man9GlcNAc2-PP-Dol in vitro to directly measure
    alpha-1,3-glucosyltransferase kinetics and the effect of disease variants on activity.
- description: >-
    Determine the cryo-EM structure of ALG6 (alone and in complex with ALG8) to map the lumenal active
    site and the donor/acceptor binding sites.