id: Q9BT22
gene_symbol: ALG1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ALG1 is the endoplasmic reticulum beta-1,4-mannosyltransferase
  (chitobiosyldiphosphodolichol beta-mannosyltransferase; EC 2.4.1.142) that
  catalyzes the first mannose-addition step of dolichol-linked oligosaccharide
  (lipid-linked oligosaccharide, LLO) assembly. Using GDP-mannose as donor, it
  transfers the first mannose onto the chitobiose core (GlcNAc2-PP-dolichol) to
  form Man1GlcNAc2-PP-dolichol, acting on the cytoplasmic face of the ER
  membrane; the product is the substrate for the next enzyme, ALG2. ALG1 is an
  ER membrane protein and contributes to the biosynthesis of the N-glycan
  precursor used in protein asparagine (N)-linked glycosylation. Loss of ALG1
  function causes ALG1-CDG (congenital disorder of glycosylation type Ik), a
  severe autosomal-recessive multisystem disorder with prominent neurological
  involvement, dysmorphism, hematologic and immune features, and high early
  mortality, characterized by hypoglycosylated serum glycoproteins.
alternative_products:
- name: '1'
  id: Q9BT22-1
- name: '2'
  id: Q9BT22-2
  sequence_note: VSP_056931
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing ALG1 in the endoplasmic reticulum.
      This is correct but general; ALG1 is more precisely an ER membrane protein
      that acts on the cytoplasmic face of the ER. Retained as an accurate,
      broader localization statement.
    action: ACCEPT
    reason: >-
      The ER localization is well supported. UniProt records ER membrane
      localization, and the reaction occurs on the cytoplasmic face of the ER.
      A more specific ER membrane term is also annotated (GO:0005789).
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0009101
    label: glycoprotein biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to glycoprotein biosynthetic process. ALG1
      builds the N-glycan precursor used for protein N-linked glycosylation, so
      this broad biosynthetic-process term is correct. It is a more general
      parent of the more specific N-linked glycosylation / LLO biosynthesis
      terms also annotated.
    action: ACCEPT
    reason: >-
      ALG1 contributes the first mannose of the dolichol-linked oligosaccharide
      that is ultimately transferred to nascent proteins to form glycoproteins.
      Correct but general relative to GO:0006487 and GO:0006488, which are also
      present; kept as an accurate higher-level term.
    supported_by:
    - reference_id: PMID:26931382
      supporting_text: encodes an ER localized β1,4 mannosyltransferase that catalyzes the transfer of the first of nine Man moieties onto the growing DLO
- term:
    id: GO:0000030
    label: mannosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation to the parent term mannosyltransferase
      activity. This is on the correct molecular-function branch but is less
      specific than the experimentally supported term
      chitobiosyldiphosphodolichol beta-mannosyltransferase activity
      (GO:0004578), which is also annotated.
    action: MODIFY
    reason: >-
      The precise activity of ALG1 is known experimentally (transfer of the
      first mannose from GDP-mannose onto GlcNAc2-PP-dolichol). The general
      parent should be refined to the specific child term GO:0004578. The
      PANTHER family (PTHR13036) covers this beta-1,4-mannosyltransferase
      orthology group, so the specific term is warranted at this node.
    proposed_replacement_terms:
    - id: GO:0004578
      label: chitobiosyldiphosphodolichol beta-mannosyltransferase activity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: PMID:14973778
      supporting_text: severely reduced activity of the beta 1,4-mannosyltransferase
- term:
    id: GO:0000030
    label: mannosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IEA) annotation to mannosyltransferase activity from
      IPR026051 (ALG1-like). Correct branch but less specific than the exact
      term GO:0004578, which is also present with experimental support.
    action: MODIFY
    reason: >-
      Same as the IBA annotation to GO:0000030: the general parent should be
      refined to the specific, experimentally supported child term GO:0004578.
    proposed_replacement_terms:
    - id: GO:0004578
      label: chitobiosyldiphosphodolichol beta-mannosyltransferase activity
    supported_by:
    - reference_id: PMID:14973778
      supporting_text: severely reduced activity of the beta 1,4-mannosyltransferase
- term:
    id: GO:0004578
    label: chitobiosyldiphosphodolichol beta-mannosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (IEA) annotation of the exact molecular function via the
      RHEA:13865 / EC:2.4.1.142 mapping. This is the correct, specific catalytic
      activity of ALG1 and matches the UniProt catalytic-activity record.
    action: ACCEPT
    reason: >-
      GO:0004578 is the precise activity of ALG1 (EC 2.4.1.142, RHEA:13865:
      GlcNAc2-PP-dolichol + GDP-mannose -> Man1GlcNAc2-PP-dolichol). Supported by
      IEA, TAS (Reactome), and IDA (PMID:14973778).
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: EC=2.4.1.142
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Automated (IEA) subcellular-location annotation (UniProt SubCell mapping)
      to ER membrane. This matches the UniProt curated subcellular location
      (single-pass ER membrane protein) and is the core location of ALG1.
    action: ACCEPT
    reason: >-
      ALG1 is a single-pass ER membrane protein; the ER membrane is where LLO
      assembly (including the ALG1 step, on the cytoplasmic face) occurs.
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: Single-pass membrane protein
- term:
    id: GO:0016757
    label: glycosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IEA) annotation to the very general term glycosyltransferase
      activity from IPR001296 (Glyco_trans_1). This is a high-level grandparent
      of the specific ALG1 activity and is uninformative when the exact term
      GO:0004578 is already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not wrong (ALG1 is a glycosyltransferase, CAZy GT33), but this is an
      over-general term; the specific chitobiosyldiphosphodolichol
      beta-mannosyltransferase activity (GO:0004578) captures the function.
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: Belongs to the glycosyltransferase group 1 family
- 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: >-
      Reactome (TAS) annotation to dolichol-linked oligosaccharide biosynthetic
      process. ALG1 performs the first mannosylation step of LLO assembly, a
      core part of building the 14-sugar dolichol-linked oligosaccharide.
    action: ACCEPT
    reason: >-
      This is a core biological process for ALG1 and is independently supported
      by IDA (PMID:14973778). Reactome R-HSA-446193 covers LLO biosynthesis and
      transfer to nascent protein.
    supported_by:
    - reference_id: PMID:14973778
      supporting_text: elongating
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: operates in the biosynthetic pathway
- term:
    id: GO:0004578
    label: chitobiosyldiphosphodolichol beta-mannosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446218
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) annotation of the exact molecular function. Reactome
      reaction R-HSA-446218 is the addition of the first mannose to the N-glycan
      precursor by ALG1 via a beta-1,4 linkage. Correct and specific.
    action: ACCEPT
    reason: >-
      This is the precise catalytic activity of ALG1, corroborated by IDA
      (PMID:14973778) and IEA (RHEA/EC).
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: addition of the first mannose residues to
- term:
    id: GO:0004578
    label: chitobiosyldiphosphodolichol beta-mannosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4549382
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) annotation of the exact molecular function via the disease
      reaction (defective ALG1 fails to transfer the first mannose). The
      normal-function attribution to GO:0004578 is correct and specific.
    action: ACCEPT
    reason: >-
      Reactome R-HSA-4549382 describes that ALG1 normally transfers a mannose to
      the LLO; this is the same specific activity captured by IDA and IEA.
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: addition of the first mannose residues to
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity (ISS) annotation to ER membrane based on the yeast/
      orthologue reference (UniProtKB:P16661). Consistent with the curated
      UniProt subcellular location and the other ER membrane annotations.
    action: ACCEPT
    reason: >-
      ALG1 is an ER membrane protein; this location is well supported across
      multiple evidence lines.
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: IDA
  original_reference_id: PMID:26931382
  qualifier: acts_upstream_of_positive_effect
  review:
    summary: >-
      Experimental (IDA) annotation, acts_upstream_of_positive_effect of protein
      N-linked glycosylation. ALG1 builds the LLO precursor required for proper
      N-linked glycosylation; loss of function causes hypoglycosylation
      (ALG1-CDG). The yeast-complementation assays in this paper directly show
      ALG1 is required for normal N-glycosylation.
    action: ACCEPT
    reason: >-
      ALG1 is upstream of and required for protein N-linked glycosylation; the
      qualifier acts_upstream_of_positive_effect is appropriate for an enzyme
      that produces an obligatory precursor of the N-glycan.
    supported_by:
    - reference_id: PMID:26931382
      supporting_text: catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation
- term:
    id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: is_active_in
  review:
    summary: >-
      Sequence-similarity (ISS) annotation placing the active enzyme on the
      cytoplasmic side of the ER membrane. This is the catalytic face for the
      early LLO-assembly steps (including the ALG1 mannose addition) and matches
      UniProt and the primary literature.
    action: ACCEPT
    reason: >-
      The first mannose addition by ALG1 occurs on the cytoplasmic (cytosolic)
      face of the ER; this location is directly stated in UniProt and in the
      discovery paper.
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: Catalyzes, on the cytoplasmic face of the
    - reference_id: PMID:14973778
      supporting_text: at the cytosolic side of
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: IDA
  original_reference_id: PMID:14973778
  qualifier: acts_upstream_of_positive_effect
  review:
    summary: >-
      Experimental (IDA) annotation from the CDG-Ik discovery paper. Patient
      fibroblasts with ALG1 deficiency showed a partial loss of N-glycan chains
      and accumulation of GlcNAc2-PP-dolichol, demonstrating ALG1 is required
      for normal protein N-linked glycosylation.
    action: ACCEPT
    reason: >-
      Direct patient-derived evidence that ALG1 deficiency impairs N-linked
      glycosylation, supporting acts_upstream_of_positive_effect of
      GO:0006487.
    supported_by:
    - reference_id: PMID:14973778
      supporting_text: a partial loss of N-glycan chains was observed, a
    - reference_id: PMID:14973778
      supporting_text: an accumulation of GlcNAc(2)-PP-dolichol and
- term:
    id: GO:0004578
    label: chitobiosyldiphosphodolichol beta-mannosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:14973778
  qualifier: enables
  review:
    summary: >-
      Experimental (IDA) annotation of the exact molecular function. Incubation
      of patient fibroblast extracts with [14C]GlcNAc2-PP-dolichol and
      GDP-mannose revealed the beta-1,4-mannosyltransferase activity that
      elongates GlcNAc2-PP-dolichol to Man1GlcNAc2-PP-dolichol. This is the
      strongest, gold-standard evidence for GO:0004578 in human ALG1.
    action: ACCEPT
    reason: >-
      Direct enzymatic assay establishes the chitobiosyldiphosphodolichol
      beta-mannosyltransferase activity (EC 2.4.1.142) of human ALG1.
    supported_by:
    - reference_id: PMID:14973778
      supporting_text: severely reduced activity of the beta 1,4-mannosyltransferase
    - reference_id: PMID:14973778
      supporting_text: elongating
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:14973778
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IDA) annotation to dolichol-linked oligosaccharide
      biosynthetic process. The ALG1 step (GlcNAc2-PP-dolichol ->
      Man1GlcNAc2-PP-dolichol) is a defined reaction within LLO assembly, and
      ALG1-deficient fibroblasts accumulate the upstream GlcNAc2-PP-dolichol
      intermediate.
    action: ACCEPT
    reason: >-
      Core biological process for ALG1, directly demonstrated by the enzymatic
      elongation of GlcNAc2-PP-dolichol and the accumulation of LLO
      intermediates in patient cells.
    supported_by:
    - reference_id: PMID:14973778
      supporting_text: elongating
    - reference_id: PMID:14973778
      supporting_text: an accumulation of GlcNAc(2)-PP-dolichol and
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4549382
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) ER membrane localization. Consistent with the curated
      UniProt subcellular location and other ER membrane annotations; this is
      the core location of ALG1.
    action: ACCEPT
    reason: >-
      ALG1 is a single-pass ER membrane protein; well supported.
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446218
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) ER membrane localization associated with the ALG1
      first-mannose-addition reaction. Consistent with the curated UniProt
      subcellular location and the other ER membrane annotations; this is the
      core location of ALG1.
    action: ACCEPT
    reason: >-
      ALG1 is a single-pass ER membrane protein; well supported.
    supported_by:
    - reference_id: file:human/ALG1/ALG1-uniprot.txt
      supporting_text: 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) annotation to the generic term membrane, from an
      NK-cell (YTS line) membrane-proteome mass-spectrometry survey in which
      ALG1 was identified among membrane-associated proteins. The location is
      correct but uninformatively general given ALG1's specific ER membrane
      localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not wrong, but "membrane" is far less informative than the specific ER
      membrane (GO:0005789) already annotated. The evidence is a proteome-wide
      membrane-enrichment survey, not a targeted localization study.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: predicted as plausible membrane proteins
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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:14973778
  title: Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital
    disorder of glycosylation type Ik.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      CDG-Ik / ALG1-CDG discovery paper. Directly establishes the human ALG1
      beta-1,4-mannosyltransferase activity (enzymatic assay in patient
      fibroblast extracts), its role in LLO assembly and N-glycosylation, and
      the S258L disease variant. Abstract-only in cache but the abstract itself
      supplies the enzymatic and localization statements used here.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      NK-cell (YTS) membrane-proteome mass-spectrometry survey; basis of the
      generic HDA "membrane" annotation. Correctly cited but only supports a
      non-specific membrane localization, not ALG1-specific function.
- id: PMID:26931382
  title: 'ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Large ALG1-CDG clinical/molecular series; full text cached. States the
      ALG1 enzymatic role (first of nine mannoses onto the DLO, ER-localized
      beta-1,4-mannosyltransferase) and demonstrates loss-of-function by yeast
      complementation, supporting the N-linked glycosylation and disease
      annotations.
- 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-446218
  title: Addition of the first mannose to the N-glycan precursor by ALG1
  findings: []
- id: Reactome:R-HSA-4549382
  title: Defective ALG1 does not transfer the first Man to the N-glycan precursor
  findings: []
- id: file:human/ALG1/ALG1-uniprot.txt
  title: UniProtKB Q9BT22 (ALG1_HUMAN) curated record
  findings: []
core_functions:
- description: >-
    Chitobiosyldiphosphodolichol beta-mannosyltransferase (EC 2.4.1.142): using
    GDP-mannose as donor, ALG1 transfers the first mannose onto the chitobiose
    core GlcNAc2-PP-dolichol via a beta-1,4 linkage to form
    Man1GlcNAc2-PP-dolichol, the first mannosylation step of dolichol-linked
    oligosaccharide (LLO) assembly, on the cytoplasmic face of the ER membrane.
    The product is the substrate for ALG2, the next enzyme in the pathway.
  molecular_function:
    id: GO:0004578
    label: chitobiosyldiphosphodolichol beta-mannosyltransferase 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
  - id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:14973778
    supporting_text: severely reduced activity of the beta 1,4-mannosyltransferase
  - reference_id: file:human/ALG1/ALG1-uniprot.txt
    supporting_text: addition of the first mannose residues to
  - reference_id: PMID:26931382
    supporting_text: encodes an ER localized β1,4 mannosyltransferase that catalyzes the transfer of the first of nine Man moieties onto the growing DLO
proposed_new_terms: []
suggested_questions:
- question: >-
    Do specific ALG1 missense variants that retain partial mannosyltransferase
    activity or impair complex formation with ALG2/ALG11 correlate with milder
    ALG1-CDG phenotypes?
suggested_experiments:
- description: >-
    Reconstitute human ALG1 with ALG2 and ALG11 and measure the kinetics of
    sequential mannose transfer onto GlcNAc2-PP-dolichol to test whether ALG1
    activity is rate-limiting for early LLO assembly on the cytoplasmic face of
    the ER.
  hypothesis: >-
    ALG1 catalytic output is rate-limiting for early cytoplasmic-face LLO
    assembly, so partial-activity variants set the ceiling on downstream
    mannosylation and correlate with residual N-glycosylation.