id: Q9NP73
gene_symbol: ALG13
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Catalytic (glycosyltransferase) subunit of the bipartite ALG13-ALG14
  UDP-N-acetylglucosamine transferase (GnTase). Together with the membrane-anchoring
  subunit ALG14, ALG13 catalyses the second step of dolichol-linked oligosaccharide
  (lipid-linked oligosaccharide, LLO) assembly on the cytoplasmic face of the endoplasmic
  reticulum membrane, transferring a beta-1,4-linked N-acetylglucosamine from UDP-GlcNAc
  onto GlcNAc-PP-dolichol to form the chitobiose core GlcNAc2-PP-dolichol (N,N'-diacetylchitobiosyl
  diphosphodolichol; EC 2.4.1.141). ALG13 provides the UDP-GlcNAc-binding/catalytic
  glycosyltransferase-28 (GT28) domain but lacks a membrane-spanning region and is
  recruited to the ER membrane by, and is catalytically active only in complex with,
  ALG14. The resulting chitobiosyl-PP-dolichol is the substrate for the next pathway
  enzyme (ALG1), feeding protein N-linked glycosylation. In humans, loss-of-function
  variants cause X-linked developmental and epileptic encephalopathy 36 (ALG13-CDG),
  an infantile-onset epileptic encephalopathy / infantile spasms phenotype with
  neurodevelopmental impairment.
alternative_products:
- name: '1'
  id: Q9NP73-1
- name: '2'
  id: Q9NP73-2
  sequence_note: VSP_039301, VSP_039302
- name: '3'
  id: Q9NP73-3
  sequence_note: VSP_039299, VSP_039300
- name: '4'
  id: Q9NP73-4
  sequence_note: VSP_039298, VSP_039303
existing_annotations:
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: Root-level molecular function term from an ARBA electronic model. ALG13
      is indeed a catalytic enzyme (a glycosyltransferase), but this term is far too
      general to be informative when the specific transferase activity is already
      annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0003824 (catalytic activity) is a top-level MF grouping term. The specific
      catalytic activity of ALG13 is captured by GO:0004577; this generic term adds
      no functional information.
- term:
    id: GO:0004577
    label: N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: This is the correct core molecular function (EC 2.4.1.141) mapped electronically
      from RHEA/EC. It is fully supported by direct experimental evidence (see the
      IDA and IMP annotations to the same term).
    action: ACCEPT
    reason: Matches the biochemically demonstrated activity of the ALG13/ALG14 complex
      and is the correct EC 2.4.1.141 term. This is a core function of ALG13.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Generic cytoplasm localization from an ARBA electronic model. ALG13 is
      a peripheral membrane protein acting on the cytoplasmic face of the ER membrane
      rather than free in the cytoplasm, and this is captured more precisely by GO:0098554
      and GO:0005789.
    action: MARK_AS_OVER_ANNOTATED
    reason: ALG13 without ALG14 partitions to the cytosol, but its functional location
      is the cytoplasmic face of the ER membrane. GO:0005737 is imprecise and less
      informative than the ER-membrane annotations already present.
    supported_by:
    - reference_id: file:human/ALG13/ALG13-uniprot.txt
      supporting_text: Recruited to the cytosolic face of the endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane localization mapped from the UniProt Subcellular Location
      vocabulary. Correct core localization, consistent with the experimental evidence.
    action: ACCEPT
    reason: ALG13 is a peripheral ER-membrane protein recruited to the ER membrane
      by ALG14; the localization is experimentally supported.
    supported_by:
    - reference_id: file:human/ALG13/ALG13-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
    - reference_id: file:human/ALG13/ALG13-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Core biological process, mapped from InterPro (Alg13-like family). ALG13
      catalyses the second sugar-addition step of dolichol-linked (lipid-linked) oligosaccharide
      assembly and is fully supported by experimental evidence.
    action: ACCEPT
    reason: The ALG13/ALG14 complex synthesizes GlcNAc2-PP-dolichol, the second step
      of LLO assembly; this is a core process for ALG13.
    supported_by:
    - reference_id: PMID:16100110
      supporting_text: required for the synthesis of the LLO
- term:
    id: GO:0016758
    label: hexosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Parent/grouping term for the specific N-acetylglucosaminyltransferase
      activity. Correct but too general given the precise EC 2.4.1.141 term (GO:0004577)
      is present and experimentally supported.
    action: MODIFY
    reason: GO:0016758 (hexosyltransferase activity) is an ancestor of the specific
      demonstrated activity GO:0004577. Replace with the specific term.
    proposed_replacement_terms:
    - id: GO:0004577
      label: N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare "protein binding" from a proteome-scale AP-MS interactome (BioPlex
      3.0), with SLC2A4 (P14672) as the interactor. This is an uninformative MF term
      derived from a high-throughput dataset and does not capture the biologically
      meaningful ALG13-ALG14 interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'GO:0005515 (protein binding) conveys no specific molecular function and
      the SLC2A4 pairing is a high-throughput AP-MS association rather than a validated
      functional interaction. The biologically relevant partner is ALG14; ALG13-ALG14
      complex membership is captured in core_functions (GO:0043541). Per curation
      policy, bare protein binding IPIs are marked as over-annotated rather than removed.'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446207
  qualifier: located_in
  review:
    summary: ER membrane localization asserted by Reactome for the reaction in which
      the ALG13:ALG14 complex adds the second GlcNAc to GlcNAc-PP-dolichol. Correct
      core localization.
    action: ACCEPT
    reason: Consistent with the experimental ER-membrane localization; the Reactome
      reaction places the ALG13:ALG14 complex at the ER membrane.
    supported_by:
    - reference_id: Reactome:R-HSA-446207
      supporting_text: This reaction is catalyzed by the ALG13:ALG14 complex
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5633241
  qualifier: located_in
  review:
    summary: ER membrane localization asserted by Reactome (defective-ALG14 variant
      reaction). Redundant with the other ER-membrane annotations but correct.
    action: ACCEPT
    reason: Correct core ER-membrane localization for the ALG13:ALG14 complex.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:16100110
  qualifier: located_in
  review:
    summary: Experimental ER-membrane localization. Gao et al. showed ALG13/Alg13 associates
      with the ER membrane and is recruited to the cytosolic face of the ER by ALG14/Alg14.
    action: ACCEPT
    reason: Directly experimentally supported core localization.
    supported_by:
    - reference_id: PMID:16100110
      supporting_text: as a membrane anchor that recruits Alg13 to the cytosolic face
        of the ER, where
- term:
    id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  evidence_type: IGI
  original_reference_id: PMID:16100110
  qualifier: is_active_in
  review:
    summary: Precise localization to the cytoplasmic face of the ER membrane, the site
      where the ALG13/ALG14 complex catalyses formation of GlcNAc2-PP-dolichol. Supported
      by genetic interaction evidence in the Gao et al. study.
    action: ACCEPT
    reason: This is the most specific and functionally accurate localization for ALG13;
      catalysis of GlcNAc2-PP-dol occurs on the cytosolic face of the ER.
    supported_by:
    - reference_id: PMID:16100110
      supporting_text: catalysis of GlcNAc2-PP-dol occurs
- term:
    id: GO:0004577
    label: N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:36200043
  qualifier: enables
  review:
    summary: Direct in vitro demonstration of GnTase (EC 2.4.1.141) activity of the
      purified human ALG13/ALG14 heterodimer, using synthesized GlcNAc-PP-dolichol
      acceptor and UDP-GlcNAc donor. This is the strongest evidence for the core molecular
      function.
    action: ACCEPT
    reason: Directly measured biochemical activity; core molecular function of ALG13.
    supported_by:
    - reference_id: PMID:36200043
      supporting_text: This dimeric ALG13/14 catalyzes the second step of LLO synthesis,
        transferring a β1,4-linked N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to
        GlcNAc-pyrophosphate-dolichol (Gn-PDol)
    - reference_id: PMID:36200043
      supporting_text: only the shorter human ALG13 isoform 2, but
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: IMP
  original_reference_id: PMID:22492991
  qualifier: acts_upstream_of_positive_effect
  review:
    summary: ALG13 acts upstream of protein N-linked glycosylation; its direct molecular
      step (adding the second GlcNAc to make GlcNAc2-PP-dolichol) feeds the LLO precursor
      that is ultimately transferred to nascent proteins. Timal et al. identified an
      X-linked ALG13 CDG-I defect and confirmed deficient enzyme activity in patient
      fibroblasts.
    action: KEEP_AS_NON_CORE
    reason: N-linked glycosylation is the pathway ALG13 feeds, but ALG13's own catalytic
      step is LLO GlcNAc2 formation (GO:0006488 / GO:0004577). The upstream-effect
      relationship to N-glycosylation is correct and worth retaining, but it is a
      downstream process rather than ALG13's direct core function.
    supported_by:
    - reference_id: PMID:22492991
      supporting_text: the first X-linked CDG-I due to a de novo mutation in
    - reference_id: PMID:22492991
      supporting_text: The pathogenicity of the mutations
- term:
    id: GO:0004577
    label: N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:22492991
  qualifier: enables
  review:
    summary: Mutational (patient-derived) evidence that ALG13 provides EC 2.4.1.141
      activity; the CDG-I defect was confirmed by deficient enzyme activity in patient
      fibroblasts. Duplicate of the core MF term with independent evidence.
    action: ACCEPT
    reason: Independent (IMP) support for the core molecular function; deficient GnTase
      activity in ALG13-CDG patient cells confirms this is ALG13's activity.
    supported_by:
    - reference_id: PMID:22492991
      supporting_text: was confirmed by showing the deficient activity
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:22492991
  qualifier: involved_in
  review:
    summary: Mutational evidence that ALG13 is required for dolichol-linked oligosaccharide
      biosynthesis; ALG13 catalyses the second of the first two steps of dolichol-PP-glycan
      assembly. Core biological process.
    action: ACCEPT
    reason: ALG13 performs a required step of LLO assembly; patient variants impair
      the pathway. Core process for ALG13.
    supported_by:
    - reference_id: PMID:22492991
      supporting_text: together the first two steps in dolichol-PP-glycan assembly
- term:
    id: GO:0043541
    label: UDP-N-acetylglucosamine transferase complex
  evidence_type: IDA
  original_reference_id: file:human/ALG13/ALG13-uniprot.txt
  qualifier: part_of
  review:
    summary: ALG13 is an active subunit of the ALG13-ALG14 UDP-N-acetylglucosamine
      transferase complex. This complex-membership term is recorded in the UniProt
      GO cross-references (IDA:UniProtKB) but is absent from the GOA TSV under review;
      added here as it is the biologically correct complex for ALG13's activity.
    action: NEW
    reason: ALG13 has GnTase activity only when bound to ALG14 in the heterodimeric
      complex; complex membership (GO:0043541) is well supported and more informative
      than the bare protein-binding IPI.
    supported_by:
    - reference_id: PMID:16100110
      supporting_text: as a membrane anchor that recruits Alg13 to the cytosolic face
        of the ER, where
    - reference_id: PMID:36200043
      supporting_text: only the shorter human ALG13 isoform 2, but
    - reference_id: Reactome:R-HSA-446207
      supporting_text: This reaction is catalyzed by the ALG13:ALG14 complex
core_functions:
- description: Catalytic subunit of the ALG13-ALG14 UDP-N-acetylglucosamine transferase;
    transfers the second (beta-1,4-linked) GlcNAc from UDP-GlcNAc onto GlcNAc-PP-dolichol
    to form GlcNAc2-PP-dolichol (chitobiose core), the second step of dolichol-linked
    oligosaccharide (LLO) assembly.
  molecular_function:
    id: GO:0004577
    label: N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity
  directly_involved_in:
  - id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  locations:
  - id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0043541
    label: UDP-N-acetylglucosamine transferase complex
  supported_by:
  - reference_id: PMID:36200043
    supporting_text: This dimeric ALG13/14 catalyzes the second step of LLO synthesis,
      transferring a β1,4-linked N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to GlcNAc-pyrophosphate-dolichol
      (Gn-PDol)
  - reference_id: PMID:16100110
    supporting_text: as a membrane anchor that recruits Alg13 to the cytosolic face
      of the ER, where
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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: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:16100110
  title: Alg14 recruits Alg13 to the cytoplasmic face of the endoplasmic reticulum
    to form a novel bipartite UDP-N-acetylglucosamine transferase required for the
    second step of N-linked glycosylation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the bipartite ALG13/ALG14 UDP-GlcNAc transferase, ALG14
      as membrane anchor recruiting ALG13 to the cytosolic face of the ER, and the
      second-step catalysis producing GlcNAc2-PP-dolichol. Human ALG13/ALG14 complement
      yeast mutants. Abstract-only in cache; assertions used are in the abstract.
- id: PMID:22492991
  title: Gene identification in the congenital disorders of glycosylation type I by
    whole-exome sequencing.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Identified the first X-linked CDG-I due to a de novo ALG13 mutation
      (DEE36/ALG13-CDG); pathogenicity confirmed by deficient enzyme activity in patient
      fibroblasts. Abstract-only in cache; supports the disease and pathway roles.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex 3.0 proteome-scale AP-MS interactome; source of the bare
      protein-binding IPI (ALG13-SLC2A4). High-throughput dataset, not a targeted
      functional study of ALG13; the specific pair is not discussed in the cached text.
- id: PMID:36200043
  title: An in vitro assay for enzymatic studies on human ALG13/14 heterodimeric UDP-N-acetylglucosamine
    transferase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text cached. Purified human ALG13/ALG14 heterodimer shows GnTase
      (EC 2.4.1.141) activity in a quantitative LC-MS assay; only short isoform 2
      (not long isoform 1) forms an active complex with ALG14; CDG variants reduce
      activity, linking GnTase deficiency to ALG13/14-CDG.
- id: Reactome:R-HSA-446207
  title: ALG13:ALG14 transfers GlcNAc from UDP-GlcNAc to GlcNAcDOLP
  findings: []
- id: Reactome:R-HSA-5633241
  title: Defective ALG14 does not transfer GlcNAc from UDP-GlcNAc to GlcNAcDOLP
  findings: []
- id: file:human/ALG13/ALG13-uniprot.txt
  title: UniProtKB entry Q9NP73 (ALG13_HUMAN)
  findings: []