id: Q9UKM7
gene_symbol: MAN1B1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: MAN1B1 (ER alpha-1,2-mannosidase I, ERManI, ERMan1) is a calcium-dependent, type II single-pass endoplasmic reticulum membrane glycosidase of glycoside hydrolase family 47 (GH47, EC 3.2.1.113) that trims terminal alpha-1,2-linked mannose residues from N-linked oligosaccharides. At low enzyme concentration it removes a single mannose from Man9GlcNAc2 to generate Man8GlcNAc2 isomer B, the first committed mannose-trimming step of N-glycan maturation; at the high local concentrations found in the ER-derived quality control compartment (ERQC) it excises additional alpha-1,2-mannoses to yield Man5-6GlcNAc2. This trimming removes misfolded glycoproteins from the calnexin/reglucosylation folding cycle and generates the demannosylated signal that commits them to ER-associated degradation (ERAD), where the trimmed glycan is recognized by downstream lectins (e.g. OS-9/XTP3-B) and delivered to the HRD1 ubiquitin-ligase machinery. ERManI thus functions as a key "mannose timer" in glycoprotein quality control. It is widely expressed, resides in the ER membrane and concentrates in mobile ER-like quality control vesicles that converge on the pericentriolar ERQC. Biallelic loss-of-function variants cause an autosomal-recessive congenital disorder of glycosylation with intellectual disability (Rafiq syndrome / MAN1B1-CDG).
existing_annotations:
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Generic membrane localization inferred phylogenetically. MAN1B1 is a single-pass type II ER membrane protein, but the more specific endoplasmic reticulum membrane term captures the location informatively.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "membrane" is uninformative relative to the specific ER membrane annotation; MAN1B1 is anchored in the ER membrane, not membranes generally.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: MAN1B1 is an ER-resident enzyme; phylogenetic assignment of ER localization is consistent with experimental evidence.
    action: ACCEPT
    reason: Correct site of action; MAN1B1 acts in the endoplasmic reticulum on nascent and misfolded glycoproteins.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: The defining molecular function of MAN1B1; phylogenetic assignment of GH47 alpha-1,2-mannosidase activity is well supported.
    action: ACCEPT
    reason: Core molecular function; corroborated by direct enzymatic assays, crystal structures, EC 3.2.1.113, and CAZy GH47 membership.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: MAN1B1 generates the trimmed-mannose ERAD signal that commits misfolded glycoproteins to degradation; phylogenetic assignment is well supported.
    action: ACCEPT
    reason: Core biological process; mannose trimming by ERManI is required for ERAD of misfolded glycoproteins.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of the core GH47 alpha-1,2-mannosidase activity, consistent with experimental evidence.
    action: ACCEPT
    reason: Correct core molecular function; redundant with IDA/EXP evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: GH47 mannosidases require a Ca2+ ion in the active site for catalysis; MAN1B1 binds calcium as a structural/catalytic cofactor. This is a real attribute but subsidiary to the mannosidase activity, not an independent calcium-signaling function.
    action: KEEP_AS_NON_CORE
    reason: Accurate structural cofactor requirement of the GH47 fold but not a standalone core function; the catalytic mannosidase activity is the informative function.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Name=Ca(2+)
    - reference_id: PMID:10409699
      supporting_text: The mannose cleavage reaction required divalent cations as indicated by inhibition with EDTA or EGTA and reversal of the inhibition by the addition of Ca(2+)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of ER membrane localization from the UniProt subcellular location; MAN1B1 is a single-pass type II ER membrane protein.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental IDA/EXP ER membrane annotations.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Single-pass type II membrane protein
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Generic carbohydrate metabolic process from InterPro; far less informative than the specific N-glycan/mannose trimming and ERAD processes MAN1B1 participates in.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general; the specific ER mannose trimming (GO:1904380) and ER N-glycan trimming (GO:0140277) terms better capture the biology.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase
- term:
    id: GO:0009100
    label: glycoprotein metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Generic glycoprotein metabolic process from ARBA; correct in essence but far less informative than the specific N-glycan trimming and ERAD annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general parent process; the specific glycan-trimming/ERAD terms are preferred.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic membrane localization from InterPro, superseded by the specific ER membrane annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative parent; MAN1B1 is specifically an ER membrane protein.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic (ARBA) assignment of the ERAD pathway, consistent with experimental evidence that ERManI mannose trimming is required for ERAD.
    action: ACCEPT
    reason: Correct core biological process; redundant with IMP/IDA evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: required for trimming to Man 5–6 GlcNAc 2 and for ERAD in cells in vivo
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4793949
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1 mannosidase activity (defective-MAN1B1 reaction context).
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901024
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1 hydrolysis of a 1,2-linked mannose (a branch).
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901036
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1 hydrolysis of a second 1,2-linked mannose (a branch).
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901039
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1 hydrolysis of a 1,2-linked mannose (c branch).
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901074
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1/EDEM2 hydrolysis of a 1,2-linked mannose (b branch).
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036008
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1 mannosidase activity (defective-MAN1B1 reaction context).
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036011
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1 mannosidase activity (defective-MAN1B1 reaction context).
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036012
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1 mannosidase activity (defective-MAN1B1 reaction context).
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9696807
  qualifier: enables
  review:
    summary: Reactome curation of MAN1B1 mannosidase activity in the context of N-glycan mannose trimming of viral (SARS-CoV-2) spike.
    action: ACCEPT
    reason: Correct core molecular function acting on a viral glycoprotein substrate; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0140277
    label: endoplasmic reticulum N-glycan trimming
  evidence_type: IMP
  original_reference_id: PMID:18003979
  qualifier: involved_in
  review:
    summary: Knockdown/inhibition of ERManI blocks N-glycan trimming in the ER, directly demonstrating its role in ER N-glycan trimming.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: required for trimming to Man 5–6 GlcNAc 2 and for ERAD in cells in vivo
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:10521544
  qualifier: involved_in
  review:
    summary: MAN1B1 generates the trimmed Man8B glycan that initiates the ERAD-targeting signal during N-glycan maturation.
    action: ACCEPT
    reason: Core biological process; ERManI mannose trimming commits misfolded glycoproteins to ERAD.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: IDA
  original_reference_id: PMID:10521544
  qualifier: involved_in
  review:
    summary: The recombinant enzyme directly removes a single alpha-1,2-mannose from Man9GlcNAc to produce Man8GlcNAc isomer B, the first ER mannose-trimming step.
    action: ACCEPT
    reason: Core biological process with direct enzymatic (IDA) demonstration of ER mannose trimming.
    supported_by:
    - reference_id: PMID:10409699
      supporting_text: the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: IMP
  original_reference_id: PMID:18003979
  qualifier: involved_in
  review:
    summary: ERManI knockdown impairs ER mannose trimming to Man5-6GlcNAc2 in cells, confirming its role in ER mannose trimming.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: required for trimming to Man 5–6 GlcNAc 2 and for ERAD in cells in vivo
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:18003979
  qualifier: located_in
  review:
    summary: ERManI is localized to the ER membrane and concentrates in the ER-derived quality control compartment.
    action: ACCEPT
    reason: Correct compartment with direct experimental support.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: ERManI is strikingly concentrated together with the ERAD substrate in the pericentriolar ER-derived quality control compartment
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901032
  qualifier: involved_in
  review:
    summary: Reactome curation of ER mannose trimming in the ER Quality Control Compartment pathway.
    action: ACCEPT
    reason: Correct core biological process; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: required for trimming to Man 5–6 GlcNAc 2 and for ERAD in cells in vivo
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: EXP
  original_reference_id: PMID:15713668
  qualifier: enables
  review:
    summary: Structural and kinetic study of the GH47 catalytic mechanism with active-site mutagenesis directly demonstrating the alpha-1,2-mannosidase activity.
    action: ACCEPT
    reason: Core molecular function with direct experimental (EXP) and structural support.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:10409699
  qualifier: located_in
  review:
    summary: Epitope-tagged ERManI displays an ER pattern of localization in cells, supporting ER membrane localization.
    action: ACCEPT
    reason: Correct compartment with experimental support.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IMP
  original_reference_id: PMID:18003979
  qualifier: enables
  review:
    summary: Functional knockdown/inhibition experiments tie loss of mannosidase activity to impaired N-glycan trimming, supporting the enables annotation.
    action: ACCEPT
    reason: Core molecular function consistent with direct enzymatic assays.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:18003979
  qualifier: involved_in
  review:
    summary: ERManI is required for ERAD of a model misfolded glycoprotein in cells; loss leads to accumulation of untrimmed glycans.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: required for trimming to Man 5–6 GlcNAc 2 and for ERAD in cells in vivo
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:21062743
  qualifier: involved_in
  review:
    summary: Mannose trimming by ERManI is required for handoff of a substrate glycoprotein from EDEM1 to the late ERAD lectin XTP3-B and the downstream HRD1/SCF(Fbs2) ligases.
    action: ACCEPT
    reason: Core biological process; experimentally links ERManI trimming to downstream ERAD steps.
    supported_by:
    - reference_id: PMID:21062743
      supporting_text: Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B
- term:
    id: GO:0019082
    label: viral protein processing
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9694548
  qualifier: involved_in
  review:
    summary: Reactome annotation of MAN1B1 in N-glycan mannose trimming of the SARS-CoV-2 spike glycoprotein. This is the generic mannosidase activity acting on a viral glycoprotein substrate, not a distinct viral function.
    action: KEEP_AS_NON_CORE
    reason: Real but peripheral; reflects the core mannosidase activity applied to a viral substrate rather than a dedicated viral-processing role.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: EC=3.2.1.113
- term:
    id: GO:0036510
    label: trimming of terminal mannose on C branch
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901039
  qualifier: involved_in
  review:
    summary: Reactome curation of the specific sub-step in which ERManI trims the terminal C-branch mannose; an accurate refinement of its trimming activity.
    action: ACCEPT
    reason: Correct specific sub-process of N-glycan mannose trimming.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IDA
  original_reference_id: PMID:25411339
  qualifier: located_in
  review:
    summary: At steady state ERManI resides in mobile ER-like quality control vesicles (QCVs) to which ERAD substrates are delivered, supporting a cytoplasmic vesicle localization.
    action: ACCEPT
    reason: Genuine localization with direct experimental support (QCVs).
    supported_by:
    - reference_id: PMID:25411339
      supporting_text: quality control vesicles (QCVs) with ER-like density, to which ERAD substrates are delivered
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IDA
  original_reference_id: PMID:10521544
  qualifier: enables
  review:
    summary: The recombinant human enzyme directly removes a single alpha-1,2-mannose from Man9GlcNAc to give Man8GlcNAc isomer B, directly demonstrating its mannosidase activity.
    action: ACCEPT
    reason: Core molecular function with direct enzymatic (IDA) support.
    supported_by:
    - reference_id: PMID:10409699
      supporting_text: the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IDA
  original_reference_id: PMID:18003979
  qualifier: located_in
  review:
    summary: ERManI is strikingly concentrated with ERAD substrate in the pericentriolar ER-derived quality control compartment (ERQC), where its high local concentration enables extensive trimming.
    action: ACCEPT
    reason: Genuine, functionally important localization with direct experimental support.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: ERManI is strikingly concentrated together with the ERAD substrate in the pericentriolar ER-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: PMID:21062743
  qualifier: located_in
  review:
    summary: ERQC localization asserted in the context of ERManI-dependent ERAD substrate delivery.
    action: ACCEPT
    reason: Consistent with direct IDA evidence for ERQC localization.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IDA
  original_reference_id: PMID:22160784
  qualifier: enables
  review:
    summary: In vitro assays show recombinant hERManI generates Man6GlcNAc2 and Man5GlcNAc2 and preferentially trims misfolded glycoproteins, directly demonstrating its mannosidase activity and conformational selectivity.
    action: ACCEPT
    reason: Core molecular function with direct in vitro enzymatic (IDA) support.
    supported_by:
    - reference_id: PMID:22160784
      supporting_text: generated Man(6)GlcNAc(2)-PA and Man(5)GlcNAc(2)-PA from 100 μM
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:22160784
  qualifier: located_in
  review:
    summary: ER localization asserted in an in vitro mannose-trimming study; consistent with the established ER residence of ERManI.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental ER membrane annotations.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: TAS
  original_reference_id: PMID:22160784
  qualifier: located_in
  review:
    summary: A Golgi localization has been reported for ERManI, but later work attributes the apparent Golgi pattern to membrane disturbance during immunofluorescence; ERManI functions in the ER/ERQC, not the Golgi.
    action: KEEP_AS_NON_CORE
    reason: Disputed/likely fixation artifact; not a genuine site of action. Retained as non-core rather than removed because a TAS source asserts it.
    supported_by:
    - reference_id: PMID:25411339
      supporting_text: Golgi pattern
- term:
    id: GO:1903561
    label: extracellular vesicle
  evidence_type: HDA
  original_reference_id: PMID:24769233
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of MAN1B1 in cerebrospinal fluid extracellular vesicles; a real but peripheral detection unrelated to its ER catalytic function.
    action: KEEP_AS_NON_CORE
    reason: Large-scale proteomics detection; not a functional site of action.
    supported_by:
    - reference_id: PMID:24769233
      supporting_text: cerebrospinal fluid
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4793949
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization (defective-MAN1B1 reaction context).
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036008
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization (defective-MAN1B1 reaction context).
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036011
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization (defective-MAN1B1 reaction context).
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036012
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization (defective-MAN1B1 reaction context).
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput membrane proteome detection of MAN1B1; consistent with its membrane anchoring but uninformative relative to the specific ER membrane term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic membrane term from proteomics; MAN1B1 is specifically an ER membrane protein.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: membrane proteome
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901024
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization.
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901036
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization.
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901039
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization.
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901074
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization.
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9696807
  qualifier: located_in
  review:
    summary: Reactome curation of ERQC localization in the spike N-glycan trimming pathway.
    action: ACCEPT
    reason: Correct compartment; redundant with IDA ERQC evidence.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IDA
  original_reference_id: PMID:12090241
  qualifier: enables
  review:
    summary: Demonstrates that the human class I ER alpha-1,2-mannosidase can trim beyond a single mannose, refining the specificity of the mannosidase activity.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; informs the broader-than-single-residue specificity underlying the mannose timer.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: at high enzyme concentrations, as found in the ER
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:18003979
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization of ERManI.
    action: ACCEPT
    reason: Correct site of action with direct experimental support.
    supported_by:
    - reference_id: PMID:18003979
      supporting_text: pericentriolar ER-derived quality control compartment
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:18003979
  qualifier: located_in
  review:
    summary: Generic membrane localization; superseded by the specific ER membrane annotation from the same evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative parent of the specific ER membrane localization.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: PMID:10409699
  qualifier: enables
  review:
    summary: Identification and characterization of human ER mannosidase I as the enzyme catalyzing the first mannose-trimming step.
    action: ACCEPT
    reason: Core molecular function with strong experimental basis.
    supported_by:
    - reference_id: PMID:10409699
      supporting_text: the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:10409699
  qualifier: located_in
  review:
    summary: ER localization asserted from the original characterization of ER mannosidase I.
    action: ACCEPT
    reason: Correct site of action; consistent with experimental ER membrane evidence.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0009311
    label: oligosaccharide metabolic process
  evidence_type: TAS
  original_reference_id: PMID:10409699
  qualifier: involved_in
  review:
    summary: Generic oligosaccharide metabolic process; correct but far less informative than the specific N-glycan/mannose trimming terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general parent process; the specific ER mannose trimming term is preferred.
    supported_by:
    - reference_id: PMID:10409699
      supporting_text: Asn-linked oligosaccharide biosynthesis
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: PMID:10521544
  qualifier: enables
  review:
    summary: Original cloning/characterization establishing the specific human alpha-1,2-mannosidase activity producing Man8GlcNAc2 isomer B.
    action: ACCEPT
    reason: Core molecular function with strong experimental basis.
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: TAS
  original_reference_id: PMID:10521544
  qualifier: enables
  review:
    summary: Calcium is required for ERManI activity; this is a structural/catalytic cofactor requirement of the GH47 fold rather than an independent calcium-signaling function.
    action: KEEP_AS_NON_CORE
    reason: Real cofactor requirement but subsidiary to the catalytic mannosidase activity.
    supported_by:
    - reference_id: PMID:10521544
      supporting_text: Calcium is required for enzyme activity
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:10521544
  qualifier: located_in
  review:
    summary: Generic membrane localization; superseded by the specific ER membrane annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative parent; MAN1B1 is specifically an ER membrane protein.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
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
  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:10409699
  title: Identification, expression, and characterization of a cDNA encoding human endoplasmic reticulum mannosidase I, the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis.
  findings:
  - statement: Human ER mannosidase I is the enzyme catalyzing the first mannose-trimming step of Asn-linked oligosaccharide biosynthesis; the reaction requires divalent cations (Ca2+).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational characterization of human ERManI; supports the mannosidase activity, ER localization, and calcium dependence.
- id: PMID:10521544
  title: Cloning and expression of a specific human alpha 1,2-mannosidase that trims Man9GlcNAc2 to Man8GlcNAc2 isomer B during N-glycan biosynthesis.
  findings:
  - statement: The recombinant human enzyme removes a single alpha-1,2-mannose from Man9GlcNAc to produce Man8GlcNAc isomer B; calcium is required and dMNJ and kifunensine inhibit activity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the specific product (Man8B) and the calcium/inhibitor profile of MAN1B1.
- id: PMID:12090241
  title: The specificity of the yeast and human class I ER alpha 1,2-mannosidases involved in ER quality control is not as strict previously reported.
  findings:
  - statement: The human class I ER alpha-1,2-mannosidase can trim more than a single mannose, revising the strict single-residue specificity model.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the broader (concentration-dependent) trimming specificity underlying the mannose timer.
- id: PMID:15713668
  title: Mechanism of class 1 (glycosylhydrolase family 47) alpha-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control.
  findings:
  - statement: Structural and mutagenesis study of the GH47 inverting hydrolytic mechanism, mapping catalytic residues of human ERManI.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Mechanistic/structural basis of the GH47 mannosidase catalysis.
- id: PMID:18003979
  title: Endoplasmic reticulum (ER) mannosidase I is compartmentalized and required for N-glycan trimming to Man5-6GlcNAc2 in glycoprotein ER-associated degradation.
  findings:
  - statement: ERManI is concentrated in the pericentriolar ER quality control compartment and is required for trimming to Man5-6GlcNAc2 and for ERAD in cells.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key in vivo evidence for ERQC localization and the ERAD/mannose-trimming requirement.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput membrane proteome; source of the generic membrane HDA annotation, peripheral to function.
- id: PMID:21062743
  title: Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B and to late endoplasmic reticulum-associated degradation steps.
  findings:
  - statement: ERManI-dependent mannose trimming is required to hand off substrate from EDEM1 to the late ERAD lectin XTP3-B and downstream HRD1/SCF(Fbs2) ligases.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Links ERManI trimming to specific downstream ERAD machinery.
- id: PMID:22160784
  title: In vitro mannose trimming property of human ER alpha-1,2 mannosidase I.
  findings:
  - statement: Recombinant hERManI generates Man6GlcNAc2 and Man5GlcNAc2 in vitro and preferentially removes mannoses from misfolded glycoproteins, indicating conformational selectivity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Demonstrates extended trimming and misfolding selectivity in vitro.
- id: PMID:24769233
  title: 'Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput CSF extracellular vesicle proteomics; source of the extracellular vesicle HDA annotation, peripheral to function.
- id: PMID:32958677
  title: The cytoplasmic tail of human mannosidase Man1b1 contributes to catalysis-independent quality control of misfolded alpha1-antitrypsin.
  findings:
  - statement: Beyond its luminal catalytic alpha-1,2-mannosidase activity, MAN1B1/ERManI contributes to ERAD of misfolded glycoproteins (NHK and Z variants of alpha1-antitrypsin) through an unconventional, catalysis-independent pathway controlled by its evolutionarily extended N-terminal cytoplasmic tail; this tail-dependent degradation does not require the substrate's N-glycans and drives proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:32958677, DOI 10.1073/pnas.1919013117). Establishes a second, catalysis-independent quality-control function of MAN1B1 mediated by its N-terminal cytoplasmic tail, distinct from the luminal mannose-trimming activity. Not cached; supporting_text not added to supported_by. Identified via Falcon deep research.
- id: PMID:25411339
  title: Mammalian ER mannosidase I resides in quality control vesicles, where it encounters its glycoprotein substrates.
  findings:
  - statement: ERManI resides at steady state in mobile ER-like quality control vesicles (QCVs) that deliver ERAD substrates and converge on the ERQC; the apparent Golgi pattern is a fixation artifact.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports cytoplasmic vesicle (QCV) localization and argues the Golgi localization is artifactual.
- id: Reactome:R-HSA-4793949
  title: Defective MAN1B1 does not hydrolyse 1,2-linked mannose (a branch)
  findings: []
- id: Reactome:R-HSA-901024
  title: MAN1B1 hydrolyses 1,2-linked mannose (a branch)
  findings: []
- id: Reactome:R-HSA-901032
  title: ER Quality Control Compartment (ERQC)
  findings: []
- id: Reactome:R-HSA-901036
  title: MAN1B1 hydrolyses a second 1,2-linked mannose (a branch)
  findings: []
- id: Reactome:R-HSA-901039
  title: MAN1B1 hydrolyses 1,2-linked mannose (c branch)
  findings: []
- id: Reactome:R-HSA-901074
  title: MAN1B1,EDEM2 hydrolyse 1,2-linked mannose (b branch)
  findings: []
- id: Reactome:R-HSA-9036008
  title: Defective MAN1B1 does not hydrolyse a second 1,2-linked mannose (a branch)
  findings: []
- id: Reactome:R-HSA-9036011
  title: Defective MAN1B1 does not hydrolyse 1,2-linked mannose (b branch)
  findings: []
- id: Reactome:R-HSA-9036012
  title: Defective MAN1B1 does not hydrolyse 1,2-linked mannose (c branch)
  findings: []
- id: Reactome:R-HSA-9694548
  title: Maturation of spike protein
  findings: []
- id: Reactome:R-HSA-9696807
  title: N-glycan mannose trimming of Spike
  findings: []
- id: file:human/MAN1B1/MAN1B1-uniprot.txt
  title: UniProt entry Q9UKM7 (MA1B1_HUMAN), Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase
  findings:
  - statement: Calcium-dependent GH47 alpha-1,2-mannosidase (EC 3.2.1.113) of the ER membrane (type II single-pass) that trims Man9GlcNAc2 to Man8GlcNAc2 isomer B and, at high concentration, to Man5-6GlcNAc2, targeting misfolded glycoproteins for ERAD; biallelic variants cause Rafiq syndrome/MAN1B1-CDG.
    reference_section_type: OTHER
core_functions:
- description: Endoplasmic reticulum membrane-anchored alpha-1,2-mannosidase that hydrolyzes terminal alpha-1,2-linked mannose residues from N-linked oligosaccharides, generating Man8GlcNAc2 isomer B and, at high local concentration, Man5-6GlcNAc2.
  molecular_function:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:10409699
    supporting_text: the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis
  - reference_id: file:human/MAN1B1/MAN1B1-uniprot.txt
    supporting_text: Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase
- description: Quality-control "mannose timer" that, by trimming N-glycans on misfolded glycoproteins in the ER/ERQC, removes them from the calnexin folding cycle and generates the demannosylated signal that commits them to ER-associated degradation.
  molecular_function:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  locations:
  - id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  supported_by:
  - reference_id: PMID:18003979
    supporting_text: required for trimming to Man 5–6 GlcNAc 2 and for ERAD in cells in vivo
  - reference_id: PMID:21062743
    supporting_text: Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
  - id: GO:1904380
    label: endoplasmic reticulum mannose trimming
proposed_new_terms: []
suggested_questions:
- question: What determines the conformational selectivity by which ERManI preferentially trims mannoses from misfolded versus correctly folded glycoproteins, and is this intrinsic to the enzyme or dependent on ERQC cofactors?
- question: How is the high local concentration of ERManI in quality control vesicles/ERQC regulated to tune the kinetics of the mannose timer?
suggested_experiments:
- description: Reconstitute ERManI trimming on defined folded versus misfolded glycoprotein substrates at controlled enzyme concentrations to quantify how local concentration and substrate conformation set the rate of progression from Man9 to Man5-6.
- description: Live-cell imaging of QCV/ERQC dynamics in cells expressing wild-type versus Rafiq-syndrome (R334C, E397K) MAN1B1 variants to test how disease mutations affect localization, vesicle trafficking, and ERAD substrate clearance.