id: Q15800
gene_symbol: MSMO1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Methylsterol monooxygenase 1 (also called C-4 methylsterol oxidase, SC4MOL, or
  ERG25) is a non-heme di-iron oxygenase of the endoplasmic reticulum membrane
  that catalyzes the sequential three-step oxidation of the C4-methyl group(s) of
  4,4-dimethyl and 4-alpha-methylsterols (methyl to alcohol, aldehyde, then
  carboxylate). This is the oxidative part of the C4-demethylation of sterols in
  cholesterol biosynthesis, and it works together with the C4-decarboxylase/
  3-dehydrogenase NSDHL. It is a multi-pass membrane protein belonging to the
  sterol desaturase / fatty acid hydroxylase family, with three histidine-box
  motifs that coordinate the di-iron center; it uses cytochrome b5 as the electron
  donor. Loss of function causes MSMO1 (SC4MOL) deficiency, an autosomal recessive
  disorder (microcephaly, congenital cataract, and psoriasiform dermatitis)
  characterized by accumulation of methylsterols.
alternative_products:
- name: '1'
  id: Q15800-1
- name: '2'
  id: Q15800-2
  sequence_note: VSP_044585
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) localization of MSMO1 to the endoplasmic reticulum
      membrane, consistent with UniProt and Reactome. MSMO1 is a multi-pass
      ER-membrane sterol oxidase.
    action: ACCEPT
    reason: >-
      The ER membrane is the well-established site of C4-methylsterol oxidation
      in cholesterol biosynthesis; the IBA call agrees with the UniProt
      subcellular location and multiple Reactome TAS annotations.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0036197
    label: zymosterol biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) involvement in zymosterol biosynthesis. MSMO1 performs
      the C4-demethylation steps between lanosterol and zymosterol, and UniProt
      places it at the zymosterol-from-lanosterol step of steroid biosynthesis.
    action: ACCEPT
    reason: >-
      Consistent with the pathway placement in UniProt (zymosterol biosynthesis;
      zymosterol from lanosterol step 3/6). This is a valid, more specific
      biosynthetic process for MSMO1's role.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: 'Steroid biosynthesis; zymosterol biosynthesis; zymosterol from'
- term:
    id: GO:0000254
    label: C-4 methylsterol oxidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of C-4 methylsterol oxidase activity, the
      core molecular function of MSMO1/SC4MOL/ERG25 across eukaryotes.
    action: ACCEPT
    reason: >-
      This is the defining molecular function of MSMO1, supported by experimental
      characterization of the human enzyme and its yeast ERG25 orthologue, and
      corroborated by EXP, IEA (RHEA/EC 1.14.18.9), and TAS annotations to the
      same term.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: demethylation of 4,4-dimethyl and 4alpha-methylsterols, which can be
- term:
    id: GO:0000254
    label: C-4 methylsterol oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (IEA) assignment of C-4 methylsterol oxidase activity via
      RHEA:55220 / EC 1.14.18.9 mapping, matching the experimentally established
      function.
    action: ACCEPT
    reason: >-
      The EC/RHEA mapping to EC 1.14.18.9 is correct for MSMO1; UniProt lists this
      EC number and the corresponding RHEA reaction as the catalytic activity of
      the enzyme.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: EC=1.14.18.9
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based (IEA) iron ion binding. MSMO1 is a non-heme di-iron
      oxygenase; its histidine-box motifs coordinate iron required for catalysis,
      and an Fe cation cofactor is documented.
    action: ACCEPT
    reason: >-
      Iron binding is essential to the C4-methylsterol oxidase mechanism; UniProt
      records an Fe cation cofactor and notes the histidine boxes are involved in
      metal ion binding, consistent with the InterPro mapping.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: The histidine box domains may contain the active site and/or be
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: 'Name=Fe cation'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Automated (IEA) ER membrane localization from the UniProt subcellular
      location keyword mapping, matching the curated ER-membrane location.
    action: ACCEPT
    reason: >-
      Redundant with, and consistent with, the UniProt subcellular location and
      the IBA/TAS ER-membrane annotations.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0008610
    label: lipid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based (IEA) lipid biosynthetic process. This is broadly correct
      (sterols are lipids) but far more general than MSMO1's specific role in
      cholesterol/sterol biosynthesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not wrong, but a high-level parent term; the more specific
      cholesterol/sterol biosynthetic process annotations capture the core
      function. Retained as non-core family-level context.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: demethylation of 4,4-dimethyl and 4alpha-methylsterols, which can be
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from high-throughput binary interactome mapping
      (HuRI) and IntAct, listing partners such as ERG28, CYP4F22, DNAJC30 and
      several TMEM proteins. Uninformative as a molecular function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" (GO:0005515) conveys no specific molecular function.
      The interactions derive from a genome-scale yeast two-hybrid/interactome
      screen; while an ERG28 interaction is biologically plausible (a scaffold for
      ER sterol enzymes), the term itself should not be treated as a core
      function. Retained (not removed) per curation policy for IPI protein-binding
      annotations.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions, or 'HuRI'
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807047
  qualifier: involved_in
  review:
    summary: >-
      Reactome TAS placing MSMO1 in cholesterol biosynthesis (Bloch pathway via
      desmosterol). MSMO1's C4-demethylation is a required step of cholesterol
      synthesis.
    action: ACCEPT
    reason: >-
      MSMO1 is an established cholesterol-biosynthetic enzyme; the pathway context
      is correct and central to its biology.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: 'Steroid biosynthesis; cholesterol biosynthesis.'
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      Automated (IEA) cholesterol biosynthetic process from UniPathway mapping,
      matching the curated pathway role.
    action: ACCEPT
    reason: >-
      Consistent with the UniProt cholesterol-biosynthesis pathway assignment and
      the Reactome TAS annotations.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: 'Steroid biosynthesis; cholesterol biosynthesis.'
- term:
    id: GO:0000254
    label: C-4 methylsterol oxidase activity
  evidence_type: EXP
  original_reference_id: PMID:21285510
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) C-4 methylsterol oxidase activity. He et al. identified
      SC4MOL/MSMO1 mutations causing an inborn error of cholesterol synthesis,
      with accumulation of C4-methylsterols, establishing the enzyme's demethylase
      function.
    action: ACCEPT
    reason: >-
      Direct experimental support for the core molecular function; the disease is
      caused by loss of C4-methylsterol oxidation and consequent methylsterol
      accumulation.
    supported_by:
    - reference_id: PMID:21285510
      supporting_text: catalyzes demethylation of C4-methylsterols in the cholesterol
- term:
    id: GO:0000254
    label: C-4 methylsterol oxidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194641
  qualifier: enables
  review:
    summary: >-
      Reactome TAS for C-4 methylsterol oxidase activity, describing the
      SC4MOL-catalyzed oxidation of 4,4-dimethylcholesta-8(9),24-dien-3beta-ol in
      the ER.
    action: ACCEPT
    reason: >-
      Correct core molecular function, redundant with the EXP and IBA annotations
      to the same term.
    supported_by:
    - reference_id: Reactome:R-HSA-194641
      supporting_text: is catalyzed by SC4MOL (C-4 methylsterol oxidase)
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807062
  qualifier: involved_in
  review:
    summary: >-
      Reactome TAS placing MSMO1 in cholesterol biosynthesis (Kandutsch-Russell /
      lathosterol pathway), the skin-prominent route to cholesterol.
    action: ACCEPT
    reason: >-
      MSMO1 acts in both the Bloch and Kandutsch-Russell branches of cholesterol
      biosynthesis; the pathway context is correct.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: 'Steroid biosynthesis; cholesterol biosynthesis.'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194641
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for ER-membrane localization, consistent with the curated
      subcellular location.
    action: ACCEPT
    reason: Correct compartment; redundant with IBA/IEA ER-membrane annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-194641
      supporting_text: This reaction, in the endoplasmic reticulum, is catalyzed by SC4MOL
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194669
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for ER-membrane localization (second demethylation reaction),
      consistent with the curated subcellular location.
    action: ACCEPT
    reason: Correct compartment; redundant with the other ER-membrane annotations.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9947203
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for ER-membrane localization (MSMO1 oxidation reaction),
      consistent with the curated subcellular location.
    action: ACCEPT
    reason: Correct compartment; redundant with the other ER-membrane annotations.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9947207
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for ER-membrane localization (MSMO1 oxidation reaction),
      consistent with the curated subcellular location.
    action: ACCEPT
    reason: Correct compartment; redundant with the other ER-membrane annotations.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0000254
    label: C-4 methylsterol oxidase activity
  evidence_type: TAS
  original_reference_id: PMID:8663358
  qualifier: enables
  review:
    summary: >-
      Older ProtInc TAS for C-4 methylsterol oxidase activity. Li and Kaplan
      identified the human ERG25 homologue (MSMO1) and characterized methyl sterol
      oxidase, establishing the function that is now supported experimentally.
    action: ACCEPT
    reason: >-
      Correct core molecular function; the human enzyme was identified as an ERG25
      (methyl sterol oxidase) homologue.
    supported_by:
    - reference_id: PMID:8663358
      supporting_text: the cloned gene was identical to ERG25, a gene that codes for
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:8663358
  qualifier: located_in
  review:
    summary: >-
      ProtInc TAS for endoplasmic reticulum localization. Immunofluorescence of
      the human ERG25 homologue placed it in the ER (and plasma membrane).
    action: ACCEPT
    reason: >-
      The ER assignment is correct and consistent with all later curation; it is a
      valid (if less specific) parent of ER membrane.
    supported_by:
    - reference_id: PMID:8663358
      supporting_text: the proteins are present in the endoplasmic
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:8663358
  qualifier: located_in
  review:
    summary: >-
      ProtInc TAS for plasma-membrane localization, based on 1996
      immunofluorescence of the human ERG25 homologue that reported both ER and
      plasma-membrane signal.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The plasma-membrane call comes from an early immunofluorescence study and is
      not supported by later, consistent ER-membrane localization in UniProt and
      Reactome. MSMO1 is a resident ER-membrane cholesterol-biosynthetic enzyme;
      retained (not removed) but flagged as likely over-annotation.
    supported_by:
    - reference_id: PMID:8663358
      supporting_text: the proteins are present in the endoplasmic
        reticulum and plasma membrane
- term:
    id: GO:0006631
    label: fatty acid metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8663358
  qualifier: involved_in
  review:
    summary: >-
      ProtInc TAS for fatty acid metabolic process. The 1996 study reported that
      iron-limited yeast erg25 mutants accumulated fatty acids, triglycerides, and
      sterol precursors, an indirect metabolic consequence rather than a direct
      MSMO1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      MSMO1 is a sterol C4-oxidase; the fatty-acid accumulation observed under
      iron limitation in yeast is a downstream/pleiotropic metabolic effect, not a
      fatty-acid-metabolic function of the enzyme. Not a core function.
    supported_by:
    - reference_id: PMID:8663358
      supporting_text: accumulation of fatty acids,
- term:
    id: GO:0008202
    label: steroid metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8663358
  qualifier: involved_in
  review:
    summary: >-
      ProtInc TAS for steroid metabolic process. Correct but a high-level parent
      of the specific sterol/cholesterol biosynthetic process that MSMO1
      participates in.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broadly accurate (sterols are steroids) but general; the specific
      cholesterol/sterol biosynthetic process annotations better capture the core
      role. Retained as non-core context.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: 'Steroid biosynthesis; cholesterol biosynthesis.'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:8663358
  qualifier: located_in
  review:
    summary: >-
      ProtInc TAS for the generic "membrane" location. MSMO1 is a multi-pass
      membrane protein, but the specific ER membrane term is more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Membrane" is uninformative given the well-supported ER membrane
      localization; superseded by GO:0005789. Retained but flagged as too general.
    supported_by:
    - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
      supporting_text: Multi-pass membrane protein
core_functions:
- description: >-
    C-4 methylsterol oxidase; catalyzes the sequential three-step oxidation of the
    C4-methyl group of 4,4-dimethyl and 4-alpha-methylsterols (the oxidative part
    of C4-demethylation) in the endoplasmic reticulum membrane as part of
    cholesterol biosynthesis, using a non-heme di-iron center.
  molecular_function:
    id: GO:0000254
    label: C-4 methylsterol oxidase activity
  supported_by:
  - reference_id: PMID:21285510
    supporting_text: catalyzes demethylation of C4-methylsterols in the cholesterol
  - reference_id: file:human/MSMO1/MSMO1-uniprot.txt
    supporting_text: demethylation of 4,4-dimethyl and 4alpha-methylsterols, which can be
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  contributes_to_molecular_function:
    id: GO:0005506
    label: iron ion binding
  locations:
  - id: GO:0005789
    label: 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:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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:21285510
  title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause
    psoriasiform dermatitis, microcephaly, and developmental delay.
  findings:
  - statement: >-
      SC4MOL/MSMO1 encodes a sterol-C4-methyl oxidase that catalyzes demethylation
      of C4-methylsterols in the cholesterol synthesis pathway; loss-of-function
      mutations cause an autosomal recessive syndrome with psoriasiform
      dermatitis, microcephaly, and developmental delay, with methylsterol
      accumulation.
    reference_section_type: ABSTRACT
    supporting_text: >-
      This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes
      demethylation of C4-methylsterols in the cholesterol synthesis pathway.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified index paper establishing MSMO1/SC4MOL function and disease
      (MCCPD). Abstract-only in cache; full text read by curators for EXP
      annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      MSMO1 protein-protein interactions are reported from the genome-scale HuRI
      binary interactome map; the individual partners are high-throughput hits
      rather than characterized functional complexes.
    reference_section_type: ABSTRACT
    supporting_text: reference interactome map of human binary protein interactions, or 'HuRI'
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Genome-scale binary interactome (HuRI); source of the uninformative bare
      protein-binding IPI annotations. Verified PMID/title against PubMed.
- id: PMID:8663358
  title: Characterization of yeast methyl sterol oxidase (ERG25) and identification
    of a human homologue.
  findings:
  - statement: >-
      The human MSMO1 gene was identified as a homologue of yeast ERG25 (methyl
      sterol oxidase); the protein is membrane bound and immunofluorescence placed
      it in the endoplasmic reticulum (and plasma membrane).
    reference_section_type: ABSTRACT
    supporting_text: the cloned gene was identical to ERG25, a gene that codes for
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original identification of the human ERG25 homologue (MSMO1); basis of the
      older ProtInc TAS annotations. Abstract-only in cache.
- id: Reactome:R-HSA-194641
  title: 4,4-dimethylcholesta-8(9),24-dien-3beta-ol is oxidized to 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol
  findings: []
- id: Reactome:R-HSA-194669
  title: 4-methylcholesta-8(9),24-dien-3beta-ol is oxidized to 4-carboxycholesta-8(9),24-dien-3beta-ol
  findings: []
- id: Reactome:R-HSA-6807047
  title: Cholesterol biosynthesis via desmosterol (Bloch pathway)
  findings: []
- id: Reactome:R-HSA-6807062
  title: Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)
  findings: []
- id: Reactome:R-HSA-9947203
  title: MSMO1 oxidizes 4,4-diMe-5-cholest-8-en-3-ol to 4a-carboxy-4b-me-5a-cholest-8-en-3b-ol
  findings: []
- id: Reactome:R-HSA-9947207
  title: MSMO1 oxidizes 4a-me-5a-cholest-8-en-3b-ol to 4a-carboxy-5a-cholest-8-ene-3b-ol
  findings: []
- id: file:human/MSMO1/MSMO1-uniprot.txt
  title: UniProtKB Q15800 (MSMO1_HUMAN) curated record
  findings: []