DHCR24

id: Q15392
gene_symbol: DHCR24
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DHCR24 encodes Delta(24)-sterol reductase (also known as seladin-1),
  the terminal enzyme in cholesterol biosynthesis that catalyzes the reduction of
  the delta-24 double bond of sterol intermediates, primarily converting desmosterol
  to cholesterol. The enzyme is FAD-dependent, requires NADPH as a cofactor, and is
  localized to the endoplasmic reticulum membrane. DHCR24 also confers neuroprotection
  against oxidative stress and amyloid-beta toxicity. Mutations in DHCR24 cause desmosterolosis,
  a rare autosomal recessive disorder of cholesterol biosynthesis characterized by
  multiple congenital anomalies and elevated desmosterol levels.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for cytoplasm is incorrect. DHCR24 is an integral ER membrane
      protein with its catalytic domain oriented toward the cytoplasm [PMID:11007892,
      PMID:22010141]. The cytoplasmic annotation reflects the cytoplasmic orientation
      of the catalytic domain rather than true cytoplasmic localization.
    action: REMOVE
    reason: This annotation incorrectly implies cytoplasmic localization
      when the protein is actually an integral ER membrane protein with a cytoplasmic-facing
      catalytic domain. The UniProt record and experimental evidence clearly establish
      ER membrane as the primary localization [PMID:11007892, PMID:22010141].
    supported_by:
    - reference_id: PMID:22010141
      supporting_text: We showed that full-length DHCR24 is localized to the membrane
        of ER, whereas the predicted transmembrane (TM) domain-deleted DHCR24 mutation
        is localized to the cytoplasm. The change of DHCR24 localization suggests
        that the N-terminal TM domain is essential for the ER membrane targeting of
        DHCR24.
- term:
    id: GO:0008202
    label: steroid metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for steroid metabolic process is accurate. DHCR24 is a
      key enzyme in cholesterol biosynthesis, which is part of steroid metabolism.
      The annotation is at an appropriate level of specificity given that cholesterol
      is the precursor for all steroid hormones.
    action: ACCEPT
    reason: DHCR24 clearly participates in steroid metabolism through its essential
      role in cholesterol biosynthesis. Cholesterol is both a steroid itself and the
      precursor for all steroid hormones. The IBA annotation is well-supported by
      experimental evidence [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: We identified the human DHCR24 cDNA, by the similarity between
        the encoded protein and a recently characterized plant enzyme—DWF1/DIM, from
        Arabidopsis thaliana —catalyzing a different but partially similar reaction
        in steroid/sterol biosynthesis in plants. Heterologous expression, in the
        yeast Saccharomyces cerevisiae, of the DHCR24 cDNA, followed by enzyme-activity
        measurements, confirmed that it encodes DHCR24
- term:
    id: GO:0000246
    label: Delta24(24-1) sterol reductase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for Delta24(24-1) sterol reductase activity is correct
      and represents a core molecular function. This term specifically describes the
      enzymatic activity of DHCR24 in reducing the delta-24 double bond in sterols,
      which is directly validated by experimental evidence [PMID:11519011].
    action: ACCEPT
    reason: This is the core molecular function of DHCR24, experimentally validated
      through multiple studies. The enzyme specifically catalyzes the reduction of
      the delta-24 double bond in sterol intermediates, including desmosterol, lanosterol,
      and zymosterol [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Conversion of desmosterol to cholesterol by DHCR24 in vitro
        is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate
        and is increased twofold by the addition of FAD to the assay
- term:
    id: GO:0050614
    label: Delta24-sterol reductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  review:
    summary: IEA annotation for Delta24-sterol reductase activity based on EC number
      mapping. This is essentially the same function as GO:0000246 but with slightly
      different terminology. Both terms correctly describe the core enzymatic function
      of DHCR24.
    action: ACCEPT
    reason: This annotation accurately describes the enzymatic activity of DHCR24.
      The term is based on EC:1.3.1.72 mapping which is experimentally validated [PMID:11519011].
      This is a duplicate of GO:0000246 with different terminology but both are correct.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: enzyme 3β-hydroxysterol Δ 24 -reductase (DHCR24), which, in
        cholesterol biosynthesis, catalyzes the reduction of the Δ 24 double bond
        of sterol intermediates
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation for Golgi membrane based on UniProt subcellular location
      vocabulary. DHCR24 is detected in Golgi to a lesser extent than ER, where
      cholesterol synthesis occurs [PMID:11007892].
    action: KEEP_AS_NON_CORE
    reason: Golgi localization occurs to a minor extent and is not the primary
      functionally relevant site. The ER membrane is the established primary location for DHCR24
      function in cholesterol biosynthesis. UniProt notes both localizations but emphasizes
      ER [PMID:11007892].
    supported_by:
    - reference_id: PMID:11007892
      supporting_text: subcellular fractionation and enzyme assays... seladin-1 is
        predominantly localized within the ER, and to a lesser amount in Golgi complexes
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation for endoplasmic reticulum membrane is accurate and represents
      the primary cellular localization. This is the established site where DHCR24
      performs its enzymatic function in cholesterol biosynthesis, confirmed by multiple
      experimental studies [PMID:11007892, PMID:22010141].
    action: ACCEPT
    reason: ER membrane is the correct and primary localization for DHCR24. This is
      where the enzyme performs its function in cholesterol biosynthesis. Multiple
      experimental studies confirm this localization [PMID:11007892, PMID:22010141].
    supported_by:
    - reference_id: PMID:11007892
      supporting_text: seladin-1 is predominantly localized within the ER, and to
        a lesser amount in Golgi complexes
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation for lipid metabolic process based on UniProt keyword mapping.
      This is accurate but very general. More specific terms like cholesterol biosynthetic
      process (GO:0006695) better describe the function.
    action: ACCEPT
    reason: While accurate, this is a very broad parent term. DHCR24 does participate
      in lipid metabolism through its role in cholesterol biosynthesis. However, more
      specific child terms provide better functional description.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: in cholesterol biosynthesis, catalyzes the reduction of the
        Δ 24 double bond of sterol intermediates
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation for steroid biosynthetic process is accurate. DHCR24 is
      essential for cholesterol biosynthesis, and cholesterol is both a steroid and
      the precursor for all steroid hormones.
    action: ACCEPT
    reason: DHCR24 directly participates in steroid biosynthesis through its essential
      role in producing cholesterol, which is a steroid molecule and the precursor
      for all steroid hormones [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: desmosterolosis is a cholesterol-biosynthesis disorder caused
        by mutations in DHCR24
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for cholesterol biosynthetic process is accurate and represents
      a core function. DHCR24 is the terminal enzyme in cholesterol biosynthesis,
      converting desmosterol to cholesterol [PMID:11519011].
    action: ACCEPT
    reason: This is a core biological process for DHCR24. The enzyme catalyzes the
      final step in cholesterol biosynthesis, converting desmosterol to cholesterol.
      This is experimentally validated [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Conversion of desmosterol to cholesterol by DHCR24 in vitro
        is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate
- term:
    id: GO:0008202
    label: steroid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Duplicate IEA annotation for steroid metabolic process (also annotated
      with IBA evidence). The annotation is accurate as DHCR24 participates in cholesterol/steroid
      metabolism.
    action: ACCEPT
    reason: Duplicate but accurate annotation. DHCR24 participates in steroid metabolism
      through cholesterol biosynthesis. The IBA version of this annotation was already
      accepted.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: cholesterol-biosynthesis disorder caused by mutations in DHCR24
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for cholesterol metabolic process is accurate. DHCR24
      is directly involved in cholesterol metabolism as the terminal enzyme in cholesterol
      biosynthesis.
    action: ACCEPT
    reason: DHCR24 is a key enzyme in cholesterol metabolism, specifically in the
      biosynthetic pathway. The annotation accurately captures this core function
      [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: enzyme 3β-hydroxysterol Δ 24 -reductase (DHCR24), which, in
        cholesterol biosynthesis, catalyzes the reduction of the Δ 24 double bond
        of sterol intermediates
- term:
    id: GO:0016126
    label: sterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation for sterol biosynthetic process is accurate. DHCR24 is
      essential for sterol biosynthesis, specifically in the final step of converting
      sterol intermediates to cholesterol.
    action: ACCEPT
    reason: DHCR24 is a key enzyme in sterol biosynthesis, catalyzing the reduction
      of the delta-24 double bond in various sterol intermediates including desmosterol,
      lanosterol, and zymosterol [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: catalyzes the reduction of the Δ 24 double bond of sterol intermediates
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation for oxidoreductase activity is accurate but very general.
      DHCR24 is indeed an oxidoreductase, specifically a FAD-dependent oxidoreductase
      that uses NADPH. More specific terms like GO:0016628 provide better functional
      description.
    action: ACCEPT
    reason: DHCR24 is a FAD-dependent oxidoreductase that catalyzes redox reactions
      using NADPH as electron donor. While accurate, more specific child terms better
      describe the function [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: member of a recently defined family of flavin adenine dinucleotide
        (FAD)-dependent oxidoreductases
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation for FAD binding based on InterPro domain mapping. This
      is accurate as DHCR24 contains a FAD-binding domain and FAD enhances its enzymatic
      activity [PMID:11519011].
    action: ACCEPT
    reason: DHCR24 is a FAD-dependent oxidoreductase with a conserved FAD-binding
      domain. Addition of FAD increases enzymatic activity twofold, suggesting noncovalent
      FAD binding [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Conversion of desmosterol to cholesterol by DHCR24 in vitro
        is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate
        and is increased twofold by the addition of FAD to the assay
- term:
    id: GO:0071949
    label: FAD binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Duplicate IEA annotation for FAD binding (same as GO:0050660). The annotation
      is accurate as DHCR24 is a FAD-dependent enzyme.
    action: ACCEPT
    reason: Duplicate of GO:0050660 but accurate. DHCR24 requires FAD as a cofactor
      for its oxidoreductase activity [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: member of a recently defined family of flavin adenine dinucleotide
        (FAD)-dependent oxidoreductases
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  review:
    summary: Generic protein binding annotation from a large-scale crosslinking mass
      spectrometry study of intact cell nuclei [PMID:30021884]. The WITH field indicates
      interaction with PGRMC1 (O00264). The DHCR24-PGRMC1 interaction was detected
      by crosslinking mass spectrometry (both are ER membrane proteins involved
      in sterol biology), but the generic protein binding term is uninformative.
    action: REMOVE
    reason: Protein binding without specificity is uninformative per curation guidelines.
      The interaction was detected in a high-throughput crosslinking study and the
      functional significance of the DHCR24-PGRMC1 interaction is not well
      characterized.
    supported_by:
    - reference_id: PMID:30021884
      supporting_text: Here we use crosslinking mass spectrometry (XL-MS) to chart
        the protein-protein interactions in intact human nuclei.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: Generic protein binding annotation from OpenCell high-throughput endogenous
      tagging study [PMID:35271311]. The WITH field indicates interaction with PGRMC1
      (O00264). While PGRMC1 is a known sterol-binding ER membrane protein, the
      generic protein binding term is uninformative per curation guidelines.
    action: REMOVE
    reason: Non-specific protein binding annotation from high-throughput study lacks
      functional context. The curation guidelines explicitly state to avoid this vague
      term. A more specific MF term should be used if the interaction is validated.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: We combined genome engineering, confocal live-cell imaging,
        mass spectrometry, and data science to systematically map the localization
        and interactions of human proteins.
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191273
  review:
    summary: TAS annotation from Reactome for cholesterol biosynthetic process. This
      is a core function of DHCR24 as the terminal enzyme in cholesterol biosynthesis.
    action: ACCEPT
    reason: DHCR24 is the terminal enzyme in cholesterol biosynthesis. This Reactome
      annotation accurately captures this core biological process [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: desmosterolosis is a cholesterol-biosynthesis disorder caused
        by mutations in DHCR24
- term:
    id: GO:0033489
    label: cholesterol biosynthetic process via desmosterol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807047
  review:
    summary: TAS annotation from Reactome for cholesterol biosynthesis via desmosterol.
      This is the primary pathway where DHCR24 functions, converting desmosterol to
      cholesterol in the Bloch pathway.
    action: ACCEPT
    reason: This specifically describes the Bloch pathway where DHCR24 catalyzes the
      conversion of desmosterol to cholesterol. This is the primary route and core
      function of DHCR24 [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Conversion of desmosterol to cholesterol by DHCR24 in vitro
        is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate
- term:
    id: GO:0033490
    label: cholesterol biosynthetic process via lathosterol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807062
  review:
    summary: TAS annotation from Reactome for cholesterol biosynthesis via lathosterol
      (Kandutsch-Russell pathway). DHCR24 can act on various sterol intermediates
      including those in this alternate pathway.
    action: ACCEPT
    reason: DHCR24 functions in both the Bloch and Kandutsch-Russell pathways of cholesterol
      biosynthesis. It can reduce the delta-24 double bond in various sterol intermediates
      [PMID:25637936].
    supported_by:
    - reference_id: PMID:25637936
      supporting_text: DHCR24 is positioned not only at the end of the Bloch pathway
        but also at the gateway of the Kandutsch-Russell pathway... able to act on
        any of the intermediates in the Bloch pathway to divert them into the Kandutsch-Russell
        pathway
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for Ras signaling transferred from orthologs. While DHCR24/seladin-1
      mediates response to Ras-induced senescence [PMID:15577914], this is a stress
      response function rather than core Ras signaling.
    action: KEEP_AS_NON_CORE
    reason: DHCR24/seladin-1 responds to oncogenic Ras stress but is not a core component
      of Ras signaling. It mediates Ras-induced senescence through p53 interactions
      [PMID:15577914]. This is a secondary, non-core function.
    supported_by:
    - reference_id: PMID:15577914
      supporting_text: Seladin-1 (also known as Dhcr24) as a key mediator of Ras-induced
        senescence. Following oncogenic and oxidative stress, Seladin-1 binds p53
        amino terminus
- term:
    id: GO:0008104
    label: intracellular protein localization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for intracellular protein localization from ortholog transfer.
      This is vague and lacks supporting evidence for DHCR24 having a role in localizing
      other proteins.
    action: REMOVE
    reason: No evidence that DHCR24 functions in protein localization. This appears
      to be an over-annotation from ortholog transfer without validation. The primary
      function is enzymatic in cholesterol biosynthesis.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: enzyme 3β-hydroxysterol Δ 24 -reductase (DHCR24), which, in
        cholesterol biosynthesis, catalyzes the reduction of the Δ 24 double bond
        of sterol intermediates
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for negative regulation of proliferation. DHCR24/seladin-1
      does mediate Ras-induced senescence and suppresses transformation [PMID:15577914],
      supporting an anti-proliferative role.
    action: KEEP_AS_NON_CORE
    reason: DHCR24/seladin-1 mediates oncogenic stress-induced senescence and suppresses
      cellular transformation [PMID:15577914]. This is a validated but non-core function
      distinct from its primary enzymatic role.
    supported_by:
    - reference_id: PMID:15577914
      supporting_text: Ablation of Seladin-1 causes the bypass of Ras-induced senescence
        in rodent and human fibroblasts, and allows Ras to transform these cells
- term:
    id: GO:0009725
    label: response to hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for response to hormone from ortholog transfer. This is
      too vague without specifying which hormones. Cholesterol biosynthesis is regulated
      by hormones but this annotation lacks specificity.
    action: REMOVE
    reason: Overly broad annotation without supporting evidence for specific hormone
      responses by DHCR24. While cholesterol biosynthesis is hormonally regulated,
      this vague annotation provides no functional insight.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: enzyme 3β-hydroxysterol Δ 24 -reductase (DHCR24), which, in
        cholesterol biosynthesis, catalyzes the reduction of the Δ 24 double bond
        of sterol intermediates
- term:
    id: GO:0009888
    label: tissue development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for tissue development from ortholog transfer. While DHCR24
      mutations cause developmental anomalies in desmosterolosis, this is an indirect
      effect of cholesterol deficiency.
    action: KEEP_AS_NON_CORE
    reason: DHCR24 deficiency causes developmental defects in desmosterolosis patients
      [PMID:11519011], but this is secondary to cholesterol deficiency rather than
      a direct developmental role. Non-core but valid consequence.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Desmosterolosis is a rare autosomal recessive disorder characterized
        by multiple congenital anomalies
- term:
    id: GO:0016125
    label: sterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for sterol metabolic process is accurate. DHCR24 is directly
      involved in sterol metabolism through its enzymatic activity on various sterol
      intermediates.
    action: ACCEPT
    reason: DHCR24 directly participates in sterol metabolism by catalyzing the reduction
      of the delta-24 double bond in multiple sterol intermediates [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: catalyzes the reduction of the Δ 24 double bond of sterol intermediates
- term:
    id: GO:0030539
    label: male genitalia development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for male genitalia development from ortholog transfer.
      While desmosterolosis can include urogenital anomalies, this is too specific
      and indirect.
    action: REMOVE
    reason: Over-specific developmental annotation. While desmosterolosis includes
      congenital anomalies, singling out male genitalia development is not supported
      as a specific function of DHCR24. This is an indirect effect of cholesterol
      deficiency.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Desmosterolosis is a rare autosomal recessive disorder characterized
        by multiple congenital anomalies
- term:
    id: GO:0031639
    label: plasminogen activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for plasminogen activation from ortholog transfer. No
      evidence supports DHCR24 involvement in plasminogen activation. This is
      an erroneous transfer.
    action: REMOVE
    reason: No evidence linking DHCR24 to plasminogen activation. This is
      an incorrect ortholog transfer. DHCR24 functions in cholesterol biosynthesis,
      not coagulation/fibrinolysis pathways.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: enzyme 3β-hydroxysterol Δ 24 -reductase (DHCR24), which, in
        cholesterol biosynthesis, catalyzes the reduction of the Δ 24 double bond
        of sterol intermediates
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for APP catabolism from ortholog transfer. While DHCR24/seladin-1
      protects against amyloid-beta toxicity [PMID:11007892], it does not directly
      catabolize APP.
    action: REMOVE
    reason: DHCR24/seladin-1 protects against amyloid-beta toxicity but does not catabolize
      APP. The protective effect is through reducing oxidative stress and caspase
      activation, not APP processing [PMID:11007892].
    supported_by:
    - reference_id: PMID:11007892
      supporting_text: Functional expression of seladin-1 in human neuroglioma H4
        cells resulted in the inhibition of caspase 3 activation after either Aβ-mediated
        toxicity or oxidative stress and protected the cells from apoptotic cell death
- term:
    id: GO:0043588
    label: skin development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for skin development from ortholog transfer. While cholesterol
      is important for skin barrier function, this is an indirect effect of DHCR24
      enzymatic activity.
    action: KEEP_AS_NON_CORE
    reason: Cholesterol biosynthesis is important for skin development and barrier
      function. DHCR24 deficiency can affect skin, but this is secondary to its enzymatic
      role. Non-core but valid indirect function.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Desmosterolosis is a rare autosomal recessive disorder characterized
        by multiple congenital anomalies
- term:
    id: GO:0061024
    label: membrane organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for membrane organization from ortholog transfer. While
      cholesterol is crucial for membrane structure, DHCR24 does not directly organize
      membranes.
    action: REMOVE
    reason: DHCR24 produces cholesterol which affects membrane properties, but the
      enzyme itself does not organize membranes. This is an over-interpretation of
      its indirect effects through cholesterol production.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: enzyme 3β-hydroxysterol Δ 24 -reductase (DHCR24), which, in
        cholesterol biosynthesis, catalyzes the reduction of the Δ 24 double bond
        of sterol intermediates
- term:
    id: GO:0050614
    label: Delta24-sterol reductase activity
  evidence_type: EXP
  original_reference_id: PMID:11519011
  review:
    summary: Experimental evidence for Delta24-sterol reductase activity from the
      key paper identifying DHCR24. This is the core molecular function, directly
      demonstrated through heterologous expression and enzyme activity measurements.
    action: ACCEPT
    reason: Direct experimental validation of DHCR24 enzymatic activity. The study
      used heterologous expression in yeast followed by enzyme activity measurements
      to confirm Delta24-sterol reductase activity [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Heterologous expression, in the yeast Saccharomyces cerevisiae,
        of the DHCR24 cDNA, followed by enzyme-activity measurements, confirmed that
        it encodes DHCR24
- term:
    id: GO:0050614
    label: Delta24-sterol reductase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9755937
  review:
    summary: TAS annotation from Reactome for Delta24-sterol reductase activity, specifically
      for lanosterol reduction. This is a validated core molecular function of DHCR24.
    action: ACCEPT
    reason: DHCR24 catalyzes the reduction of the delta-24 double bond in multiple
      sterols including lanosterol. This Reactome annotation correctly captures this
      enzymatic activity [PMID:11519011].
    supported_by:
    - reference_id: file:human/DHCR24/DHCR24-uniprot.txt
      supporting_text: Reaction=lanosterol + NADPH + H(+) = 24,25-dihydrolanosterol
        + NADP(+)
- term:
    id: GO:0000246
    label: Delta24(24-1) sterol reductase activity
  evidence_type: IMP
  original_reference_id: PMID:11519011
  review:
    summary: IMP evidence for Delta24(24-1) sterol reductase activity from mutant
      phenotype analysis. Mutations in DHCR24 cause desmosterolosis with accumulation
      of desmosterol, proving this enzymatic function.
    action: ACCEPT
    reason: Mutations in DHCR24 cause desmosterolosis with elevated desmosterol levels,
      directly demonstrating the enzyme's Delta24-sterol reductase activity through
      mutant phenotype [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Patients with desmosterolosis have elevated levels of the cholesterol
        precursor desmosterol, in plasma, tissue, and cultured cells; this abnormality
        suggests a deficiency of the enzyme 3β-hydroxysterol Δ 24 -reductase (DHCR24)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:11007892
  review:
    summary: NAS evidence for ER membrane localization from the seladin-1 paper. Subcellular
      fractionation confirmed predominant ER localization. This is the primary and
      functionally relevant cellular location.
    action: ACCEPT
    reason: Experimental subcellular fractionation demonstrated that seladin-1/DHCR24
      is predominantly localized to the ER membrane, where it performs its enzymatic
      function [PMID:11007892].
    supported_by:
    - reference_id: PMID:11007892
      supporting_text: subcellular fractionation and enzyme assays... seladin-1 is
        predominantly localized within the ER, and to a lesser amount in Golgi complexes
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:11519011
  review:
    summary: IMP evidence for cholesterol biosynthetic process from mutant phenotype.
      DHCR24 mutations cause desmosterolosis with defective cholesterol biosynthesis,
      proving this core function.
    action: ACCEPT
    reason: Mutations in DHCR24 cause desmosterolosis, a cholesterol biosynthesis
      disorder, directly demonstrating the enzyme's essential role in cholesterol
      biosynthesis [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Our data demonstrate that desmosterolosis is a cholesterol-biosynthesis
        disorder caused by mutations in DHCR24
- term:
    id: GO:0033489
    label: cholesterol biosynthetic process via desmosterol
  evidence_type: IMP
  original_reference_id: PMID:11519011
  review:
    summary: IMP evidence for cholesterol biosynthesis via desmosterol pathway. Patients
      with DHCR24 mutations accumulate desmosterol, proving this is the enzyme that
      converts desmosterol to cholesterol.
    action: ACCEPT
    reason: DHCR24 deficiency causes desmosterol accumulation, directly demonstrating
      its role in the desmosterol-to-cholesterol conversion in the Bloch pathway [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Patients with desmosterolosis have elevated levels of the cholesterol
        precursor desmosterol... Conversion of desmosterol to cholesterol by DHCR24
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25637936
  review:
    summary: IPI evidence for protein binding with DHCR7. While this specific DHCR7
      interaction is functionally important, the generic "protein binding" term should
      be avoided per curation guidelines.
    action: REMOVE
    reason: Generic protein binding annotation should be removed even for specific
      interactions. The functionally relevant DHCR7 interaction and its regulatory
      effect on enzyme activity is better captured by more specific functional terms.
    supported_by:
    - reference_id: PMID:25637936
      supporting_text: when the DHCR24 gene is knocked down by siRNA, DHCR7 activity
        is also ablated. Conversely, overexpression of DHCR24 enhances DHCR7 activity,
        but only when a functional form of DHCR24 is used
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-196417
  review:
    summary: TAS annotation from Reactome for ER membrane localization. This is the
      correct primary localization where DHCR24 performs its enzymatic function.
    action: ACCEPT
    reason: ER membrane is the established localization for DHCR24 where it catalyzes
      the conversion of desmosterol to cholesterol [PMID:11007892, PMID:22010141].
    supported_by:
    - reference_id: PMID:22010141
      supporting_text: The membrane topological analysis of 3β-hydroxysteroid-delta24
        reductase (DHCR24) on endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807064
  review:
    summary: Another TAS annotation from Reactome for ER membrane. This is a duplicate
      but correct annotation for the primary cellular localization.
    action: ACCEPT
    reason: Duplicate but accurate ER membrane localization annotation from Reactome.
      Multiple evidence sources confirm this localization [PMID:11007892].
    supported_by:
    - reference_id: PMID:11007892
      supporting_text: seladin-1 is predominantly localized within the ER
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9755937
  review:
    summary: Another TAS annotation from Reactome for ER membrane. Multiple Reactome
      pathways correctly place DHCR24 at the ER membrane.
    action: ACCEPT
    reason: Another duplicate but accurate ER membrane annotation. The ER is where
      DHCR24 performs its enzymatic function in cholesterol biosynthesis [PMID:11007892].
    supported_by:
    - reference_id: PMID:11007892
      supporting_text: seladin-1 is predominantly localized within the ER
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: HDA evidence for membrane localization from NK cell proteomics study.
      This is very general compared to the specific ER membrane localization established
      by other studies.
    action: ACCEPT
    reason: While less specific than ER membrane annotations, this high-throughput
      data confirms DHCR24 is membrane-associated, consistent with its ER membrane
      localization [PMID:19946888].
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: Defining the membrane proteome of NK cells
- term:
    id: GO:0016628
    label: oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP
      as acceptor
  evidence_type: IDA
  original_reference_id: PMID:11519011
  review:
    summary: IDA evidence for specific oxidoreductase activity. This accurately describes
      DHCR24 mechanism - it reduces C-C double bonds (delta-24) using NADPH as electron
      donor.
    action: ACCEPT
    reason: Direct experimental demonstration that DHCR24 is an oxidoreductase acting
      on CH-CH groups (the delta-24 double bond) with NADPH as acceptor. This is more
      specific than general oxidoreductase activity [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Conversion of desmosterol to cholesterol by DHCR24 in vitro
        is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for cholesterol biosynthetic process based on sequence
      similarity. This is a duplicate annotation but correctly identifies a core function.
    action: ACCEPT
    reason: Sequence similarity-based annotation that correctly identifies DHCR24
      role in cholesterol biosynthesis. This is validated by experimental evidence
      [PMID:11519011].
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: desmosterolosis is a cholesterol-biosynthesis disorder caused
        by mutations in DHCR24
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:15577914
  review:
    summary: IPI evidence for enzyme binding from the seladin-1 stress response paper.
      DHCR24/seladin-1 binds to Mdm2 (an E3 ubiquitin ligase) to regulate p53. This
      is a non-core stress response function.
    action: KEEP_AS_NON_CORE
    reason: DHCR24/seladin-1 binds the E3 ubiquitin ligase Mdm2 during stress response,
      affecting p53 regulation. This is a validated but non-core function distinct
      from its primary enzymatic role [PMID:15577914].
    supported_by:
    - reference_id: PMID:15577914
      supporting_text: Seladin-1 binds p53 amino terminus and displaces E3 ubiquitin
        ligase Mdm2 from p53... Additionally, Seladin-1 associates with Mdm2 independently
        of p53
- term:
    id: GO:0043588
    label: skin development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for skin development based on sequence similarity. While
      cholesterol is important for skin, this is an indirect effect of DHCR24 enzymatic
      function.
    action: KEEP_AS_NON_CORE
    reason: Cholesterol biosynthesis impacts skin development and barrier function.
      DHCR24 deficiency can cause skin abnormalities, but this is secondary to its
      enzymatic role. Non-core indirect function.
    supported_by:
    - reference_id: PMID:11519011
      supporting_text: Desmosterolosis is a rare autosomal recessive disorder characterized
        by multiple congenital anomalies
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:15577914
  review:
    summary: IDA evidence for nuclear localization from stress response study.
      DHCR24/seladin-1 translocates to the nucleus during oncogenic and oxidative
      stress [PMID:15577914], though the primary functional localization is ER membrane.
    action: KEEP_AS_NON_CORE
    reason: DHCR24/seladin-1 can localize to nucleus during stress response to interact
      with p53/Mdm2, but this is not the primary localization. Main function occurs
      at ER membrane [PMID:15577914, PMID:11007892].
    supported_by:
    - reference_id: PMID:15577914
      supporting_text: Following oncogenic and oxidative stress, Seladin-1 binds p53
        amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:11007892
  review:
    summary: IDA evidence for ER localization from the seladin-1 paper. This is the
      correct primary localization, though ER membrane (GO:0005789) is more specific.
    action: ACCEPT
    reason: Direct experimental evidence for ER localization through subcellular fractionation.
      The more specific ER membrane term is also annotated [PMID:11007892].
    supported_by:
    - reference_id: PMID:11007892
      supporting_text: subcellular fractionation and enzyme assays... seladin-1 is
        predominantly localized within the ER
- term:
    id: GO:0009888
    label: tissue development
  evidence_type: IMP
  original_reference_id: PMID:12457401
  review:
    summary: IMP evidence for tissue development from a desmosterolosis case report
      showing developmental delay and anomalies. This is an indirect effect of cholesterol
      deficiency rather than a direct developmental role.
    action: KEEP_AS_NON_CORE
    reason: DHCR24 deficiency causes developmental anomalies in desmosterolosis due
      to cholesterol deficiency. This is an indirect consequence rather than a direct
      developmental function [PMID:12457401].
    supported_by:
    - reference_id: PMID:12457401
      supporting_text: Desmosterolosis presenting with multiple congenital anomalies
        and profound developmental delay
- term:
    id: GO:0042605
    label: peptide antigen binding
  evidence_type: IPI
  original_reference_id: PMID:15577914
  review:
    summary: IPI evidence for peptide antigen binding from the seladin-1 stress response
      study [PMID:15577914]. The WITH field shows UniProtKB:P04637 (p53), indicating
      the annotation was made based on seladin-1 binding the p53 N-terminus.
      However, this interaction is protein-protein binding to p53 during stress
      response, not peptide antigen binding in an immunological sense. The GO term
      peptide antigen binding (GO:0042605) refers to binding of antigenic peptides
      for immune presentation, which does not describe the DHCR24-p53 interaction.
    action: REMOVE
    reason: This is a misannotation. PMID:15577914 describes DHCR24/seladin-1
      binding to the p53 amino terminus during oncogenic and oxidative stress, displacing
      Mdm2. This is a protein-protein interaction, not peptide antigen binding in the
      immunological sense. No MHC or antigen presentation function is described.
    supported_by:
    - reference_id: PMID:15577914
      supporting_text: Following oncogenic and oxidative stress, Seladin-1 binds p53
        amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53, thus
        resulting in p53 accumulation.
core_functions:
- description: Catalyzes the reduction of the delta-24 double bond in sterol intermediates
    using NADPH and FAD as cofactors, converting desmosterol to cholesterol as the
    terminal step of cholesterol biosynthesis
  molecular_function:
    id: GO:0050614
    label: Delta24-sterol reductase activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  - id: GO:0033489
    label: cholesterol biosynthetic process via desmosterol
  - id: GO:0033490
    label: cholesterol biosynthetic process via lathosterol
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  substrates:
  - id: CHEBI:17737
    label: desmosterol
  - id: CHEBI:16521
    label: lanosterol
  - id: CHEBI:18252
    label: zymosterol
- description: Positively regulates DHCR7 oxidoreductase activity through direct protein
    interaction, enhancing 7-dehydrocholesterol reductase function in cholesterol
    biosynthesis
  supported_by:
  - reference_id: PMID:25637936
    supporting_text: when the DHCR24 gene is knocked down by siRNA, DHCR7 activity
      is also ablated. Conversely, overexpression of DHCR24 enhances DHCR7 activity
  molecular_function:
    id: GO:0050614
    label: Delta24-sterol reductase activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  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:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  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:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara.
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods.
  findings: []
- id: PMID:11007892
  title: The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's
    disease-associated neurodegeneration and oxidative stress.
  findings: []
- id: PMID:11519011
  title: Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis,
    an autosomal recessive disorder of cholesterol biosynthesis.
  findings: []
- id: PMID:12457401
  title: Desmosterolosis presenting with multiple congenital anomalies and profound
    developmental delay.
  findings: []
- id: PMID:15577914
  title: Regulation of cellular response to oncogenic and oxidative stress by Seladin-1.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:25637936
  title: The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact
    physically and functionally.
  findings: []
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
    in Intact Cell Nuclei.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: Reactome:R-HSA-191273
  title: Cholesterol biosynthesis
  findings: []
- id: Reactome:R-HSA-196417
  title: Reduction of desmosterol to cholesterol
  findings: []
- id: Reactome:R-HSA-6807047
  title: Cholesterol biosynthesis via desmosterol
  findings: []
- id: Reactome:R-HSA-6807062
  title: Cholesterol biosynthesis via lathosterol
  findings: []
- id: Reactome:R-HSA-6807064
  title: DHCR24 reduces ZYMOL to ZYMSTNL
  findings: []
- id: Reactome:R-HSA-9755937
  title: DHCR24 reduces LAN to 24,25-dhLAN
  findings: []
suggested_questions:
- question: How does DHCR24 coordinate cholesterol biosynthesis with membrane homeostasis
    and cellular sterol requirements?
- question: What are the regulatory mechanisms that control DHCR24 expression and
    activity in response to sterol levels?
- question: How do mutations in DHCR24 lead to desmosterolosis and what
    are the developmental consequences of altered sterol metabolism?
- question: What determines the subcellular localization of DHCR24 and how does this
    affect its function in sterol metabolism?
suggested_experiments:
- description: Lipidomics analysis to characterize the complete sterol profile in
    DHCR24-deficient cells and tissues
- description: Live-cell imaging using fluorescent sterol analogs to track cholesterol
    metabolism and membrane distribution in real-time
- description: Cryo-EM structure determination of DHCR24 to understand the molecular
    basis of sterol reduction and enzyme specificity
- description: Developmental analysis of DHCR24 mutant model organisms to study the
    role of cholesterol in embryogenesis and organogenesis
status: COMPLETE