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Showing MSMO1 — SC4MOL is a alias.

MSMO1

Methylsterol monooxygenase 1 · UniProt Q15800

Length
293 aa
Mass
35.2 kDa
Annotated
2026-06-10
28 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MSMO1 (SC4MOL/ERG25) is an endoplasmic reticulum-resident, membrane-bound sterol C-4 methyl oxidase that catalyzes the first step in removal of the C-4 methyl groups during cholesterol/ergosterol biosynthesis, acting downstream of lanosterol on 4,4-dimethylzymosterol (PMID:8552601, PMID:9326581). Functional studies in fungal orthologs establish that the enzyme carries histidine-rich clusters characteristic of nonheme iron membrane oxidases and a C-terminal ER retrieval signal, and that these histidine residues are essential for catalytic activity (PMID:8552601, PMID:10783002, PMID:12546417). The human enzyme localizes to the ER, removes C4-methylsterols (meiosis-activating sterols), and its loss-of-function causes accumulation of these methylsterols that act as ligands for liver X receptors LXRα/β, driving cell overproliferation and immune dysfunction in a multisystem human syndrome (PMID:8663358, PMID:21285510). MSMO1 is the most tightly regulated enzyme of the C4-demethylation step: its protein is rapidly turned over by ERAD and MARCHF6-mediated ubiquitination in response to sterol levels, while its transcript is controlled by SREBP-2 and by METTL16/IGF2BP2 m6A modification, and knockdown lowers total cellular cholesterol (PMID:12667960, PMID:32868373, PMID:36958722, PMID:41845506). Accumulation of its 8,9-unsaturated sterol substrates promotes oligodendrocyte differentiation, and MSMO1 expression modulates adipogenesis and tumor cell behavior through downstream cholesterol-homeostasis and stress-signaling axes (PMID:35128409, PMID:30582412, PMID:39950465).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 High

    Established the enzymatic identity and catalytic mechanism of the gene by showing the yeast ortholog ERG25 is the C-4 sterol methyl oxidase acting on 4,4-dimethylzymosterol, and that the human homolog exists and is ER-localized.

    Evidence Genetic complementation, disruptant sterol profiling, and sequence analysis in yeast; cloning, mapping, Western, immunofluorescence, and fractionation for the human homolog

    PMID:8552601 PMID:8663358

    Open questions at the time
    • Direct demonstration of nonheme iron coordination was inferred from sequence motifs, not measured
    • The two human protein species (34 and 75 kDa) were not mechanistically resolved
    • No reconstituted enzymatic assay of the human protein
  2. 2002 Medium

    Defined which residues are required for catalysis, confirming the functional importance of the histidine-rich clusters and specific point positions through conditional-lethal alleles.

    Evidence Random mutagenesis generating temperature-sensitive erg25 alleles (e.g. N48D, V133A, F135S) with substrate accumulation readout in Candida and S. cerevisiae

    PMID:10783002 PMID:12546417

    Open questions at the time
    • Residue-level mapping done in fungal orthologs, not human MSMO1
    • No structural model of the active site
  3. 1997 High

    Placed the enzyme at a defined position in the sterol pathway, demonstrating it acts downstream of lanosterol.

    Evidence Genetic epistasis and suppressor analysis with heme/erg11 mutations and sterol profiling in S. cerevisiae

    PMID:9326581

    Open questions at the time
    • Pathway ordering established in yeast
    • Did not address regulation of the enzyme
  4. 2003 Medium

    Identified transcriptional control of the gene by linking its expression to the SREBP-2 sterol-sensing program.

    Evidence RT-PCR, Western, EMSA, SREBP-2 overexpression rescue, and SREBP-catabolism inhibitor in vascular cells

    PMID:12667960

    Open questions at the time
    • Direct SREBP-2 binding to the MSMO1 promoter not mapped
    • Single cell-type context
  5. 2011 High

    Connected enzyme loss-of-function to human disease and a signaling mechanism, showing accumulated C4-methylsterols act as LXR ligands driving overproliferation and immune dysfunction.

    Evidence Patient mutation identification, biochemical sterol analysis, proliferation and immunocyte functional assays

    PMID:21285510

    Open questions at the time
    • Tissue-specific contributions of LXR activation not fully dissected
    • Did not address protein-level regulation
  6. 2020 High

    Revealed post-translational regulation of the enzyme by demonstrating it is an ERAD substrate whose turnover tracks sterol synthesis.

    Evidence Substrate-trapping proteomics, ubiquitination assays, and genetic epistasis with ERAD ubiquitin ligase mutants in yeast

    PMID:32868373

    Open questions at the time
    • Specific ubiquitin ligase identity established in yeast, not human
    • Degradation signal on the protein not mapped
  7. 2021 High

    Established a cell-fate consequence of substrate accumulation, showing the enzyme's 8,9-unsaturated sterol substrates promote oligodendrocyte differentiation.

    Evidence Genetic suppression, selective inhibitor (CW4142), exogenous sterol rescue distinguishing saturated vs unsaturated analogs, and in vivo brain sterol profiling

    PMID:35128409

    Open questions at the time
    • Receptor/effector mediating the differentiation response not defined
    • Link to LXR vs other sterol sensors not resolved
  8. 2023 High

    Identified the human E3 ligase and reciprocal sterol-dependent protein/transcript regulation, naming MSMO1 the most regulated enzyme of the C4-demethylation complex.

    Evidence siRNA knockdown, sterol manipulation, protein stability and cholesterol assays in human and CHO cells; MARCHF6 identified as the E3 ligase

    PMID:36958722

    Open questions at the time
    • MARCHF6 recognition determinants on MSMO1 not mapped
    • Interplay between ERAD and MARCHF6 pathways not reconciled
  9. 2026 Medium

    Added an RNA-level regulatory layer and a disease-signaling output, showing METTL16/IGF2BP2 m6A modification stabilizes MSMO1 mRNA and that elevated MSMO1 drives ER stress and inflammatory signaling.

    Evidence MeRIP-seq/qPCR, RIP, Co-IP, IP-MS, RNA stability assays, and xenografts in colorectal cancer cells

    PMID:41845506

    Open questions at the time
    • Causal chain from MSMO1 elevation to TAK1/TAB activation is correlative in part
    • Single tumor context

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MSMO1 substrate accumulation is decoded into distinct downstream outcomes (LXR activation, oligodendrocyte differentiation, ER-stress/MAPK signaling, AKT/PI3K activity) across tissues remains unresolved.
  • No unified model linking specific sterol species to specific effector pathways
  • Human active-site structure and direct iron coordination unconfirmed
  • Tissue-specific regulatory and signaling wiring not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0016787 hydrolase activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1430728 Metabolism 4
Partners
IGF2BP2MARCHF6METTL16NSDHL
Complex memberships
C4-demethylation complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 ERG25 (yeast ortholog of MSMO1) encodes a C-4 sterol methyl oxidase that catalyzes the first of three enzymatic steps required to remove the two C-4 methyl groups in sterol biosynthesis. The protein contains a C-terminal ER retrieval signal (KKXX) and three histidine-rich clusters found in eukaryotic membrane desaturases and bacterial alkane hydroxylases, consistent with a nonheme iron-binding mechanism. Disruption of ERG25 leads to accumulation of 4,4-dimethylzymosterol. Genetic complementation, mutagenesis, sterol profile analysis by disruption mutant Proceedings of the National Academy of Sciences of the United States of America High 8552601
1996 The human homolog of ERG25 (MSMO1/SC4MOL) was cloned, sequenced, and mapped to chromosome 4q32-34. Western analysis showed two proteins of 34 and 75 kDa; both are membrane-bound and contain one N-glycosyl unit. Immunofluorescence localized the proteins to the endoplasmic reticulum and plasma membrane. ERG25 protein levels are regulated by an end product of the ergosterol pathway rather than by iron. Western blot, immunofluorescence, subcellular fractionation, glycosylation analysis The Journal of biological chemistry Medium 8663358
2000 A temperature-sensitive point mutation within the histidine-cluster region of Candida albicans Erg25p (ortholog of MSMO1) causes conditional lethality, confirming that the histidine-rich clusters are functionally essential for C-4 sterol methyl oxidase activity. Random mutagenesis, temperature-sensitive allele rescue, sequence analysis Lipids Medium 10783002
2002 Temperature-sensitive erg25 mutations including substitutions N48D, V133A, and F135S cause accumulation of 4,4-dimethylzymosterol at non-permissive temperature, confirming ERG25 is required for C-4 demethylation and that these residues are important for enzyme function. Random mutagenesis, sterol profiling at non-permissive temperature The Journal of antibiotics Medium 12546417
1997 Genetic epistasis analysis in S. cerevisiae shows that erg25 auxotrophy can be suppressed by combining erg11 with leaky heme biosynthesis mutations (slu1/slu2, alleles of HEM2 and HEM4), resulting in accumulation of lanosterol which supports growth. This places ERG25 downstream of lanosterol in the ergosterol pathway and demonstrates that lanosterol can substitute for ergosterol under these conditions. Genetic epistasis, suppressor screen, sterol profiling Proceedings of the National Academy of Sciences of the United States of America High 9326581
2011 Loss-of-function mutations in human SC4MOL (MSMO1) cause accumulation of C4-methylsterols (meiosis-activating sterols, MASs). These accumulated MASs act as ligands for liver X receptors LXRα and LXRβ, leading to cell overproliferation in skin and blood and substantially altered immunocyte phenotype and in vitro function. This establishes MSMO1 as the enzyme catalyzing C4-methylsterol demethylation in human cholesterol synthesis. Patient mutation identification, biochemical sterol analysis, cell proliferation assays, immunocyte functional assays The Journal of clinical investigation High 21285510
2003 ERG25/SC4MOL expression in vascular endothelial and smooth muscle cells is downregulated by LDL in a time- and dose-dependent manner. This downregulation is mediated through SREBP-2: LDL reduces SREBP-2 mRNA, and overexpression of SREBP-2 blocks LDL-induced ERG25 downregulation. An inhibitor of SREBP catabolism abolishes LDL-induced ERG25 downregulation. RT-PCR, Western blot, EMSA, transient transfection with SREBP-2 overexpression, pharmacological inhibitor Cardiovascular research Medium 12667960
2020 Yeast Erg25 (ortholog of MSMO1) is a substrate for ER-associated degradation (ERAD): it is ubiquitinated, associates with stalled proteasomes, and its degradation depends on ERAD-associated ubiquitin ligases. Its turnover is regulated by sterol synthesis levels. Substrate trapping proteomics, affinity isolation, LC-MS/MS, ubiquitination assay, genetic epistasis with ERAD ubiquitin ligase mutants Molecular & cellular proteomics : MCP High 32868373
2023 Human SC4MOL (MSMO1) protein is rapidly turned over and is a substrate of the E3 ubiquitin ligase MARCHF6. Sterol depletion stabilizes SC4MOL protein levels, while sterol excess downregulates both SC4MOL transcript and protein. SC4MOL depletion by siRNA causes a significant decrease in total cellular cholesterol, identifying it as the most regulated enzyme in the C4-demethylation complex. siRNA knockdown, sterol manipulation, protein stability assays, cholesterol measurement in cultured mammalian cells (human and CHO) Journal of lipid research High 36958722
2021 Genetic suppression of SC4MOL (MSMO1) increases oligodendrocyte formation from progenitor cells. The mechanism involves cellular accumulation of SC4MOL's 8,9-unsaturated sterol substrates, as exogenous addition of purified SC4MOL substrates (but not their 8,9-saturated analogs) promotes oligodendrocyte differentiation. A selective SC4MOL inhibitor (CW4142) induces accumulation of SC4MOL's sterol substrates in mouse brain in vivo. Genetic suppression, small-molecule inhibitors, exogenous sterol addition, in vivo brain sterol profiling RSC chemical biology High 35128409
2018 MSMO1 overexpression inhibits 3T3-L1 adipogenesis and downregulates adipogenic marker genes, while MSMO1 knockdown has the opposite effect. MSMO1 and its partner NSDHL show a synergized (co-regulated) expression pattern during adipogenesis. Overexpression, siRNA knockdown, RNA-Seq, Oil Red O staining, adipogenic marker gene expression Bioscience, biotechnology, and biochemistry Medium 30582412
2026 METTL16 methyltransferase adds m6A modifications to MSMO1 mRNA, stabilizing the transcript via the reader protein IGF2BP2. Elevated MSMO1 disrupts intracellular cholesterol homeostasis, triggering ER stress and activating MAPK-p38/NF-κB signaling by promoting TAK1/TAB complex formation and TAK1 autophosphorylation in colorectal cancer cells. MeRIP-seq, MeRIP-qPCR, RIP, co-immunoprecipitation, IP-MS, RNA stability assays, RNA-seq, xenograft models Journal of experimental & clinical cancer research : CR Medium 41845506
2026 MSMO1 regulates the metabolism of 14-demethyllanosterol (T-MAS), and elevated MSMO1 contributes to chemotherapy resistance in breast cancer via the PERK/eIF2α/ATF4/CHOP signaling pathway. Exosome liquid biopsy transcriptomics, in vitro functional assays, pathway inhibition experiments iScience Low 41782822
2023 miR-19b-3p directly targets MSMO1 mRNA (validated by dual luciferase reporter assay), reducing MSMO1 protein levels. Estrogen directly promotes MSMO1 transcription via estrogen receptor α (ERα) and also upregulates MSMO1 indirectly by suppressing miR-19b-3p. In LMH cells, MSMO1 targeting by miR-19b-3p decreases intracellular cholesterol content. Dual luciferase reporter assay, Western blot, miRNA overexpression/knockdown, estrogen receptor antagonist treatment, site-directed mutation of ERα binding site Poultry science Medium 37939591
2025 miR-584-5p directly targets MSMO1 mRNA (validated by luciferase reporter assay). MSMO1 overexpression enhances breast cancer cell migration and invasion, and silencing MSMO1 diminishes AKT pathway activity, placing MSMO1 upstream of AKT/PI3K signaling. Luciferase reporter assay, Western blotting, siRNA knockdown, overexpression, in vivo xenograft Protein and peptide letters Medium 39950465

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Cloning and characterization of ERG25, the Saccharomyces cerevisiae gene encoding C-4 sterol methyl oxidase. Proceedings of the National Academy of Sciences of the United States of America 137 8552601
2011 Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay. The Journal of clinical investigation 88 21285510
1996 Characterization of yeast methyl sterol oxidase (ERG25) and identification of a human homologue. The Journal of biological chemistry 87 8663358
1997 A yeast sterol auxotroph (erg25) is rescued by addition of azole antifungals and reduced levels of heme. Proceedings of the National Academy of Sciences of the United States of America 42 9326581
2014 Two C4-sterol methyl oxidases (Erg25) catalyse ergosterol intermediate demethylation and impact environmental stress adaptation in Aspergillus fumigatus. Microbiology (Reading, England) 39 25107308
2003 Modulation of ERG25 expression by LDL in vascular cells. Cardiovascular research 27 12667960
2018 RNA-Seq analysis reveals a negative role of MSMO1 with a synergized NSDHL expression during adipogenesis of 3T3-L1. Bioscience, biotechnology, and biochemistry 23 30582412
2000 Cloning and sequencing of the Candida albicans C-4 sterol methyl oxidase gene (ERG25) and expression of an ERG25 conditional lethal mutation in Saccharomyces cerevisiae. Lipids 20 10783002
2022 Down-regulation of MSMO1 promotes the development and progression of pancreatic cancer. Journal of Cancer 19 36046654
2023 Cholesterol synthesis enzyme SC4MOL is fine-tuned by sterols and targeted for degradation by the E3 ligase MARCHF6. Journal of lipid research 18 36958722
2023 miR-19b-3p regulated by estrogen controls lipid synthesis through targeting MSMO1 and ELOVL5 in LMH cells. Poultry science 14 37939591
2020 New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis. Cytogenetic and genome research 14 33161406
2022 Erg25 Controls Host-Cholesterol Uptake Mediated by Aus1p-Associated Sterol-Rich Membrane Domains in Candida glabrata. Frontiers in cell and developmental biology 13 35399500
2021 Inhibition of SC4MOL and HSD17B7 shifts cellular sterol composition and promotes oligodendrocyte formation. RSC chemical biology 12 35128409
2022 MAGEA6 positively regulates MSMO1 and promotes the migration and invasion of oesophageal cancer cells. Experimental and therapeutic medicine 11 35126707
2024 Identifying MSMO1, ELOVL6, AACS, and CERS2 related to lipid metabolism as biomarkers of Parkinson's disease. Scientific reports 10 39080336
2025 miR-584-5p Regulates MSMO1 to Modulate the AKT/PI3K Pathway and Inhibit Breast Cancer Progression. Protein and peptide letters 8 39950465
2023 MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly. Clinical dysmorphology 5 37195326
2020 The Capture of a Disabled Proteasome Identifies Erg25 as a Substrate for Endoplasmic Reticulum Associated Degradation. Molecular & cellular proteomics : MCP 5 32868373
2024 Nickel tolerance is channeled through C-4 methyl sterol oxidase Erg25 in the sterol biosynthesis pathway. PLoS genetics 2 39283915
2023 Evaluation of Antifungal Selective Toxicity Using Candida glabrata ERG25 and Human SC4MOL Knock-In Strains. Journal of fungi (Basel, Switzerland) 2 37888291
2002 Isolation of temperature-sensitive Saccharomyces cerevisiae with a mutation in erg25 for C-4 sterol methyl oxidase. The Journal of antibiotics 1 12546417
2026 Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review. Reports (MDPI) 0 41718295
2026 MSMO1 promotes chemotherapy resistance through modulation of T-MAS metabolism via PERK/elF2α/ATF4/CHOP pathway. iScience 0 41782822
2026 METTL16-mediated m6A modification of MSMO1 modulates cholesterol metabolism and activates MAPK-p38/NF-κB signaling in colorectal cancer. Journal of experimental & clinical cancer research : CR 0 41845506
2026 Effects of the androstenedione-MSMO1 axis on proliferation, apoptosis, and steroid hormone synthesis and secretion in porcine granulosa cells. Animal reproduction science 0 41903379
2025 CRISPR-Cas9 RNP-Mediated Deletion of ERG25 in Non-albicans Candida Species, Including Candida auris. Medical mycology journal 0 40451886
2025 P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use. The British journal of dermatology 0 41413001

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