Component

HMG-CoA reductase (HMGCR)

Human HMG-CoA reductase studied in HepG2 cells.

8 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

  1. Human HMG-CoA reductase catalyzes mevalonate formation; substrate/cofactor-bound structures locate HMG-CoA and the nicotinamide cofactor in the catalytic domain.

    HMG-CoA reductase (HMGCR) → Mevalonate source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Human recombinant catalytic-domain crystallography and biochemical background.
    limitations
    Shared human machinery; the source is not an experiment administering red yeast rice.
    nutrient_topic
    Red yeast rice collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Red yeast rice
    plain_language
    This enzyme supplies a shared precursor pathway.
    primary_references
    [10698924] Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10698924/ · DOI 10.1093/emboj/19.5.819

    Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 76–82

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant catalytic-domain crystallography and biochemical background. · source_derived_draft · unverified_draft

    ## red-yeast-rice-human-mevalonate-machinery This enzyme supplies a shared precursor pathway. Human HMG-CoA reductase catalyzes mevalonate formation; substrate/cofactor-bound structures locate HMG-CoA and the nicotinamide cofactor in the catalytic domain. Model: Human recombinant catalytic-domain crystallography and biochemical background. Limitations: Shared human machinery; the source is not an experiment administering red yeast rice. Evidence access: Primary abstract [10698924] Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10698924/ · DOI 10.1093/emboj/19.5.819
    Complete structured claim and evidence

What acts on it

  1. Statins occupy a portion of the HMG-CoA binding site of HMG-CoA reductase and block access of the substrate to the active site.

    Atorvastatin → HMG-CoA reductase (HMGCR) source_derived_draftungraded
    Experimental context and source evidence
    duration
    Not applicable
    evidence_access
    Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    experimental_model
    Catalytic portion of human HMG-CoA reductase, X-ray structures with six statins
    exposure
    Statin-enzyme complexes, inhibition constants in the nanomolar range
    limitations
    The abstract reports structures with six statins without naming them, so this is a class binding mode rather than an atorvastatin-specific structure. Several catalytically relevant residues near the carboxyl terminus are disordered in the complexes.
    organism
    Catalytic portion of human HMG-CoA reductase, X-ray structures with six statins
    plain_language
    Statins occupy a portion of the HMG-CoA binding site of HMG-CoA reductase and block access of the substrate to the active site.
    primary_references
    Structural mechanism for statin inhibition of HMG-CoA reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11349148/ DOI: 10.1126/science.1059344
    route
    Structural
    tissue
    Enzyme active-site occupancy

    Atorvastatin: mechanism of action from target occupancy to isoprenoids, transport, muscle and metabolism (2026-09-22) · lines 13–22

    Original AI-assisted curation of twelve primary studies resolved by PubMed title search and cross-checked against live PubMed metadata. Findings obtained with mevastatin, simvastatin or the statin class are recorded against those subjects. Study-specific citations, doses, negative findings and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

    ## atorvastatin-hmgcr-occupancy Statins occupy a portion of the HMG-CoA binding site of HMG-CoA reductase and block access of the substrate to the active site. Model/species: Catalytic portion of human HMG-CoA reductase, X-ray structures with six statins Tissue/system: Enzyme active-site occupancy Exposure: Statin-enzyme complexes, inhibition constants in the nanomolar range Route: Structural Duration: Not applicable Limits: The abstract reports structures with six statins without naming them, so this is a class binding mode rather than an atorvastatin-specific structure. Several catalytically relevant residues near the carboxyl terminus are disordered in the complexes. Primary reference: Structural mechanism for statin inhibition of HMG-CoA reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11349148/ DOI: 10.1126/science.1059344 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    Complete structured claim and evidence

  2. Simvastatin inhibits HMG-CoA reductase, an upstream enzyme in the mevalonate pathway shared by sterol and CoQ precursor production.

    Simvastatin → HMG-CoA reductase (HMGCR) source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/coq10-research/7828383.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e6aac0f5f784ab8a43755c6c878ea010b8673acc19bfa41f7a1272880c745197", "start_char": 0, "end_char": 800, "text_sha256": "e6aac0f5f784ab8a43755c6c878ea010b8673acc19bfa41f7a1272880c745197"}
    experimental_model
    Short-term treatment with serum and muscle sampling
    exposure
    Four weeks of simvastatin
    limitations
    Established biochemical background described in this primary report; enzyme target engagement was not the independent endpoint of this serum/muscle study.
    nutrient_topic
    Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system
    organism
    Humans with hypercholesterolemia
    plain_language
    A cholesterol-lowering drug acts upstream of more than cholesterol.
    primary_references
    [coq10-p7828383] Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. (1995). https://pubmed.ncbi.nlm.nih.gov/7828383/ DOI: 10.1016/0009-9236(95)90266-x
    tissue_or_cell_type
    Serum versus skeletal-muscle CoQ

    Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 905–916

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Short-term treatment with serum and muscle sampling · source_derived_draft · unverified_draft

    ### coq10-statin-target Simvastatin inhibits HMG-CoA reductase, an upstream enzyme in the mevalonate pathway shared by sterol and CoQ precursor production. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A cholesterol-lowering drug acts upstream of more than cholesterol. organism: Humans with hypercholesterolemia tissue_or_cell_type: Serum versus skeletal-muscle CoQ experimental_model: Short-term treatment with serum and muscle sampling limitations: Established biochemical background described in this primary report; enzyme target engagement was not the independent endpoint of this serum/muscle study. exposure: Four weeks of simvastatin evidence_span: {"source_cache": "artifacts/coq10-research/7828383.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e6aac0f5f784ab8a43755c6c878ea010b8673acc19bfa41f7a1272880c745197", "start_char": 0, "end_char": 800, "text_sha256": "e6aac0f5f784ab8a43755c6c878ea010b8673acc19bfa41f7a1272880c745197"} [coq10-p7828383] Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. (1995). https://pubmed.ncbi.nlm.nih.gov/7828383/ DOI: 10.1016/0009-9236(95)90266-x
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. Sixteen weeks of atorvastatin reduced total cholesterol and low-density-lipoprotein cholesterol in type 2 diabetic patients with hypercholesterolaemia.

    Atorvastatin → LDL cholesterol concentration source_derived_draftungraded
    Experimental context and source evidence
    duration
    16 weeks
    evidence_access
    Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    experimental_model
    84 Japanese type 2 diabetic patients with hypercholesterolaemia
    exposure
    Atorvastatin for 16 weeks, multicentre open-label
    limitations
    Open-label and without a placebo arm, and responders were defined by reaching an LDL target rather than randomised.
    organism
    84 Japanese type 2 diabetic patients with hypercholesterolaemia
    plain_language
    Sixteen weeks of atorvastatin reduced total cholesterol and low-density-lipoprotein cholesterol in type 2 diabetic patients with hypercholesterolaemia.
    primary_references
    Atorvastatin lowers plasma low-density lipoprotein cholesterol and C-reactive protein in Japanese type 2 diabetic patients. (2006). https://pubmed.ncbi.nlm.nih.gov/16324921/ DOI: 10.1016/j.metabol.2005.07.017
    route
    Oral
    tissue
    Plasma lipids

    Atorvastatin: mechanism of action from target occupancy to isoprenoids, transport, muscle and metabolism (2026-09-22) · lines 34–43

    Original AI-assisted curation of twelve primary studies resolved by PubMed title search and cross-checked against live PubMed metadata. Findings obtained with mevastatin, simvastatin or the statin class are recorded against those subjects. Study-specific citations, doses, negative findings and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

    ## atorvastatin-ldl-cholesterol Sixteen weeks of atorvastatin reduced total cholesterol and low-density-lipoprotein cholesterol in type 2 diabetic patients with hypercholesterolaemia. Model/species: 84 Japanese type 2 diabetic patients with hypercholesterolaemia Tissue/system: Plasma lipids Exposure: Atorvastatin for 16 weeks, multicentre open-label Route: Oral Duration: 16 weeks Limits: Open-label and without a placebo arm, and responders were defined by reaching an LDL target rather than randomised. Primary reference: Atorvastatin lowers plasma low-density lipoprotein cholesterol and C-reactive protein in Japanese type 2 diabetic patients. (2006). https://pubmed.ncbi.nlm.nih.gov/16324921/ DOI: 10.1016/j.metabol.2005.07.017 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    Complete structured claim and evidence

  2. The mevalonate pathway produces isoprenoids required for functions ranging from cholesterol synthesis to growth control, under feedback regulation that also governs low-density-lipoprotein receptors.

    Mevalonate → Geranylgeranyl diphosphate / GGPP source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    experimental_model
    Review of mammalian mevalonate-pathway regulation
    exposure
    Not applicable
    limitations
    A review of regulatory architecture, not a measurement of any one statin's effect on any one isoprenoid pool.
    organism
    Review of mammalian mevalonate-pathway regulation
    plain_language
    The mevalonate pathway produces isoprenoids required for functions ranging from cholesterol synthesis to growth control, under feedback regulation that also governs low-density-lipoprotein receptors.
    primary_references
    Regulation of the mevalonate pathway. (1990). https://pubmed.ncbi.nlm.nih.gov/1967820/ DOI: 10.1038/343425a0
    route
    Not applicable
    tissue
    Isoprenoid and sterol end-products

    Atorvastatin: mechanism of action from target occupancy to isoprenoids, transport, muscle and metabolism (2026-09-22) · lines 24–32

    Original AI-assisted curation of twelve primary studies resolved by PubMed title search and cross-checked against live PubMed metadata. Findings obtained with mevastatin, simvastatin or the statin class are recorded against those subjects. Study-specific citations, doses, negative findings and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

    ## mevalonate-supplies-isoprenoids The mevalonate pathway produces isoprenoids required for functions ranging from cholesterol synthesis to growth control, under feedback regulation that also governs low-density-lipoprotein receptors. Model/species: Review of mammalian mevalonate-pathway regulation Tissue/system: Isoprenoid and sterol end-products Exposure: Not applicable Route: Not applicable Limits: A review of regulatory architecture, not a measurement of any one statin's effect on any one isoprenoid pool. Primary reference: Regulation of the mevalonate pathway. (1990). https://pubmed.ncbi.nlm.nih.gov/1967820/ DOI: 10.1038/343425a0 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    Complete structured claim and evidence

  3. Delta-tocotrienol stimulated HMG-CoA reductase ubiquitination in isolated SV-589 fibroblast membrane fractions supplemented with ubiquitin-activating enzyme; gamma-tocotrienol showed the same activity. The reconstituted result supported action without further tocotrienol metabolism.

    Delta-tocotrienol → HMG-CoA reductase ubiquitination source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    false
    experimental_model
    Isolated membranes from sterol-depleted SV-589 human fibroblasts; FLAG-ubiquitin and purified E1 assay
    exposure
    Figure 5B: purified E1 5 µg/mL, FLAG-ubiquitin 0.1 mg/mL, ubiquitin-aldehyde 0.01 mg/mL and ATP-regenerating system; tocotrienol concentration not fully retrieved.
    limitations
    The assay does not prove direct molecular binding of tocotrienol to HMGCR or INSIG. No human cholesterol outcome follows from this reconstituted experiment.
    nutrient_topic
    Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E
    organism
    Homo sapiens
    plain_language
    These tocotrienols promoted attachment of degradation tags to the cholesterol-synthesis enzyme in isolated cell membranes.
    primary_references
    [song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. (2006). https://pubmed.ncbi.nlm.nih.gov/16831864/ DOI: 10.1074/jbc.m605575200
    tissue_or_cell_type
    Fibroblast-derived membrane fractions

    Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1128–1139

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated membranes from sterol-depleted SV-589 human fibroblasts; FLAG-ubiquitin and purified E1 assay · source_derived_draft · unverified_draft

    ### e-sig-delta-te-hmgcr-ubiquitination Delta-tocotrienol stimulated HMG-CoA reductase ubiquitination in isolated SV-589 fibroblast membrane fractions supplemented with ubiquitin-activating enzyme; gamma-tocotrienol showed the same activity. The reconstituted result supported action without further tocotrienol metabolism. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: These tocotrienols promoted attachment of degradation tags to the cholesterol-synthesis enzyme in isolated cell membranes. organism: Homo sapiens tissue_or_cell_type: Fibroblast-derived membrane fractions experimental_model: Isolated membranes from sterol-depleted SV-589 human fibroblasts; FLAG-ubiquitin and purified E1 assay limitations: The assay does not prove direct molecular binding of tocotrienol to HMGCR or INSIG. No human cholesterol outcome follows from this reconstituted experiment. exposure: Figure 5B: purified E1 5 µg/mL, FLAG-ubiquitin 0.1 mg/mL, ubiquitin-aldehyde 0.01 mg/mL and ATP-regenerating system; tocotrienol concentration not fully retrieved. cross_nutrient: false [song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. (2006). https://pubmed.ncbi.nlm.nih.gov/16831864/ DOI: 10.1074/jbc.m605575200
    Complete structured claim and evidence

  4. At 10 µM gamma-tocotrienol, HepG2 HMG-CoA reductase degradation increased 2.4-fold and its half-life fell from 3.73 to 1.59 h, measured by [35S]methionine pulse-chase and immunoprecipitation.

    Gamma-tocotrienol → HMG-CoA reductase protein degradation source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    false
    experimental_model
    Radiolabeled protein pulse-chase and HMGCR immunoprecipitation
    exposure
    10 µM gamma-tocotrienol; reported HMGCR half-life 3.73 h control versus 1.59 h treated.
    limitations
    Primary abstract only; these data do not by themselves identify Insig proteins or prove direct binding to the reductase. Human supplementation effects cannot be inferred.
    nutrient_topic
    Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E
    organism
    Homo sapiens
    plain_language
    Gamma-tocotrienol made the cholesterol-synthesis enzyme turn over faster in cultured human liver tumor cells.
    primary_references
    [parker1993] Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. (1993). https://pubmed.ncbi.nlm.nih.gov/8388388/ DOI: 10.1016/s0021-9258(18)82115-9
    tissue_or_cell_type
    Hepatoma cell culture

    Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1115–1126

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabeled protein pulse-chase and HMGCR immunoprecipitation · source_derived_draft · unverified_draft

    ### e-sig-gamma-te-hmgcr-turnover At 10 µM gamma-tocotrienol, HepG2 HMG-CoA reductase degradation increased 2.4-fold and its half-life fell from 3.73 to 1.59 h, measured by [35S]methionine pulse-chase and immunoprecipitation. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Gamma-tocotrienol made the cholesterol-synthesis enzyme turn over faster in cultured human liver tumor cells. organism: Homo sapiens tissue_or_cell_type: Hepatoma cell culture experimental_model: Radiolabeled protein pulse-chase and HMGCR immunoprecipitation limitations: Primary abstract only; these data do not by themselves identify Insig proteins or prove direct binding to the reductase. Human supplementation effects cannot be inferred. exposure: 10 µM gamma-tocotrienol; reported HMGCR half-life 3.73 h control versus 1.59 h treated. cross_nutrient: false [parker1993] Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. (1993). https://pubmed.ncbi.nlm.nih.gov/8388388/ DOI: 10.1016/s0021-9258(18)82115-9
    Complete structured claim and evidence

  5. Combined RNAi against INSIG1 and INSIG2 abolished gamma- and delta-tocotrienol-stimulated degradation of endogenous HMG-CoA reductase in sterol-depleted SV-589 fibroblasts supplied with 10 mM mevalonate.

    Combined INSIG1 and INSIG2 depletion → HMG-CoA reductase protein degradation source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    cross_nutrient
    false
    experimental_model
    Combined INSIG1/INSIG2 RNA interference in immortalized human SV-589 fibroblasts
    exposure
    Sterol depletion 16 h; gamma- or delta-tocotrienol plus 10 mM mevalonate for 5 h; tocotrienol concentration not retrieved from the accessible Figure 3 text.
    limitations
    Combined knockdown establishes a machinery requirement in this model, not the unique role of either INSIG isoform or nutritional deficiency. Does not quantify viability or predict supplement benefit.
    nutrient_topic
    Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E
    organism
    Homo sapiens
    plain_language
    Removing both INSIG regulators prevented these tocotrienols from accelerating loss of the reductase protein in this cell experiment.
    primary_references
    [song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. (2006). https://pubmed.ncbi.nlm.nih.gov/16831864/ DOI: 10.1074/jbc.m605575200
    tissue_or_cell_type
    Human fibroblast cell culture
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1141–1152

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Combined INSIG1/INSIG2 RNA interference in immortalized human SV-589 fibroblasts · source_derived_draft · unverified_draft

    ### e-sig-insig-depletion-hmgcr-turnover Combined RNAi against INSIG1 and INSIG2 abolished gamma- and delta-tocotrienol-stimulated degradation of endogenous HMG-CoA reductase in sterol-depleted SV-589 fibroblasts supplied with 10 mM mevalonate. Condition category: machinery_impairment nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing both INSIG regulators prevented these tocotrienols from accelerating loss of the reductase protein in this cell experiment. organism: Homo sapiens tissue_or_cell_type: Human fibroblast cell culture experimental_model: Combined INSIG1/INSIG2 RNA interference in immortalized human SV-589 fibroblasts limitations: Combined knockdown establishes a machinery requirement in this model, not the unique role of either INSIG isoform or nutritional deficiency. Does not quantify viability or predict supplement benefit. exposure: Sterol depletion 16 h; gamma- or delta-tocotrienol plus 10 mM mevalonate for 5 h; tocotrienol concentration not retrieved from the accessible Figure 3 text. cross_nutrient: false [song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. (2006). https://pubmed.ncbi.nlm.nih.gov/16831864/ DOI: 10.1074/jbc.m605575200
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

    This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

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