Nutrient chapter
Selenium
Elemental selenium considered as the upstream nutrient input.
124 recorded mechanisms · 33 availability situations · 6 preserved sources. Draft and verified records are labeled separately.
The mechanisms
What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.
Selenium availability supports the specialized Sec-tRNA pool.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 11–20
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
# I. THE CLEANEST CHAIN — SELENOK → Ca²⁺ → NFAT → IL-2 This is the one to memorize. It's a direct, non-redox, molecule-by-molecule path from a selenium atom to a cytokine. ``` 1. Se → Sec-tRNA → SELENOK (ER membrane, single C-terminal Sec, tail in cytosol) 2. SELENOK binds ZDHHC6 (ER palmitoyl-S-acyltransferase, DHHC motif) → SELENOK is required as a COFACTOR to stabilize the palmitoyl-ZDHHC6 acyl-enzyme intermediate
Complete structured claim and evidenceSec-tRNA enables translation of SELENOK.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 11–20
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
# I. THE CLEANEST CHAIN — SELENOK → Ca²⁺ → NFAT → IL-2 This is the one to memorize. It's a direct, non-redox, molecule-by-molecule path from a selenium atom to a cytokine. ``` 1. Se → Sec-tRNA → SELENOK (ER membrane, single C-terminal Sec, tail in cytosol) 2. SELENOK binds ZDHHC6 (ER palmitoyl-S-acyltransferase, DHHC motif) → SELENOK is required as a COFACTOR to stabilize the palmitoyl-ZDHHC6 acyl-enzyme intermediate
Complete structured claim and evidenceSELENOK supports ZDHHC6 by stabilizing the palmitoyl-ZDHHC6 acyl-enzyme intermediate.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 11–20
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
# I. THE CLEANEST CHAIN — SELENOK → Ca²⁺ → NFAT → IL-2 This is the one to memorize. It's a direct, non-redox, molecule-by-molecule path from a selenium atom to a cytokine. ``` 1. Se → Sec-tRNA → SELENOK (ER membrane, single C-terminal Sec, tail in cytosol) 2. SELENOK binds ZDHHC6 (ER palmitoyl-S-acyltransferase, DHHC motif) → SELENOK is required as a COFACTOR to stabilize the palmitoyl-ZDHHC6 acyl-enzyme intermediate
Selenium: the molecular cascade · lines 135–143
Selenium molecular cascade draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
**SELENOO** — the strangest protein in the set. Its bacterial ortholog **SelO** looks exactly like a protein kinase but binds ATP **flipped backwards** in the pocket, so it transfers **AMP instead of phosphate**. It's an **AMPylase**, activated by oxidative stress, AMPylating GAPDH and other redox enzymes. A pseudokinase that runs in reverse. Human SELENOO is mitochondrial and largely uncharacterized. **MSRB1 (SELENOR)** — redox control of the cytoskeleton. **MICAL1/2** oxidizes actin **Met44 and Met47** to the R-sulfoxide → actin depolymerizes. MSRB1 reduces it back → repolymerization. In macrophages this gates phagocytic cup formation. **Selenium is a direct rheostat on actin dynamics.** Almost nobody knows this. **SELENOK** — not a peroxidase. It's the essential cofactor for **ZDHHC6**, the palmitoyl transferase. No SELENOK → failed palmitoylation of IP3R, calnexin, and others → broken Ca²⁺ flux in T cells. **Selenium regulating lipid post-translational modification.** **SELENOI (EPT1)** — the only selenoprotein with **zero redox function**. It's an ethanolamine phosphotransferase making phosphatidylethanolamine. Mutations → hereditary spastic paraplegia **SPG81**. (And PE is exactly the lipid GPX4 protects. There's a loop there worth pulling on.) **SELENON** — ER membrane, regulates **RyR1** redox state and SERCA2b. Mutations → SEPN1-related myopathy / rigid spine syndrome.
Complete structured claim and evidenceZDHHC6 palmitoylates IP3R, producing the palmitoylated receptor state.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 22–28
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
3. ZDHHC6 palmitoylates: • IP3R (all three isoforms) • calnexin • itself (autopalmitoylation) 4. Palmitoylated IP3R = stable, correctly localized, functional channel Non-palmitoylated IP3R = degraded / non-functional
Selenium: the molecular cascade · lines 135–143
Selenium molecular cascade draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
**SELENOO** — the strangest protein in the set. Its bacterial ortholog **SelO** looks exactly like a protein kinase but binds ATP **flipped backwards** in the pocket, so it transfers **AMP instead of phosphate**. It's an **AMPylase**, activated by oxidative stress, AMPylating GAPDH and other redox enzymes. A pseudokinase that runs in reverse. Human SELENOO is mitochondrial and largely uncharacterized. **MSRB1 (SELENOR)** — redox control of the cytoskeleton. **MICAL1/2** oxidizes actin **Met44 and Met47** to the R-sulfoxide → actin depolymerizes. MSRB1 reduces it back → repolymerization. In macrophages this gates phagocytic cup formation. **Selenium is a direct rheostat on actin dynamics.** Almost nobody knows this. **SELENOK** — not a peroxidase. It's the essential cofactor for **ZDHHC6**, the palmitoyl transferase. No SELENOK → failed palmitoylation of IP3R, calnexin, and others → broken Ca²⁺ flux in T cells. **Selenium regulating lipid post-translational modification.** **SELENOI (EPT1)** — the only selenoprotein with **zero redox function**. It's an ethanolamine phosphotransferase making phosphatidylethanolamine. Mutations → hereditary spastic paraplegia **SPG81**. (And PE is exactly the lipid GPX4 protects. There's a loop there worth pulling on.) **SELENON** — ER membrane, regulates **RyR1** redox state and SERCA2b. Mutations → SEPN1-related myopathy / rigid spine syndrome.
Complete structured claim and evidencePalmitoylated IP3R is described as stable, correctly localized, and functional.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 22–28
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
3. ZDHHC6 palmitoylates: • IP3R (all three isoforms) • calnexin • itself (autopalmitoylation) 4. Palmitoylated IP3R = stable, correctly localized, functional channel Non-palmitoylated IP3R = degraded / non-functional
Complete structured claim and evidenceFunctional IP3R enables release of calcium from the ER.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceER calcium release causes store depletion.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceER store depletion activates STIM1 oligomerization.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceOligomerized STIM1 activates ORAI1 and the CRAC channel state.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceORAI1 enables sustained calcium entry.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceCalcium binding forms the calcium/calmodulin signaling complex.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceCalcium/calmodulin activates calcineurin.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceCalcineurin dephosphorylates NFAT.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceDephosphorylated NFAT partners with AP-1 to activate IL2 transcription.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceThe activated IL2 gene undergoes IL2 transcription.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceIL2 transcription produces IL-2 protein.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceTCR signaling produces IP3 through the source-described receptor-proximal cascade.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceIP3 activates functional IP3R.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceAP-1 cooperates with dephosphorylated NFAT at the IL2 transcriptional step.
Experimental context and source evidence
- cell_type
- · T cell
- evidence_scope
- Source-derived draft; primary-source verification required
- organism
- · Human
Selenium in immune cells · lines 30–38
Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft
5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription
Complete structured claim and evidenceWild-type APT2 overexpression reduced radiolabeled palmitate incorporation into ZDHHC6 in HeLa cells.
Experimental context and source evidence
- evidence_cache
- artifacts/discovery-research/round6-sources/zdhhc6-primary-passages.json; SHA256 a02040bb8922a9170e095cdfb5e875a5e7f513b682c0ec69c19feacb3dc191b0
- experimental_model
- Human HeLa; tagged human APT2 and ZDHHC6 constructs
- exposure
- 24-hour plasmid expression, then 2-hour tritiated-palmitate labeling; normalized to ZDHHC6 protein; n=6.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 2E,F; Rapid APT2-mediated ZDHHC6 depalmitoylation
- primary_references
- https://doi.org/10.7554/eLife.27826
- source_access
- Selected primary Results, figure legends and methods via indexed publisher text. No supplement or raw-data reanalysis.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 74–82
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human HeLa; tagged human APT2 and ZDHHC6 constructs · source_derived_draft · unverified_draft
Wild-type APT2 overexpression reduced radiolabeled palmitate incorporation into ZDHHC6 in HeLa cells. primary_references: https://doi.org/10.7554/eLife.27826 primary_locator: Figure 2E,F; Rapid APT2-mediated ZDHHC6 depalmitoylation source_access: Selected primary Results, figure legends and methods via indexed publisher text. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/zdhhc6-primary-passages.json; SHA256 a02040bb8922a9170e095cdfb5e875a5e7f513b682c0ec69c19feacb3dc191b0 experimental_model: Human HeLa; tagged human APT2 and ZDHHC6 constructs organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: 24-hour plasmid expression, then 2-hour tritiated-palmitate labeling; normalized to ZDHHC6 protein; n=6. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements.
Complete structured claim and evidencePalmitoylation-deficient APT2-C2S overexpression did not reproduce the significant reduction in ZDHHC6 palmitoylation caused by wild-type APT2.
Experimental context and source evidence
- availability_state
- machinery_impairment Imported condition classification; unverified.
- evidence_cache
- artifacts/discovery-research/round6-sources/zdhhc6-primary-passages.json; SHA256 a02040bb8922a9170e095cdfb5e875a5e7f513b682c0ec69c19feacb3dc191b0
- experimental_model
- Human HeLa; tagged human APT2-C2S and ZDHHC6 constructs
- exposure
- 24-hour plasmid expression, then 2-hour tritiated-palmitate labeling; normalized to ZDHHC6 protein; n=6.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. This mutant result supports a role for APT2 palmitoylation in this substrate assay; it is not a sulforaphane experiment.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 2E,F; Rapid APT2-mediated ZDHHC6 depalmitoylation
- primary_references
- https://doi.org/10.7554/eLife.27826
- source_access
- Selected primary Results, figure legends and methods via indexed publisher text. No supplement or raw-data reanalysis.
- trigger_kind
- machinery_impairment Imported condition classification; unverified.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 85–93
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human HeLa; tagged human APT2-C2S and ZDHHC6 constructs · source_derived_draft · unverified_draft
Palmitoylation-deficient APT2-C2S overexpression did not reproduce the significant reduction in ZDHHC6 palmitoylation caused by wild-type APT2. primary_references: https://doi.org/10.7554/eLife.27826 primary_locator: Figure 2E,F; Rapid APT2-mediated ZDHHC6 depalmitoylation source_access: Selected primary Results, figure legends and methods via indexed publisher text. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/zdhhc6-primary-passages.json; SHA256 a02040bb8922a9170e095cdfb5e875a5e7f513b682c0ec69c19feacb3dc191b0 experimental_model: Human HeLa; tagged human APT2-C2S and ZDHHC6 constructs organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: 24-hour plasmid expression, then 2-hour tritiated-palmitate labeling; normalized to ZDHHC6 protein; n=6. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. This mutant result supports a role for APT2 palmitoylation in this substrate assay; it is not a sulforaphane experiment.
Complete structured claim and evidenceLYPLA2 silencing accelerated ZDHHC6 decay in HeLa pulse-chase experiments, shortening the reported apparent half-life from about 16 hours to about 3 hours.
Experimental context and source evidence
- availability_state
- machinery_impairment Imported condition classification; unverified.
- evidence_cache
- artifacts/discovery-research/round6-sources/zdhhc6-primary-passages.json; SHA256 a02040bb8922a9170e095cdfb5e875a5e7f513b682c0ec69c19feacb3dc191b0
- experimental_model
- Human HeLa; LYPLA2 siRNA and tagged ZDHHC6
- exposure
- 72-hour siRNA protocol; 2-hour metabolic protein pulse followed by chase. Reported apparent half-lives, not raw-data refits.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. C328 mutation abolished sensitivity and MG132 rescued degradation in the reported experiments. Higher regulatory palmitoylation is not equivalent to sustained higher ZDHHC6 abundance.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 3A-E; ZDHHC6 palmitoylation controls degradation
- primary_references
- https://doi.org/10.7554/eLife.27826
- source_access
- Selected primary Results, figure legends and methods via indexed publisher text. No supplement or raw-data reanalysis.
- trigger_kind
- machinery_impairment Imported condition classification; unverified.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 96–104
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human HeLa; LYPLA2 siRNA and tagged ZDHHC6 · source_derived_draft · unverified_draft
LYPLA2 silencing accelerated ZDHHC6 decay in HeLa pulse-chase experiments, shortening the reported apparent half-life from about 16 hours to about 3 hours. primary_references: https://doi.org/10.7554/eLife.27826 primary_locator: Figure 3A-E; ZDHHC6 palmitoylation controls degradation source_access: Selected primary Results, figure legends and methods via indexed publisher text. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/zdhhc6-primary-passages.json; SHA256 a02040bb8922a9170e095cdfb5e875a5e7f513b682c0ec69c19feacb3dc191b0 experimental_model: Human HeLa; LYPLA2 siRNA and tagged ZDHHC6 organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: 72-hour siRNA protocol; 2-hour metabolic protein pulse followed by chase. Reported apparent half-lives, not raw-data refits. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. C328 mutation abolished sensitivity and MG132 rescued degradation in the reported experiments. Higher regulatory palmitoylation is not equivalent to sustained higher ZDHHC6 abundance.
Complete structured claim and evidenceAPT2 shRNA increased GPX4 palmitoylation measured by acyl-biotin exchange in A375 cells.
Experimental context and source evidence
- availability_state
- machinery_impairment Imported condition classification; unverified.
- evidence_cache
- artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc
- experimental_model
- Human A375 melanoma; lentiviral APT2 shRNA; exogenous GPX4
- exposure
- ABE assay with and without hydroxylamine; representative of three independent experiments; exact shRNA exposure duration unresolved.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The Results prose calls this deletion, but Figure 5d specifies shRNA; record the figure-defined knockdown, not a knockout.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 5d and Results: APT2 mediates the depalmitoylation of GPX4
- primary_references
- https://doi.org/10.1038/s41467-025-56344-5
- source_access
- Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis.
- trigger_kind
- machinery_impairment Imported condition classification; unverified.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 107–115
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human A375 melanoma; lentiviral APT2 shRNA; exogenous GPX4 · source_derived_draft · unverified_draft
APT2 shRNA increased GPX4 palmitoylation measured by acyl-biotin exchange in A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 5d and Results: APT2 mediates the depalmitoylation of GPX4 source_access: Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc experimental_model: Human A375 melanoma; lentiviral APT2 shRNA; exogenous GPX4 organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: ABE assay with and without hydroxylamine; representative of three independent experiments; exact shRNA exposure duration unresolved. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The Results prose calls this deletion, but Figure 5d specifies shRNA; record the figure-defined knockdown, not a knockout.
Complete structured claim and evidenceAPT2 knockdown increased GPX4 protein stability in A375 cycloheximide-chase experiments.
Experimental context and source evidence
- availability_state
- machinery_impairment Imported condition classification; unverified.
- evidence_cache
- artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc
- experimental_model
- Human A375 melanoma; lentiviral APT2 shRNA
- exposure
- Cycloheximide chase; three independent experiments; exact CHX concentration and time series not resolved from reviewed legend.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 5i,j
- primary_references
- https://doi.org/10.1038/s41467-025-56344-5
- source_access
- Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis.
- trigger_kind
- machinery_impairment Imported condition classification; unverified.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 118–126
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human A375 melanoma; lentiviral APT2 shRNA · source_derived_draft · unverified_draft
APT2 knockdown increased GPX4 protein stability in A375 cycloheximide-chase experiments. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 5i,j source_access: Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc experimental_model: Human A375 melanoma; lentiviral APT2 shRNA organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: Cycloheximide chase; three independent experiments; exact CHX concentration and time series not resolved from reviewed legend. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements.
Complete structured claim and evidenceAPT2 knockdown did not significantly change GPX4 mRNA in the reported A375 and HT1080 RT-qPCR experiments.
Experimental context and source evidence
- availability_state
- machinery_impairment Imported condition classification; unverified.
- evidence_cache
- artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc
- experimental_model
- Human A375 and HT1080 cancer cells; lentiviral APT2 shRNA
- exposure
- RT-qPCR; three independent experiments; exposure timing unresolved.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The actor names the A375 arm; the parallel HT1080 observation is preserved in the context. No transcriptional effect is inferred.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 5f
- primary_references
- https://doi.org/10.1038/s41467-025-56344-5
- source_access
- Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis.
- trigger_kind
- machinery_impairment Imported condition classification; unverified.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 129–137
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human A375 and HT1080 cancer cells; lentiviral APT2 shRNA · source_derived_draft · unverified_draft
APT2 knockdown did not significantly change GPX4 mRNA in the reported A375 and HT1080 RT-qPCR experiments. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 5f source_access: Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc experimental_model: Human A375 and HT1080 cancer cells; lentiviral APT2 shRNA organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: RT-qPCR; three independent experiments; exposure timing unresolved. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The actor names the A375 arm; the parallel HT1080 observation is preserved in the context. No transcriptional effect is inferred.
Complete structured claim and evidenceAPT2 knockdown reduced RSL3-induced cell death measured with SYTOX Green in A375 cells.
Experimental context and source evidence
- availability_state
- machinery_impairment Imported condition classification; unverified.
- evidence_cache
- artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc
- experimental_model
- Human A375 melanoma; lentiviral APT2 shRNA
- exposure
- 4 micromolar RSL3 for 6 hours; SYTOX Green staining; three independent experiments.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. This is a response to a GPX4 inhibitor in cancer cells. It does not establish an effect of sulforaphane or dietary selenium.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 6c,d
- primary_references
- https://doi.org/10.1038/s41467-025-56344-5
- source_access
- Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis.
- trigger_kind
- machinery_impairment Imported condition classification; unverified.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 140–148
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human A375 melanoma; lentiviral APT2 shRNA · source_derived_draft · unverified_draft
APT2 knockdown reduced RSL3-induced cell death measured with SYTOX Green in A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 6c,d source_access: Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc experimental_model: Human A375 melanoma; lentiviral APT2 shRNA organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: 4 micromolar RSL3 for 6 hours; SYTOX Green staining; three independent experiments. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. This is a response to a GPX4 inhibitor in cancer cells. It does not establish an effect of sulforaphane or dietary selenium.
Complete structured claim and evidenceGPX1-overexpressing mice showed reduced insulin-stimulated receptor phosphorylation in liver and Akt phosphorylation in liver and soleus.
Experimental context and source evidence
- curation_topic
- selenium · Selenium
- experimental_condition
- Wild-type mice on the same diet GPX1 overexpression · Mouse Gpx1 overexpression genotype Condition belongs to the full experimental contrast; do not separate a joint intervention.
- experimental_contrast
- {"intervention": "GPX1 overexpression", "comparator": "Wild-type mice on the same diet", "endpoint": "Insulin-stimulated phosphorylation", "effect_direction": "decrease", "combination": "single", "conditions": [{"entity_slug": "mouse-gpx1-overexpression", "state": "GPX1 overexpression"}]} Explicit extracted experimental comparison; source-derived draft.
- experimental_model
- Male transgenic mice; selenium-adequate 0.4 mg/kg diet, ages 8 to 24 weeks
- limitations
- Overexpression experiment, not dietary selenium excess. Excess ROS quenching is a proposed explanation rather than a measured universal mechanism.
- primary_references
- McClung et al. 2004; DOI:10.1073/pnas.0308096101; PMID:15184668; https://pmc.ncbi.nlm.nih.gov/articles/PMC428436/
Diabetes cascade: targeted primary-source supplement · lines 30–30
See claim-local references; curated paraphrases reviewed 2026-09-20. · supports · Male transgenic mice; selenium-adequate 0.4 mg/kg diet, ages 8 to 24 weeks · source_derived_draft · unverified_draft
GPX1-overexpressing mice showed reduced insulin-stimulated receptor phosphorylation in liver and Akt phosphorylation in liver and soleus. Model: Male transgenic mice; selenium-adequate 0.4 mg/kg diet, ages 8 to 24 weeks. Limits: Overexpression experiment, not dietary selenium excess. Excess ROS quenching is a proposed explanation rather than a measured universal mechanism. Primary reference: McClung et al. 2004; DOI:10.1073/pnas.0308096101; PMID:15184668; https://pmc.ncbi.nlm.nih.gov/articles/PMC428436/
Complete structured claim and evidenceGPX1-overexpressing mice had a smaller blood-glucose fall after insulin challenge and developed hyperglycemia, hyperinsulinemia and greater adiposity.
Experimental context and source evidence
- curation_topic
- selenium · Selenium
- experimental_condition
- Wild-type mice GPX1 overexpression · Mouse Gpx1 overexpression genotype Condition belongs to the full experimental contrast; do not separate a joint intervention.
- experimental_contrast
- {"intervention": "GPX1 overexpression", "comparator": "Wild-type mice", "endpoint": "Glucose fall after insulin", "effect_direction": "decrease", "combination": "single", "conditions": [{"entity_slug": "mouse-gpx1-overexpression", "state": "GPX1 overexpression"}]} Explicit extracted experimental comparison; source-derived draft.
- experimental_model
- Male transgenic mice on selenium-adequate diet, evaluated at 24 weeks
- limitations
- Does not establish that suppressing GPX1 is beneficial in other settings.
- primary_references
- McClung et al. 2004; DOI:10.1073/pnas.0308096101; PMID:15184668; https://pmc.ncbi.nlm.nih.gov/articles/PMC428436/
Diabetes cascade: targeted primary-source supplement · lines 33–33
See claim-local references; curated paraphrases reviewed 2026-09-20. · supports · Male transgenic mice on selenium-adequate diet, evaluated at 24 weeks · source_derived_draft · unverified_draft
GPX1-overexpressing mice had a smaller blood-glucose fall after insulin challenge and developed hyperglycemia, hyperinsulinemia and greater adiposity. Model: Male transgenic mice on selenium-adequate diet, evaluated at 24 weeks. Limits: Does not establish that suppressing GPX1 is beneficial in other settings. Primary reference: McClung et al. 2004; DOI:10.1073/pnas.0308096101; PMID:15184668; https://pmc.ncbi.nlm.nih.gov/articles/PMC428436/
Complete structured claim and evidenceSELENON links low calcium inside the ER to regulation of its calcium-refilling pump.
ER calcium depletion changes SELENON oligomerization and exposes reductase activity toward SERCA2 in the tested biochemical/cell systems.
Experimental context and source evidence
- experimental_model
- Calcium-binding peptides and human cell experiments, including engineered SELENON variants.
- limitations
- Some assays use engineered Sec-to-Cys protein; these results do not define human nutrient-response thresholds.
- organism
- Human cell systems and recombinant peptides
Selenium: literature corrections and mechanism additions · lines 1064–1073
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Calcium-binding peptides and human cell experiments, including engineered SELENON variants. · secondary_verified · secondary_verified
## selenon-serca-redox-control SELENON links low calcium inside the ER to regulation of its calcium-refilling pump. ER calcium depletion changes SELENON oligomerization and exposes reductase activity toward SERCA2 in the tested biochemical/cell systems. Experimental model: Calcium-binding peptides and human cell experiments, including engineered SELENON variants. Organism: Human cell systems and recombinant peptides Limitations: Some assays use engineered Sec-to-Cys protein; these results do not define human nutrient-response thresholds. Primary reference: [Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity](https://pmc.ncbi.nlm.nih.gov/articles/PMC7474598/)
Complete structured claim and evidenceIn the studied mice, pancreatic cells needed SELENOT for normal insulin output.
Pancreatic beta-cell Selenot deletion in mice produced an insulin production/secretion deficit and impaired glucose tolerance.
Experimental context and source evidence
- experimental_model
- Human/mouse pancreatic expression and beta-cell-specific Selenot-knockout mice.
- limitations
- Production versus secretion and the direct enzymatic substrate are not fully separated here; the knockout is not a human supplementation trial.
- organism
- Mouse knockout; human and mouse expression
Selenium: literature corrections and mechanism additions · lines 1097–1106
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human/mouse pancreatic expression and beta-cell-specific Selenot-knockout mice. · secondary_verified · secondary_verified
## selenot-beta-cell-insulin In the studied mice, pancreatic cells needed SELENOT for normal insulin output. Pancreatic beta-cell Selenot deletion in mice produced an insulin production/secretion deficit and impaired glucose tolerance. Experimental model: Human/mouse pancreatic expression and beta-cell-specific Selenot-knockout mice. Organism: Mouse knockout; human and mouse expression Limitations: Production versus secretion and the direct enzymatic substrate are not fully separated here; the knockout is not a human supplementation trial. Primary reference: [The PACAP-regulated gene selenoprotein T is abundantly expressed in mouse and human beta-cells and its targeted inactivation impairs glucose tolerance](https://pubmed.ncbi.nlm.nih.gov/23913443/)
Complete structured claim and evidenceTXNRD1 recharges thioredoxin so it can reduce other proteins.
Cytosolic TXNRD1 uses NADPH-derived reducing equivalents to reduce oxidized thioredoxin through its flavin and C-terminal redox centers.
Experimental context and source evidence
- experimental_model
- Purified rat liver cytosolic thioredoxin reductase and recombinant active-site variants.
- limitations
- This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
- organism
- Rat protein and recombinant enzyme assays
Selenium: literature corrections and mechanism additions · lines 965–974
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Purified rat liver cytosolic thioredoxin reductase and recombinant active-site variants. · secondary_verified · secondary_verified
## txnrd1-reduces-txn1 TXNRD1 recharges thioredoxin so it can reduce other proteins. Cytosolic TXNRD1 uses NADPH-derived reducing equivalents to reduce oxidized thioredoxin through its flavin and C-terminal redox centers. Experimental model: Purified rat liver cytosolic thioredoxin reductase and recombinant active-site variants. Organism: Rat protein and recombinant enzyme assays Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Mammalian thioredoxin reductase: C-terminal redox center and selenium-to-sulfur substitution](https://pmc.ncbi.nlm.nih.gov/articles/PMC15961/)
Complete structured claim and evidenceGPX1 uses glutathione to remove hydrogen peroxide.
Classical GPX1 couples hydrogen-peroxide reduction to oxidation of reduced glutathione; water and glutathione disulfide are products.
Experimental context and source evidence
- experimental_model
- Animal selenium status and erythrocyte glutathione-peroxidase biochemistry.
- limitations
- This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
- organism
- Rat
Selenium: literature corrections and mechanism additions · lines 954–963
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Animal selenium status and erythrocyte glutathione-peroxidase biochemistry. · secondary_verified · secondary_verified
## gpx1-peroxide-reduction GPX1 uses glutathione to remove hydrogen peroxide. Classical GPX1 couples hydrogen-peroxide reduction to oxidation of reduced glutathione; water and glutathione disulfide are products. Experimental model: Animal selenium status and erythrocyte glutathione-peroxidase biochemistry. Organism: Rat Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Selenium: biochemical role as a component of glutathione peroxidase](https://pubmed.ncbi.nlm.nih.gov/4686466/)
Complete structured claim and evidenceSELENOF partners with a protein-folding inspection enzyme.
SELENOF associates with human UGGT1 in binding and photo-crosslinking experiments involving ER glycoprotein quality-control proteins.
Experimental context and source evidence
- experimental_model
- Recombinant SELENOF and truncated human UGGT1 binding/crosslinking assays.
- limitations
- Binding is directly measured; exact physiological glycoprotein substrates and obligatory disulfide-repair steps are not established by this result.
- organism
- Human protein constructs
Selenium: literature corrections and mechanism additions · lines 1053–1062
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Recombinant SELENOF and truncated human UGGT1 binding/crosslinking assays. · secondary_verified · secondary_verified
## selenof-binds-uggt1 SELENOF partners with a protein-folding inspection enzyme. SELENOF associates with human UGGT1 in binding and photo-crosslinking experiments involving ER glycoprotein quality-control proteins. Experimental model: Recombinant SELENOF and truncated human UGGT1 binding/crosslinking assays. Organism: Human protein constructs Limitations: Binding is directly measured; exact physiological glycoprotein substrates and obligatory disulfide-repair steps are not established by this result. Primary reference: [Analysis of Selenoprotein F Binding to UDP-Glucose:Glycoprotein Glucosyltransferase by a Photoreactive Crosslinker](https://pubmed.ncbi.nlm.nih.gov/36219527/)
Complete structured claim and evidenceThe SELENOS-p97 connection helps dispose of a tested faulty protein.
SELENOS-p97 interaction contributes to degradation of the ERAD substrate tested in the mutational study.
Experimental context and source evidence
- experimental_model
- Cultured-cell SELENOS mutation, protein-interaction and degradation assays.
- limitations
- Do not generalize one substrate assay to every ERAD substrate or assume dietary deficiency reproduces a binding-site mutation.
- organism
- Cultured mammalian cells
Selenium: literature corrections and mechanism additions · lines 1086–1095
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cultured-cell SELENOS mutation, protein-interaction and degradation assays. · secondary_verified · secondary_verified
## selenos-supports-erad The SELENOS-p97 connection helps dispose of a tested faulty protein. SELENOS-p97 interaction contributes to degradation of the ERAD substrate tested in the mutational study. Experimental model: Cultured-cell SELENOS mutation, protein-interaction and degradation assays. Organism: Cultured mammalian cells Limitations: Do not generalize one substrate assay to every ERAD substrate or assume dietary deficiency reproduces a binding-site mutation. Primary reference: [Pro178 and Pro183 of Selenoprotein S Are Essential Residues for Interaction with p97 during ER-associated Degradation](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022850/)
Complete structured claim and evidenceSELENOS helps connect ER quality control to the p97 protein-handling machinery.
SELENOS interacts with p97/VCP; mutation of Pro178 or Pro183 disrupted this association in the tested cell experiments.
Experimental context and source evidence
- experimental_model
- Cultured-cell SELENOS mutation, protein-interaction and degradation assays.
- limitations
- This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
- organism
- Cultured mammalian cells
Selenium: literature corrections and mechanism additions · lines 1075–1084
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cultured-cell SELENOS mutation, protein-interaction and degradation assays. · secondary_verified · secondary_verified
## selenos-binds-p97 SELENOS helps connect ER quality control to the p97 protein-handling machinery. SELENOS interacts with p97/VCP; mutation of Pro178 or Pro183 disrupted this association in the tested cell experiments. Experimental model: Cultured-cell SELENOS mutation, protein-interaction and degradation assays. Organism: Cultured mammalian cells Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Pro178 and Pro183 of Selenoprotein S Are Essential Residues for Interaction with p97 during ER-associated Degradation](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022850/)
Complete structured claim and evidenceSELENOW interacts with a signaling-regulator protein called 14-3-3 beta.
SELENOW interacts with 14-3-3 beta in the reported cultured-cell redox and thioredoxin-perturbation experiments.
Experimental context and source evidence
- experimental_model
- Cultured-cell protein interactions and etoposide/thioredoxin perturbations.
- limitations
- The tested interaction is not a complete physiological substrate map or proof that all selenium-responsive processes use this partner.
- organism
- Cultured mammalian cells
Selenium: literature corrections and mechanism additions · lines 1108–1117
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cultured-cell protein interactions and etoposide/thioredoxin perturbations. · secondary_verified · secondary_verified
## selenow-interacts-14-3-3 SELENOW interacts with a signaling-regulator protein called 14-3-3 beta. SELENOW interacts with 14-3-3 beta in the reported cultured-cell redox and thioredoxin-perturbation experiments. Experimental model: Cultured-cell protein interactions and etoposide/thioredoxin perturbations. Organism: Cultured mammalian cells Limitations: The tested interaction is not a complete physiological substrate map or proof that all selenium-responsive processes use this partner. Primary reference: [Compensatory Protection of Thioredoxin-Deficient Cells from Etoposide-Induced Cell Death by Selenoprotein W via Interaction with 14-3-3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8508763/)
Complete structured claim and evidenceMSRB1 repairs one specific form of oxidized methionine in proteins.
MSRB1 reduces protein methionine-R-sulfoxide back toward the methionine state; stereochemistry and protein context matter.
Experimental context and source evidence
- experimental_model
- Human and mouse MsrB protein characterization and localization.
- limitations
- This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
- organism
- Human and mouse proteins
Selenium: literature corrections and mechanism additions · lines 1042–1051
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human and mouse MsrB protein characterization and localization. · secondary_verified · secondary_verified
## msrb1-repairs-methionine MSRB1 repairs one specific form of oxidized methionine in proteins. MSRB1 reduces protein methionine-R-sulfoxide back toward the methionine state; stereochemistry and protein context matter. Experimental model: Human and mouse MsrB protein characterization and localization. Organism: Human and mouse proteins Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Methionine sulfoxide reduction in mammals: characterization of methionine-R-sulfoxide reductases](https://pubmed.ncbi.nlm.nih.gov/14699060/)
Complete structured claim and evidenceTXNRD3 helps manage protein sulfur bonds as sperm mature.
Txnrd3 deletion in mice altered sperm protein thiol status, supporting a role for TXNRD3 in sperm redox remodeling.
Experimental context and source evidence
- experimental_model
- Txnrd3-knockout mice, sperm thiol assays and in-vitro fertilization.
- limitations
- This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
- organism
- Mouse
Selenium: literature corrections and mechanism additions · lines 976–985
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Txnrd3-knockout mice, sperm thiol assays and in-vitro fertilization. · secondary_verified · secondary_verified
## txnrd3-sperm-thiol-control TXNRD3 helps manage protein sulfur bonds as sperm mature. Txnrd3 deletion in mice altered sperm protein thiol status, supporting a role for TXNRD3 in sperm redox remodeling. Experimental model: Txnrd3-knockout mice, sperm thiol assays and in-vitro fertilization. Organism: Mouse Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Selenoprotein TXNRD3 supports male fertility via the redox regulation of spermatogenesis](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352919/)
Complete structured claim and evidenceRemoving TXNRD3 impaired fertility in the studied mice.
Male Txnrd3-knockout mice showed impaired reproductive performance and reduced fertilization in the reported assays.
Experimental context and source evidence
- experimental_model
- Txnrd3-knockout mice, sperm thiol assays and in-vitro fertilization.
- limitations
- This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
- organism
- Mouse
Selenium: literature corrections and mechanism additions · lines 987–996
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Txnrd3-knockout mice, sperm thiol assays and in-vitro fertilization. · secondary_verified · secondary_verified
## txnrd3-mouse-fertility Removing TXNRD3 impaired fertility in the studied mice. Male Txnrd3-knockout mice showed impaired reproductive performance and reduced fertilization in the reported assays. Experimental model: Txnrd3-knockout mice, sperm thiol assays and in-vitro fertilization. Organism: Mouse Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Selenoprotein TXNRD3 supports male fertility via the redox regulation of spermatogenesis](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352919/)
Complete structured claim and evidenceThe first SECIS element helps the ribosome continue selenium insertion downstream.
SELENOP SECIS1 supports downstream processive Sec incorporation in the tested constructs.
Experimental context and source evidence
- cell_type
- Transfected cells
- experimental_model
- SELENOP reporter SECIS/UGA mutations in mammalian cells
- limitations
- Transcript structure and experimental setting matter.
- organism
- Zebrafish transcript in mammalian cells
Selenium: literature corrections and mechanism additions · lines 1142–1152
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · SELENOP reporter SECIS/UGA mutations in mammalian cells · secondary_verified · secondary_verified
## secis1-processivity The first SECIS element helps the ribosome continue selenium insertion downstream. SELENOP SECIS1 supports downstream processive Sec incorporation in the tested constructs. Organism: Zebrafish transcript in mammalian cells Cell type: Transfected cells Experimental model: SELENOP reporter SECIS/UGA mutations in mammalian cells Limitations: Transcript structure and experimental setting matter. Primary reference: [Efficient incorporation of multiple selenocysteines involves an inefficient decoding step serving as a potential translational checkpoint and ribosome bottleneck](https://pmc.ncbi.nlm.nih.gov/articles/PMC1698516/)
Complete structured claim and evidenceThe second SECIS element mainly helps the first selenium insertion.
SELENOP SECIS2 preferentially supports first-UGA decoding in the tested constructs.
Experimental context and source evidence
- cell_type
- Transfected cells
- experimental_model
- SELENOP reporter SECIS/UGA mutations in mammalian cells
- limitations
- Functional preference, not exclusive wiring or a universal rate.
- organism
- Zebrafish transcript in mammalian cells
Selenium: literature corrections and mechanism additions · lines 1130–1140
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · SELENOP reporter SECIS/UGA mutations in mammalian cells · secondary_verified · secondary_verified
## secis2-first The second SECIS element mainly helps the first selenium insertion. SELENOP SECIS2 preferentially supports first-UGA decoding in the tested constructs. Organism: Zebrafish transcript in mammalian cells Cell type: Transfected cells Experimental model: SELENOP reporter SECIS/UGA mutations in mammalian cells Limitations: Functional preference, not exclusive wiring or a universal rate. Primary reference: [Efficient incorporation of multiple selenocysteines involves an inefficient decoding step serving as a potential translational checkpoint and ribosome bottleneck](https://pmc.ncbi.nlm.nih.gov/articles/PMC1698516/)
Complete structured claim and evidenceResearchers have experimentally studied spreading ferroptotic death.
Ferroptotic death propagated in the studied cell cultures and embryonic avian tissue.
Experimental context and source evidence
- cell_type
- Studied cultures/tissue
- experimental_model
- Cultured cells and embryonic avian tissue
- limitations
- Does not validate all combustion analogies, numerical thresholds or dietary selenium effects.
- organism
- Mammalian cell cultures and embryonic avian tissue
Selenium: literature corrections and mechanism additions · lines 1480–1490
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cultured cells and embryonic avian tissue · secondary_verified · secondary_verified
## ferroptosis-waves Researchers have experimentally studied spreading ferroptotic death. Ferroptotic death propagated in the studied cell cultures and embryonic avian tissue. Organism: Mammalian cell cultures and embryonic avian tissue Cell type: Studied cultures/tissue Experimental model: Cultured cells and embryonic avian tissue Limitations: Does not validate all combustion analogies, numerical thresholds or dietary selenium effects. Primary reference: [Emergence of large-scale cell death through ferroptotic trigger waves](https://www.nature.com/articles/s41586-024-07623-6)
Complete structured claim and evidenceThese B-cell subsets need GPX4 protection in the mouse experiments.
Gpx4 protects B1 and marginal-zone B cells against lipid peroxidation and ferroptosis in tested mouse deletion models.
Experimental context and source evidence
- cell_type
- B1 and marginal-zone B cells
- experimental_model
- Mouse B-cell-specific Gpx4 deletion
- limitations
- Does not prove ordinary human dietary deficiency deletes these subsets.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1324–1334
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mouse B-cell-specific Gpx4 deletion · secondary_verified · secondary_verified
## b1-gpx4 These B-cell subsets need GPX4 protection in the mouse experiments. Gpx4 protects B1 and marginal-zone B cells against lipid peroxidation and ferroptosis in tested mouse deletion models. Organism: Mus musculus Cell type: B1 and marginal-zone B cells Experimental model: Mouse B-cell-specific Gpx4 deletion Limitations: Does not prove ordinary human dietary deficiency deletes these subsets. Primary reference: [B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/31775041/)
Complete structured claim and evidenceMembrane incorporation follows fatty-acid activation.
LPCAT3-mediated acyl incorporation contributes to arachidonoyl PE formation after fatty-acid activation.
Experimental context and source evidence
- cell_type
- Lung epithelial cells
- experimental_model
- Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics
- limitations
- Substrate preference and ferroptosis dependence vary by cell.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1227–1237
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics · secondary_verified · secondary_verified
## lpcat3-incorporation Membrane incorporation follows fatty-acid activation. LPCAT3-mediated acyl incorporation contributes to arachidonoyl PE formation after fatty-acid activation. Organism: Mus musculus Cell type: Lung epithelial cells Experimental model: Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics Limitations: Substrate preference and ferroptosis dependence vary by cell. Primary reference: [Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis](https://pubmed.ncbi.nlm.nih.gov/27842066/)
Complete structured claim and evidenceThis tRNA modification helps make some selenium proteins more than others.
Sec-tRNA Um34 modification contributes to efficient expression of selected stress-responsive selenoproteins including GPX1.
Experimental context and source evidence
- cell_type
- Mouse tissues and human melanoma cells
- experimental_model
- Transgenic mouse tRNA replacement; mutant affects i6A37 as well as Um34; Biochemistry, human melanoma cells and mouse metastasis/xenograft models
- limitations
- Older tRNA mutant also affects i6A37; no universal exclusive stress/housekeeping routing.
- organism
- Mus musculus and Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1178–1189
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Transgenic mouse tRNA replacement; mutant affects i6A37 as well as Um34; Biochemistry, human melanoma cells and mouse metastasis/xenograft models · secondary_verified · secondary_verified
## um34-selective This tRNA modification helps make some selenium proteins more than others. Sec-tRNA Um34 modification contributes to efficient expression of selected stress-responsive selenoproteins including GPX1. Organism: Mus musculus and Homo sapiens Cell type: Mouse tissues and human melanoma cells Experimental model: Transgenic mouse tRNA replacement; mutant affects i6A37 as well as Um34; Biochemistry, human melanoma cells and mouse metastasis/xenograft models Limitations: Older tRNA mutant also affects i6A37; no universal exclusive stress/housekeeping routing. Primary reference: [Selective rescue of selenoprotein expression in mice lacking a highly specialized methyl group in selenocysteine tRNA](https://digitalcommons.unl.edu/biochemgladyshev/54/) Primary reference: [Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis](https://www.nature.com/articles/s43018-024-00844-8)
Complete structured claim and evidenceAn antioxidant system can enable an inflammatory response in some settings.
The Trx1 system controls excessive ROS and permits NLRP3-dependent IL-1beta production in the tested Txnip-independent macrophage settings.
Experimental context and source evidence
- cell_type
- Macrophages
- experimental_model
- Mouse macrophage gene perturbation/inflammasome experiments
- limitations
- Specific lineage/stimuli; not a universal dietary selenium effect.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1372–1382
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mouse macrophage gene perturbation/inflammasome experiments · secondary_verified · secondary_verified
## trx1-inflammasome An antioxidant system can enable an inflammatory response in some settings. The Trx1 system controls excessive ROS and permits NLRP3-dependent IL-1beta production in the tested Txnip-independent macrophage settings. Organism: Mus musculus Cell type: Macrophages Experimental model: Mouse macrophage gene perturbation/inflammasome experiments Limitations: Specific lineage/stimuli; not a universal dietary selenium effect. Primary reference: [Thioredoxin-1 distinctly promotes NF-kB target DNA binding and NLRP3 inflammasome activation independently of Txnip](https://elifesciences.org/articles/53627)
Complete structured claim and evidenceDendritic cells can supply cysteine by exporting and breaking down glutathione.
Dendritic-cell GSH secretion followed by extracellular cleavage contributes extracellular cysteine in mouse DC/T-cell coculture.
Experimental context and source evidence
- cell_type
- Dendritic cells and T cells
- experimental_model
- Mouse DC/T-cell cocultures
- limitations
- Distinct from an unproven secreted TrxR1 circuit; not the sole established route in humans.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1312–1322
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mouse DC/T-cell cocultures · secondary_verified · secondary_verified
## dc-gsh-cysteine Dendritic cells can supply cysteine by exporting and breaking down glutathione. Dendritic-cell GSH secretion followed by extracellular cleavage contributes extracellular cysteine in mouse DC/T-cell coculture. Organism: Mus musculus Cell type: Dendritic cells and T cells Experimental model: Mouse DC/T-cell cocultures Limitations: Distinct from an unproven secreted TrxR1 circuit; not the sole established route in humans. Primary reference: [Extracellular redox modulation by regulatory T cells](https://pmc.ncbi.nlm.nih.gov/articles/PMC2760945/)
Complete structured claim and evidenceMethylselenol can cycle between redox states under suitable conditions.
Methylselenol participates in aerobic redox cycling with thioredoxin/glutaredoxin reductant systems in biochemical assays.
Experimental context and source evidence
- cell_type
- Purified reductant systems
- experimental_model
- Purified reductant systems and cell comparisons
- limitations
- Depends on generation, oxygen and reductants; not a direct prediction of cellular ROS or clinical benefit.
- organism
- Biochemical systems
Selenium: literature corrections and mechanism additions · lines 1420–1430
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Purified reductant systems and cell comparisons · secondary_verified · secondary_verified
## methylselenol-cycling Methylselenol can cycle between redox states under suitable conditions. Methylselenol participates in aerobic redox cycling with thioredoxin/glutaredoxin reductant systems in biochemical assays. Organism: Biochemical systems Cell type: Purified reductant systems Experimental model: Purified reductant systems and cell comparisons Limitations: Depends on generation, oxygen and reductants; not a direct prediction of cellular ROS or clinical benefit. Primary reference: [Methylselenol Formed by Spontaneous Methylation of Selenide Is a Superior Selenium Substrate to the Thioredoxin and Glutaredoxin Systems](https://pmc.ncbi.nlm.nih.gov/articles/PMC3511371/)
Complete structured claim and evidenceEfficiency depends on the RNA and test conditions.
Human SECIS elements show widely differing reporter recoding activities, precluding a universal endogenous 5–10 percent efficiency inference.
Experimental context and source evidence
- cell_type
- HEK293 and HepG2 reporters
- experimental_model
- 26 human SECIS reporters in HEK293/HepG2 and cell-free translation
- limitations
- Reporter activity is not a direct count of all endogenous translation outcomes.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1203–1213
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · 26 human SECIS reporters in HEK293/HepG2 and cell-free translation · secondary_verified · secondary_verified
## secis-variable Efficiency depends on the RNA and test conditions. Human SECIS elements show widely differing reporter recoding activities, precluding a universal endogenous 5–10 percent efficiency inference. Organism: Homo sapiens Cell type: HEK293 and HepG2 reporters Experimental model: 26 human SECIS reporters in HEK293/HepG2 and cell-free translation Limitations: Reporter activity is not a direct count of all endogenous translation outcomes. Primary reference: [Novel structural determinants in human SECIS elements modulate the translational recoding of UGA as selenocysteine](https://pmc.ncbi.nlm.nih.gov/articles/PMC2761289/)
Complete structured claim and evidenceInflammation can reduce selenium-carrier production independently of intake.
IL-6 lowers hepatic SELENOP expression and secretion in human hepatocyte cultures.
Experimental context and source evidence
- cell_type
- Hepatocytes
- experimental_model
- Human hepatocyte cultures
- limitations
- Adaptive withholding untested; acute illness can coexist with true deficiency.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1408–1418
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human hepatocyte cultures · secondary_verified · secondary_verified
## il6-selenop Inflammation can reduce selenium-carrier production independently of intake. IL-6 lowers hepatic SELENOP expression and secretion in human hepatocyte cultures. Organism: Homo sapiens Cell type: Hepatocytes Experimental model: Human hepatocyte cultures Limitations: Adaptive withholding untested; acute illness can coexist with true deficiency. Primary reference: [Gene-specific regulation of hepatic selenoprotein expression by interleukin-6](https://pubs.rsc.org/en/content/articlelanding/2015/mt/c5mt00211g)
Complete structured claim and evidenceActivated T cells can import cystine; resting cells need separate treatment.
Activated human CD4/CD8 T lymphocytes upregulate xCT and cystine uptake after TCR stimulation.
Experimental context and source evidence
- cell_type
- Activated CD4 and CD8 T cells
- experimental_model
- TCR-stimulated human CD4/CD8 lymphocytes
- limitations
- Not universal basal uptake in resting cells or a selenium supplementation result.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1300–1310
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · TCR-stimulated human CD4/CD8 lymphocytes · secondary_verified · secondary_verified
## activated-xct Activated T cells can import cystine; resting cells need separate treatment. Activated human CD4/CD8 T lymphocytes upregulate xCT and cystine uptake after TCR stimulation. Organism: Homo sapiens Cell type: Activated CD4 and CD8 T cells Experimental model: TCR-stimulated human CD4/CD8 lymphocytes Limitations: Not universal basal uptake in resting cells or a selenium supplementation result. Primary reference: [Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes](https://pmc.ncbi.nlm.nih.gov/articles/PMC5065394/)
Complete structured claim and evidenceSome archaea also make cysteine while it is attached to tRNA.
Archaeal SepCysS converts tRNA-bound phosphoserine into Cys-tRNA; Sec is therefore not uniquely synthesized on tRNA across all life.
Experimental context and source evidence
- cell_type
- Archaeal cells
- experimental_model
- Methanocaldococcus jannaschii enzymes and Methanococcus maripaludis genetics
- limitations
- This is not a human cysteine biosynthesis pathway.
- organism
- Methanocaldococcus jannaschii and Methanococcus maripaludis
Selenium: literature corrections and mechanism additions · lines 1166–1176
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Methanocaldococcus jannaschii enzymes and Methanococcus maripaludis genetics · secondary_verified · secondary_verified
## archaeal-cys-trna Some archaea also make cysteine while it is attached to tRNA. Archaeal SepCysS converts tRNA-bound phosphoserine into Cys-tRNA; Sec is therefore not uniquely synthesized on tRNA across all life. Organism: Methanocaldococcus jannaschii and Methanococcus maripaludis Cell type: Archaeal cells Experimental model: Methanocaldococcus jannaschii enzymes and Methanococcus maripaludis genetics Limitations: This is not a human cysteine biosynthesis pathway. Primary reference: [RNA-Dependent Cysteine Biosynthesis in Archaea](https://pubmed.ncbi.nlm.nih.gov/15790858/)
Complete structured claim and evidenceTXNIP can help activate this inflammatory pathway in particular settings.
TXNIP contributes to NLRP3 activation in the metabolic/oxidative-stress settings tested by Zhou and colleagues.
Experimental context and source evidence
- cell_type
- Studied metabolic/inflammatory cells
- experimental_model
- Cellular and mouse metabolic/oxidative-stress models
- limitations
- Other macrophage settings show Txnip-independent IL-1beta production.
- organism
- Mus musculus and cell models
Selenium: literature corrections and mechanism additions · lines 1360–1370
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cellular and mouse metabolic/oxidative-stress models · secondary_verified · secondary_verified
## txnip-nlrp3 TXNIP can help activate this inflammatory pathway in particular settings. TXNIP contributes to NLRP3 activation in the metabolic/oxidative-stress settings tested by Zhou and colleagues. Organism: Mus musculus and cell models Cell type: Studied metabolic/inflammatory cells Experimental model: Cellular and mouse metabolic/oxidative-stress models Limitations: Other macrophage settings show Txnip-independent IL-1beta production. Primary reference: [Thioredoxin-interacting protein links oxidative stress to inflammasome activation](https://pubmed.ncbi.nlm.nih.gov/20023662/)
Complete structured claim and evidenceReplacing selenium with sulfur retains some function but weakens peroxide resistance.
GPX4 Sec-to-Cys substitution retains context-dependent residual function but increases peroxide-induced inactivation and ferroptosis susceptibility.
Experimental context and source evidence
- cell_type
- Knock-in tissues and derived/engineered cells
- experimental_model
- Gpx4 Sec-to-Cys knock-in mice, tissue assays and cell peroxide challenges
- limitations
- Tissue PCOOH activity was undetectable in reported brain/kidney assays; mutation is not nutritional deficiency.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1263–1273
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Gpx4 Sec-to-Cys knock-in mice, tissue assays and cell peroxide challenges · secondary_verified · secondary_verified
## gpx4-cys-vulnerability Replacing selenium with sulfur retains some function but weakens peroxide resistance. GPX4 Sec-to-Cys substitution retains context-dependent residual function but increases peroxide-induced inactivation and ferroptosis susceptibility. Organism: Mus musculus Cell type: Knock-in tissues and derived/engineered cells Experimental model: Gpx4 Sec-to-Cys knock-in mice, tissue assays and cell peroxide challenges Limitations: Tissue PCOOH activity was undetectable in reported brain/kidney assays; mutation is not nutritional deficiency. Primary reference: [Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/29290465/)
Complete structured claim and evidenceAn enzyme environment can make cysteine reactive near physiological pH.
Purified bacterial AhpC catalytic cysteine has a measured pKa near 5.9, below the free-cysteine value generalized in the source.
Experimental context and source evidence
- cell_type
- Purified enzyme
- experimental_model
- Purified Salmonella typhimurium AhpC kinetic/spectroscopic assays
- limitations
- One bacterial peroxiredoxin, not a numerical pKa for every protein.
- organism
- Salmonella typhimurium
Selenium: literature corrections and mechanism additions · lines 1239–1249
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Purified Salmonella typhimurium AhpC kinetic/spectroscopic assays · secondary_verified · secondary_verified
## ahpc-low-pka An enzyme environment can make cysteine reactive near physiological pH. Purified bacterial AhpC catalytic cysteine has a measured pKa near 5.9, below the free-cysteine value generalized in the source. Organism: Salmonella typhimurium Cell type: Purified enzyme Experimental model: Purified Salmonella typhimurium AhpC kinetic/spectroscopic assays Limitations: One bacterial peroxiredoxin, not a numerical pKa for every protein. Primary reference: [Cysteine pKa values for the bacterial peroxiredoxin AhpC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2645924/)
Complete structured claim and evidenceRemoving the Y505 phosphate can release LCK inhibition.
CD45 removal of inhibitory LCK Y505 phosphorylation can favor an open activation-competent state.
Experimental context and source evidence
- cell_type
- T-cell and biochemical assays
- experimental_model
- Biochemical LCK/CD45 phosphorylation assays; CD45-deficient cells and LCK binding/phosphorylation experiments
- limitations
- Net effect depends on concentration/localization and both sites; no selenium-dependent site effect established.
- organism
- Mammalian biochemical and T-cell systems
Selenium: literature corrections and mechanism additions · lines 1275–1286
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical LCK/CD45 phosphorylation assays; CD45-deficient cells and LCK binding/phosphorylation experiments · secondary_verified · secondary_verified
## cd45-y505 Removing the Y505 phosphate can release LCK inhibition. CD45 removal of inhibitory LCK Y505 phosphorylation can favor an open activation-competent state. Organism: Mammalian biochemical and T-cell systems Cell type: T-cell and biochemical assays Experimental model: Biochemical LCK/CD45 phosphorylation assays; CD45-deficient cells and LCK binding/phosphorylation experiments Limitations: Net effect depends on concentration/localization and both sites; no selenium-dependent site effect established. Primary reference: [The noncatalytic domains of Lck regulate its dephosphorylation by CD45](https://pubmed.ncbi.nlm.nih.gov/12922168/) Primary reference: [CD45 specifically modulates binding of Lck to a phosphopeptide encompassing the negative regulatory tyrosine of Lck.](https://pubmed.ncbi.nlm.nih.gov/8428589/)
Complete structured claim and evidenceAnother defense changes how vulnerable cells are to GPX4 loss.
FSP1 reduces CoQ and supplies a lipid-radical defense operating in parallel with GPX4.
Experimental context and source evidence
- cell_type
- Experimental cultured cells
- experimental_model
- Cell genetics and biochemical experiments
- limitations
- Capacity and dependence vary by cell; not a universal dietary threshold.
- organism
- Human cell models
Selenium: literature corrections and mechanism additions · lines 1492–1502
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cell genetics and biochemical experiments · secondary_verified · secondary_verified
## fsp1-parallel Another defense changes how vulnerable cells are to GPX4 loss. FSP1 reduces CoQ and supplies a lipid-radical defense operating in parallel with GPX4. Organism: Human cell models Cell type: Experimental cultured cells Experimental model: Cell genetics and biochemical experiments Limitations: Capacity and dependence vary by cell; not a universal dietary threshold. Primary reference: [The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis](https://www.nature.com/articles/s41586-019-1705-2)
Complete structured claim and evidenceThe PLCG1/calcium execution phase follows gasdermin cleavage.
GSDMD-N-induced cytotoxicity involves PLCG1 and calcium downstream of GSDMD cleavage in the tested macrophage model.
Experimental context and source evidence
- cell_type
- Macrophages
- experimental_model
- Myeloid Gpx4 models, macrophage cytosolic LPS/E. coli and mouse sepsis
- limitations
- Does not put PLCG1 downstream in every inflammatory signaling pathway.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1396–1406
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Myeloid Gpx4 models, macrophage cytosolic LPS/E. coli and mouse sepsis · secondary_verified · secondary_verified
## gsdmd-plcg1 The PLCG1/calcium execution phase follows gasdermin cleavage. GSDMD-N-induced cytotoxicity involves PLCG1 and calcium downstream of GSDMD cleavage in the tested macrophage model. Organism: Mus musculus Cell type: Macrophages Experimental model: Myeloid Gpx4 models, macrophage cytosolic LPS/E. coli and mouse sepsis Limitations: Does not put PLCG1 downstream in every inflammatory signaling pathway. Primary reference: [Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis](https://pmc.ncbi.nlm.nih.gov/articles/PMC6043361/)
Complete structured claim and evidenceSEPSECS uses selenium from the donor to finish the tRNA-bound amino acid.
PLP-dependent SEPSECS converts phosphoseryl-tRNA Sec to Sec-tRNA through phosphate elimination and selenium donation from selenophosphate, not incorporation of intact selenophosphate.
Experimental context and source evidence
- cell_type
- Purified enzyme/tRNA
- experimental_model
- Human enzyme/tRNA crystallography and biochemical assays
- limitations
- Not a measurement of dietary intake effects.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1154–1164
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human enzyme/tRNA crystallography and biochemical assays · secondary_verified · secondary_verified
## sepsecs-chemistry SEPSECS uses selenium from the donor to finish the tRNA-bound amino acid. PLP-dependent SEPSECS converts phosphoseryl-tRNA Sec to Sec-tRNA through phosphate elimination and selenium donation from selenophosphate, not incorporation of intact selenophosphate. Organism: Homo sapiens Cell type: Purified enzyme/tRNA Experimental model: Human enzyme/tRNA crystallography and biochemical assays Limitations: Not a measurement of dietary intake effects. Primary reference: [The human SepSecS–tRNASec complex reveals mechanism of selenocysteine formation](https://pubmed.ncbi.nlm.nih.gov/19608919/)
Complete structured claim and evidenceCaspases cut gasdermin before its execution fragment acts.
Inflammatory caspase activation cleaves GSDMD to produce its cytotoxic N-terminal fragment in the inspected pyroptosis pathway.
Experimental context and source evidence
- cell_type
- Macrophages
- experimental_model
- Myeloid Gpx4 models, macrophage cytosolic LPS/E. coli and mouse sepsis
- limitations
- Not a demonstrated complete human dietary-deficiency sequence.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1384–1394
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Myeloid Gpx4 models, macrophage cytosolic LPS/E. coli and mouse sepsis · secondary_verified · secondary_verified
## caspase-gsdmd Caspases cut gasdermin before its execution fragment acts. Inflammatory caspase activation cleaves GSDMD to produce its cytotoxic N-terminal fragment in the inspected pyroptosis pathway. Organism: Mus musculus Cell type: Macrophages Experimental model: Myeloid Gpx4 models, macrophage cytosolic LPS/E. coli and mouse sepsis Limitations: Not a demonstrated complete human dietary-deficiency sequence. Primary reference: [Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis](https://pmc.ncbi.nlm.nih.gov/articles/PMC6043361/)
Complete structured claim and evidenceACSL4 prepares the fatty acid for membrane incorporation.
ACSL4 activates arachidonic acid to arachidonoyl-CoA upstream of phospholipid incorporation.
Experimental context and source evidence
- cell_type
- Experimental cell models
- experimental_model
- Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics
- limitations
- Not proof of ACSL4 dependence in every ferroptosis model.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1215–1225
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics · secondary_verified · secondary_verified
## acsl4-activation ACSL4 prepares the fatty acid for membrane incorporation. ACSL4 activates arachidonic acid to arachidonoyl-CoA upstream of phospholipid incorporation. Organism: Mus musculus Cell type: Experimental cell models Experimental model: Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics Limitations: Not proof of ACSL4 dependence in every ferroptosis model. Primary reference: [Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis](https://pubmed.ncbi.nlm.nih.gov/27842066/)
Complete structured claim and evidenceThis distinct metabolite can inhibit tested histone-deacetylase activity.
Methylselenopyruvate inhibits HDAC activity in the reported enzyme/cancer-cell experiments.
Experimental context and source evidence
- cell_type
- Cancer cells and biochemical systems
- experimental_model
- Enzyme and human cancer-cell assays
- limitations
- Not interchangeable with parent compounds or proof of dietary cancer prevention.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1432–1442
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Enzyme and human cancer-cell assays · secondary_verified · secondary_verified
## msp-hdac This distinct metabolite can inhibit tested histone-deacetylase activity. Methylselenopyruvate inhibits HDAC activity in the reported enzyme/cancer-cell experiments. Organism: Homo sapiens Cell type: Cancer cells and biochemical systems Experimental model: Enzyme and human cancer-cell assays Limitations: Not interchangeable with parent compounds or proof of dietary cancer prevention. Primary reference: [α-Keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells](https://pmc.ncbi.nlm.nih.gov/articles/PMC2718078/)
Complete structured claim and evidenceThis second distinct metabolite can also inhibit tested histone-deacetylase activity.
Keto-methylselenobutyrate inhibits HDAC activity in the reported enzyme/cancer-cell experiments.
Experimental context and source evidence
- cell_type
- Cancer cells and biochemical systems
- experimental_model
- Enzyme and human cancer-cell assays
- limitations
- Not interchangeable with parent compounds or proof of dietary cancer prevention.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1444–1454
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Enzyme and human cancer-cell assays · secondary_verified · secondary_verified
## kmsb-hdac This second distinct metabolite can also inhibit tested histone-deacetylase activity. Keto-methylselenobutyrate inhibits HDAC activity in the reported enzyme/cancer-cell experiments. Organism: Homo sapiens Cell type: Cancer cells and biochemical systems Experimental model: Enzyme and human cancer-cell assays Limitations: Not interchangeable with parent compounds or proof of dietary cancer prevention. Primary reference: [α-Keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells](https://pmc.ncbi.nlm.nih.gov/articles/PMC2718078/)
Complete structured claim and evidenceSharing a receptor does not mean uptake requires the same signaling adaptor.
ApoER2 intracellular-domain mutant experiments separate selenium uptake from its Dab1-associated signaling requirement.
Experimental context and source evidence
- cell_type
- Brain and testis tissue
- experimental_model
- ApoER2 domain-mutant mice; brain/testis selenium assays
- limitations
- Does not rule out every possible cross-talk or competition mechanism.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1468–1478
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · ApoER2 domain-mutant mice; brain/testis selenium assays · secondary_verified · secondary_verified
## lrp8-dab1-separation Sharing a receptor does not mean uptake requires the same signaling adaptor. ApoER2 intracellular-domain mutant experiments separate selenium uptake from its Dab1-associated signaling requirement. Organism: Mus musculus Cell type: Brain and testis tissue Experimental model: ApoER2 domain-mutant mice; brain/testis selenium assays Limitations: Does not rule out every possible cross-talk or competition mechanism. Primary reference: [Differential Functions of the Apoer2 Intracellular Domain in Selenium Uptake and Cell Signaling](https://pmc.ncbi.nlm.nih.gov/articles/PMC2642607/)
Complete structured claim and evidenceSome overoxidized cysteine enzymes can be repaired.
Sulfiredoxin catalyzes ATP-dependent repair of typical 2-Cys peroxiredoxin sulfinic acid.
Experimental context and source evidence
- cell_type
- Purified enzymes
- experimental_model
- Purified human sulfiredoxin/peroxiredoxin enzymology
- limitations
- Does not establish repair of GPX4-Cys or every cysteine sulfinic acid.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1251–1261
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Purified human sulfiredoxin/peroxiredoxin enzymology · secondary_verified · secondary_verified
## srxn-repair Some overoxidized cysteine enzymes can be repaired. Sulfiredoxin catalyzes ATP-dependent repair of typical 2-Cys peroxiredoxin sulfinic acid. Organism: Homo sapiens Cell type: Purified enzymes Experimental model: Purified human sulfiredoxin/peroxiredoxin enzymology Limitations: Does not establish repair of GPX4-Cys or every cysteine sulfinic acid. Primary reference: [Reduction of cysteine sulfinic acid in peroxiredoxin by sulfiredoxin proceeds directly through a sulfinic phosphoryl ester intermediate](https://pubmed.ncbi.nlm.nih.gov/18579529/)
Complete structured claim and evidenceThe same deletion did not eliminate the measured germinal-center response.
Follicular B2 development, germinal-center reactions and antibody responses were preserved after B-cell Gpx4 deletion in the tested mice.
Experimental context and source evidence
- cell_type
- Follicular B2 and germinal-center B cells
- experimental_model
- Mouse B-cell-specific Gpx4 deletion
- limitations
- Restricted to tested genetic/immunization conditions, not universal dispensability.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1336–1346
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mouse B-cell-specific Gpx4 deletion · secondary_verified · secondary_verified
## b2-gpx4-context The same deletion did not eliminate the measured germinal-center response. Follicular B2 development, germinal-center reactions and antibody responses were preserved after B-cell Gpx4 deletion in the tested mice. Organism: Mus musculus Cell type: Follicular B2 and germinal-center B cells Experimental model: Mouse B-cell-specific Gpx4 deletion Limitations: Restricted to tested genetic/immunization conditions, not universal dispensability. Primary reference: [B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/31775041/)
Complete structured claim and evidenceRemoving the Y394 phosphate reduces an activating LCK signal.
CD45 removal of activation-loop LCK Y394 phosphorylation reduces activating phosphorylation.
Experimental context and source evidence
- cell_type
- Purified kinase/phosphatase
- experimental_model
- Biochemical LCK/CD45 phosphorylation assays
- limitations
- Site effect does not determine total cellular output or dietary selenium response.
- organism
- Mammalian biochemical systems
Selenium: literature corrections and mechanism additions · lines 1288–1298
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical LCK/CD45 phosphorylation assays · secondary_verified · secondary_verified
## cd45-y394 Removing the Y394 phosphate reduces an activating LCK signal. CD45 removal of activation-loop LCK Y394 phosphorylation reduces activating phosphorylation. Organism: Mammalian biochemical systems Cell type: Purified kinase/phosphatase Experimental model: Biochemical LCK/CD45 phosphorylation assays Limitations: Site effect does not determine total cellular output or dietary selenium response. Primary reference: [The noncatalytic domains of Lck regulate its dephosphorylation by CD45](https://pubmed.ncbi.nlm.nih.gov/12922168/)
Complete structured claim and evidenceFTSJ1 is the enzyme for the formerly unassigned methylation step.
FTSJ1 catalyzes Sec-tRNA U34 ribose methylation producing the Um34-containing form.
Experimental context and source evidence
- cell_type
- Melanoma cells and biochemical systems
- experimental_model
- Biochemistry, human melanoma cells and mouse metastasis/xenograft models
- limitations
- FTSJ1 deletion is not ordinary dietary selenium deficiency.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1191–1201
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemistry, human melanoma cells and mouse metastasis/xenograft models · secondary_verified · secondary_verified
## ftsj1-um34 FTSJ1 is the enzyme for the formerly unassigned methylation step. FTSJ1 catalyzes Sec-tRNA U34 ribose methylation producing the Um34-containing form. Organism: Homo sapiens Cell type: Melanoma cells and biochemical systems Experimental model: Biochemistry, human melanoma cells and mouse metastasis/xenograft models Limitations: FTSJ1 deletion is not ordinary dietary selenium deficiency. Primary reference: [Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis](https://www.nature.com/articles/s43018-024-00844-8)
Complete structured claim and evidenceProtection of helper T cells is a distinct route to supporting antibody responses.
GPX4 protects follicular helper T cells from ferroptosis in the studied T-cell-specific models.
Experimental context and source evidence
- cell_type
- Follicular helper T cells
- experimental_model
- Mouse T-cell/Tfh experiments and young-adult influenza vaccination study
- limitations
- Not B-cell-intrinsic or proof of all vaccine effects; interpret corrected article.
- organism
- Mus musculus
Selenium: literature corrections and mechanism additions · lines 1348–1358
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mouse T-cell/Tfh experiments and young-adult influenza vaccination study · secondary_verified · secondary_verified
## tfh-gpx4 Protection of helper T cells is a distinct route to supporting antibody responses. GPX4 protects follicular helper T cells from ferroptosis in the studied T-cell-specific models. Organism: Mus musculus Cell type: Follicular helper T cells Experimental model: Mouse T-cell/Tfh experiments and young-adult influenza vaccination study Limitations: Not B-cell-intrinsic or proof of all vaccine effects; interpret corrected article. Primary reference: [Selenium-GPX4 axis protects follicular helper T cells from ferroptosis](https://www.nature.com/articles/s41590-021-00996-0)
Complete structured claim and evidenceSeMet can supply functional selenium as well as enter protein storage.
SeMet supplementation increased functional selenium biomarkers including SELENOP and plasma GPX activity in selenium-deficient people.
Experimental context and source evidence
- cell_type
- Circulating biomarkers
- experimental_model
- Randomized SeMet supplementation in selenium-deficient people
- limitations
- Baseline-deficient population; not disease-prevention evidence in selenium-replete people.
- organism
- Homo sapiens
Selenium: literature corrections and mechanism additions · lines 1456–1466
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Randomized SeMet supplementation in selenium-deficient people · secondary_verified · secondary_verified
## semet-functional SeMet can supply functional selenium as well as enter protein storage. SeMet supplementation increased functional selenium biomarkers including SELENOP and plasma GPX activity in selenium-deficient people. Organism: Homo sapiens Cell type: Circulating biomarkers Experimental model: Randomized SeMet supplementation in selenium-deficient people Limitations: Baseline-deficient population; not disease-prevention evidence in selenium-replete people. Primary reference: [Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: a placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects](https://pubmed.ncbi.nlm.nih.gov/20573787/)
Complete structured claim and evidenceSEPHS2 prepares selenium for the machinery that builds selenoproteins.
SEPHS2 supplies the activated selenium donor used for Sec-tRNA synthesis; mammalian loss/rescue experiments establish its biosynthetic requirement.
Experimental context and source evidence
- experimental_model
- Mammalian cell knockdown/rescue and selenoprotein synthesis assays.
- limitations
- Requirement for biosynthesis does not prove that SEPHS2 is always the last selenoprotein preserved during dietary restriction.
- organism
- Mammalian cultured cells
Selenium: literature corrections and mechanism additions · lines 1119–1128
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mammalian cell knockdown/rescue and selenoprotein synthesis assays. · secondary_verified · secondary_verified
## sephs2-selenium-donor-supply SEPHS2 prepares selenium for the machinery that builds selenoproteins. SEPHS2 supplies the activated selenium donor used for Sec-tRNA synthesis; mammalian loss/rescue experiments establish its biosynthetic requirement. Experimental model: Mammalian cell knockdown/rescue and selenoprotein synthesis assays. Organism: Mammalian cultured cells Limitations: Requirement for biosynthesis does not prove that SEPHS2 is always the last selenoprotein preserved during dietary restriction. Primary reference: [Selenophosphate synthetase 2 is essential for selenoprotein biosynthesis](https://pmc.ncbi.nlm.nih.gov/articles/PMC1868833/)
Complete structured claim and evidenceDIO3 lowers thyroid-hormone activity by converting T4 to reverse T3.
DIO3 catalyzes inner-ring deiodination of T4 to reverse T3 in functional placental-enzyme studies.
Experimental context and source evidence
- experimental_model
- Human placental DIO3 cloning and functional expression.
- limitations
- This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
- organism
- Human placental protein in an expression system
Selenium: literature corrections and mechanism additions · lines 1020–1029
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human placental DIO3 cloning and functional expression. · secondary_verified · secondary_verified
## dio3-thyroxine-inactivation DIO3 lowers thyroid-hormone activity by converting T4 to reverse T3. DIO3 catalyzes inner-ring deiodination of T4 to reverse T3 in functional placental-enzyme studies. Experimental model: Human placental DIO3 cloning and functional expression. Organism: Human placental protein in an expression system Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Type 3 iodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme](https://www.jci.org/articles/view/118299)
Complete structured claim and evidenceDIO3 lowers thyroid-hormone activity by converting T3 to 3,3-prime-T2.
DIO3 catalyzes inner-ring deiodination of T3 to 3,3-prime-T2 in functional placental-enzyme studies.
Experimental context and source evidence
- experimental_model
- Human placental DIO3 cloning and functional expression.
- limitations
- This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
- organism
- Human placental protein in an expression system
Selenium: literature corrections and mechanism additions · lines 1031–1040
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human placental DIO3 cloning and functional expression. · secondary_verified · secondary_verified
## dio3-triiodothyronine-inactivation DIO3 lowers thyroid-hormone activity by converting T3 to 3,3-prime-T2. DIO3 catalyzes inner-ring deiodination of T3 to 3,3-prime-T2 in functional placental-enzyme studies. Experimental model: Human placental DIO3 cloning and functional expression. Organism: Human placental protein in an expression system Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Type 3 iodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme](https://www.jci.org/articles/view/118299)
Complete structured claim and evidenceDIO2 converts T4 into the active thyroid hormone T3.
DIO2 catalyzes outer-ring deiodination of T4 to T3 in functional enzyme-expression experiments.
Experimental context and source evidence
- experimental_model
- Rat and human DIO2 cDNA characterization and functional expression.
- limitations
- This reaction alone cannot diagnose hidden tissue hypothyroidism from normal blood tests or quantify benefit from selenium intake.
- organism
- Human and rat
Selenium: literature corrections and mechanism additions · lines 1009–1018
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Rat and human DIO2 cDNA characterization and functional expression. · secondary_verified · secondary_verified
## dio2-t4-to-t3 DIO2 converts T4 into the active thyroid hormone T3. DIO2 catalyzes outer-ring deiodination of T4 to T3 in functional enzyme-expression experiments. Experimental model: Rat and human DIO2 cDNA characterization and functional expression. Organism: Human and rat Limitations: This reaction alone cannot diagnose hidden tissue hypothyroidism from normal blood tests or quantify benefit from selenium intake. Primary reference: [Cloning of the mammalian type II iodothyronine deiodinase](https://www.jci.org/articles/view/118806)
Complete structured claim and evidenceDIO1 converts T4 into the active thyroid hormone T3.
DIO1 catalyzes outer-ring deiodination of T4 to T3 in functional enzyme-expression experiments.
Experimental context and source evidence
- experimental_model
- Human liver/kidney cDNA cloning and heterologous enzyme expression.
- limitations
- This reaction alone cannot diagnose hidden tissue hypothyroidism from normal blood tests or quantify benefit from selenium intake.
- organism
- Human protein in a heterologous expression system
Selenium: literature corrections and mechanism additions · lines 998–1007
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human liver/kidney cDNA cloning and heterologous enzyme expression. · secondary_verified · secondary_verified
## dio1-t4-to-t3 DIO1 converts T4 into the active thyroid hormone T3. DIO1 catalyzes outer-ring deiodination of T4 to T3 in functional enzyme-expression experiments. Experimental model: Human liver/kidney cDNA cloning and heterologous enzyme expression. Organism: Human protein in a heterologous expression system Limitations: This reaction alone cannot diagnose hidden tissue hypothyroidism from normal blood tests or quantify benefit from selenium intake. Primary reference: [Cloning and in vitro expression of the human selenoprotein, type I iodothyronine deiodinase](https://pubmed.ncbi.nlm.nih.gov/1400883/)
Complete structured claim and evidenceA separate enzyme completes the characteristic plasmalogen bond.
TMEM189/PEDS1 introduces the vinyl ether double bond that converts plasmanyl-PE to plasmenyl-PE.
Experimental context and source evidence
- cell_type
- HAP1 cells and tissues
- experimental_model
- Knockout and rescue
- limitations
- TMEM189 is not a selenoprotein; reaction is downstream of SELENOI.
- organism
- human and mouse
Selenium: literature corrections and mechanism additions · lines 750–760
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Knockout and rescue · secondary_verified · secondary_verified
## tmem189-forms-plasmenyl-pe A separate enzyme completes the characteristic plasmalogen bond. TMEM189/PEDS1 introduces the vinyl ether double bond that converts plasmanyl-PE to plasmenyl-PE. Organism: human and mouse Cell type: HAP1 cells and tissues Experimental model: Knockout and rescue Limitations: TMEM189 is not a selenoprotein; reaction is downstream of SELENOI. Primary reference: [The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens](https://pubmed.ncbi.nlm.nih.gov/32209662/)
Complete structured claim and evidenceSELENOI also builds an ether-linked PE precursor.
SELENOI uses CDP-ethanolamine and alkyl-acylglycerol to produce plasmanyl-PE and CMP.
Experimental context and source evidence
- cell_type
- patient fibroblasts and HeLa
- experimental_model
- Lipid synthesis and genetic studies
- limitations
- Plasmanyl-PE is distinct from plasmenyl-PE.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 738–748
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Lipid synthesis and genetic studies · secondary_verified · secondary_verified
## selenoi-synthesizes-plasmanyl-pe SELENOI also builds an ether-linked PE precursor. SELENOI uses CDP-ethanolamine and alkyl-acylglycerol to produce plasmanyl-PE and CMP. Organism: human Cell type: patient fibroblasts and HeLa Experimental model: Lipid synthesis and genetic studies Limitations: Plasmanyl-PE is distinct from plasmenyl-PE. Primary reference: [EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans](https://pmc.ncbi.nlm.nih.gov/articles/PMC5983406/)
Complete structured claim and evidenceGPX3 can remove peroxide outside cells.
Purified human plasma glutathione peroxidase reduced hydrogen peroxide using glutathione.
Experimental context and source evidence
- cell_type
- plasma
- experimental_model
- Purified enzyme kinetics
- limitations
- Assay glutathione availability does not define every physiological electron donor.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 678–688
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Purified enzyme kinetics · secondary_verified · secondary_verified
## gpx3-reduces-extracellular-peroxide GPX3 can remove peroxide outside cells. Purified human plasma glutathione peroxidase reduced hydrogen peroxide using glutathione. Organism: human Cell type: plasma Experimental model: Purified enzyme kinetics Limitations: Assay glutathione availability does not define every physiological electron donor. Primary reference: [Characterization of the major hydroperoxide-reducing activity of human plasma. Purification and properties of a selenium-dependent glutathione peroxidase.](https://www.sciencedirect.com/science/article/pii/S0021925818453926)
Complete structured claim and evidenceSELENOM supported a cellular thioredoxin activity readout.
SELENOM perturbations changed thioredoxin activity, with loss reducing the measured activity.
Experimental context and source evidence
- cell_type
- hypothalamic cells
- experimental_model
- Loss and expression experiments
- limitations
- The direct SELENOM substrate was not established.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 798–808
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Loss and expression experiments · secondary_verified · secondary_verified
## selenom-supports-thioredoxin-activity SELENOM supported a cellular thioredoxin activity readout. SELENOM perturbations changed thioredoxin activity, with loss reducing the measured activity. Organism: mouse Cell type: hypothalamic cells Experimental model: Loss and expression experiments Limitations: The direct SELENOM substrate was not established. Primary reference: [Selenoprotein M Promotes Hypothalamic Leptin Signaling and Thioredoxin Antioxidant Activity](https://pmc.ncbi.nlm.nih.gov/articles/PMC8617589/)
Complete structured claim and evidenceSELENOM helped these cells respond to leptin.
SELENOM depletion reduced leptin-evoked STAT3 phosphorylation in hypothalamic-cell experiments.
Experimental context and source evidence
- cell_type
- mHypoE-44 hypothalamic cells
- experimental_model
- Knockdown and knockout
- limitations
- Does not demonstrate direct enzymatic action on STAT3.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 786–796
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Knockdown and knockout · secondary_verified · secondary_verified
## selenom-supports-leptin-stat3-response SELENOM helped these cells respond to leptin. SELENOM depletion reduced leptin-evoked STAT3 phosphorylation in hypothalamic-cell experiments. Organism: mouse Cell type: mHypoE-44 hypothalamic cells Experimental model: Knockdown and knockout Limitations: Does not demonstrate direct enzymatic action on STAT3. Primary reference: [Selenoprotein M Promotes Hypothalamic Leptin Signaling and Thioredoxin Antioxidant Activity](https://pmc.ncbi.nlm.nih.gov/articles/PMC8617589/)
Complete structured claim and evidenceGPX1 protein rose as an incomplete compensatory response.
Gpx2 deletion increased intestinal GPX1 protein without a matching mRNA increase.
Experimental context and source evidence
- cell_type
- intestinal epithelium
- experimental_model
- Gpx2 knockout
- limitations
- Compensation did not erase the crypt phenotype.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 666–676
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Gpx2 knockout · secondary_verified · secondary_verified
## gpx2-loss-increases-gpx1-protein GPX1 protein rose as an incomplete compensatory response. Gpx2 deletion increased intestinal GPX1 protein without a matching mRNA increase. Organism: mouse Cell type: intestinal epithelium Experimental model: Gpx2 knockout Limitations: Compensation did not erase the crypt phenotype. Primary reference: [Loss of GPx2 increases apoptosis, mitosis, and GPx1 expression in the intestine of mice](https://pubmed.ncbi.nlm.nih.gov/20828612/)
Complete structured claim and evidenceLoss of GPX2 increased cell death in intestinal crypts.
Gpx2 deletion increased intestinal crypt-base apoptosis in mice.
Experimental context and source evidence
- cell_type
- intestinal crypt epithelium
- experimental_model
- Gpx2 knockout across selenium diets
- limitations
- Genetic loss is not equivalent to nutritional deficiency.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 654–664
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Gpx2 knockout across selenium diets · secondary_verified · secondary_verified
## gpx2-loss-increases-crypt-apoptosis Loss of GPX2 increased cell death in intestinal crypts. Gpx2 deletion increased intestinal crypt-base apoptosis in mice. Organism: mouse Cell type: intestinal crypt epithelium Experimental model: Gpx2 knockout across selenium diets Limitations: Genetic loss is not equivalent to nutritional deficiency. Primary reference: [Loss of GPx2 increases apoptosis, mitosis, and GPx1 expression in the intestine of mice](https://pubmed.ncbi.nlm.nih.gov/20828612/)
Complete structured claim and evidenceGPX2 can remove peroxide using glutathione.
Expressed human GPX2 exhibited glutathione-dependent hydrogen-peroxide reduction.
Experimental context and source evidence
- cell_type
- MCF-7 transfectants
- experimental_model
- GPX2 cDNA expression and enzyme assays
- limitations
- Expression model; not an intestinal clinical outcome.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 642–652
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · GPX2 cDNA expression and enzyme assays · secondary_verified · secondary_verified
## gpx2-reduces-peroxide GPX2 can remove peroxide using glutathione. Expressed human GPX2 exhibited glutathione-dependent hydrogen-peroxide reduction. Organism: human Cell type: MCF-7 transfectants Experimental model: GPX2 cDNA expression and enzyme assays Limitations: Expression model; not an intestinal clinical outcome. Primary reference: [Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI](https://pubmed.ncbi.nlm.nih.gov/8428933/)
Complete structured claim and evidenceSELENOI builds phosphatidylethanolamine from an activated headgroup and a lipid backbone.
SELENOI transfers phosphoethanolamine from CDP-ethanolamine to diacylglycerol, producing diacyl PE and CMP.
Experimental context and source evidence
- cell_type
- patient fibroblasts and HeLa
- experimental_model
- Lipid synthesis and genetic studies
- limitations
- Other enzymes can contribute to diacyl PE.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 726–736
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Lipid synthesis and genetic studies · secondary_verified · secondary_verified
## selenoi-synthesizes-diacyl-pe SELENOI builds phosphatidylethanolamine from an activated headgroup and a lipid backbone. SELENOI transfers phosphoethanolamine from CDP-ethanolamine to diacylglycerol, producing diacyl PE and CMP. Organism: human Cell type: patient fibroblasts and HeLa Experimental model: Lipid synthesis and genetic studies Limitations: Other enzymes can contribute to diacyl PE. Primary reference: [EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans](https://pmc.ncbi.nlm.nih.gov/articles/PMC5983406/)
Complete structured claim and evidenceManganese acts as a cofactor in this reaction.
Mn2+ supports the reported SELENOO NAD-hydrolysis activity.
Experimental context and source evidence
- cell_type
- experimental cells
- experimental_model
- Metal-dependent enzyme assays
- limitations
- Cofactor dependence does not establish nutritional limitation.
- organism
- mammalian
Selenium: literature corrections and mechanism additions · lines 450–460
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Metal-dependent enzyme assays · secondary_verified · secondary_verified
## manganese-supports-selenoo-nadase Manganese acts as a cofactor in this reaction. Mn2+ supports the reported SELENOO NAD-hydrolysis activity. Organism: mammalian Cell type: experimental cells Experimental model: Metal-dependent enzyme assays Limitations: Cofactor dependence does not establish nutritional limitation. Primary reference: [NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis](https://pubmed.ncbi.nlm.nih.gov/41806834/)
Complete structured claim and evidenceSELENOO can split NAD into two smaller molecules.
SELENOO catalyzes NAD+ hydrolysis to NMN and AMP.
Experimental context and source evidence
- cell_type
- experimental cells
- experimental_model
- Biochemical and cellular assays
- limitations
- Recent 2026 finding; no dietary-dose inference.
- organism
- mammalian
Selenium: literature corrections and mechanism additions · lines 438–448
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical and cellular assays · secondary_verified · secondary_verified
## selenoo-hydrolyzes-nad SELENOO can split NAD into two smaller molecules. SELENOO catalyzes NAD+ hydrolysis to NMN and AMP. Organism: mammalian Cell type: experimental cells Experimental model: Biochemical and cellular assays Limitations: Recent 2026 finding; no dietary-dose inference. Primary reference: [NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis](https://pubmed.ncbi.nlm.nih.gov/41806834/)
Complete structured claim and evidenceThe AMP modification reduced GLUD1 activity in these experiments.
AMPylation decreased GLUD1 enzymatic activity in the tested assays.
Experimental context and source evidence
- cell_type
- experimental assay
- experimental_model
- Modified-enzyme activity measurements
- limitations
- No human dietary response established.
- organism
- mammalian
Selenium: literature corrections and mechanism additions · lines 498–508
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Modified-enzyme activity measurements · secondary_verified · secondary_verified
## glud1-ampylation-decreases-activity The AMP modification reduced GLUD1 activity in these experiments. AMPylation decreased GLUD1 enzymatic activity in the tested assays. Organism: mammalian Cell type: experimental assay Experimental model: Modified-enzyme activity measurements Limitations: No human dietary response established. Primary reference: [A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism](https://www.nature.com/articles/s41467-025-63014-z)
Complete structured claim and evidenceRemoving SELENOO increased respiratory complex-II activity in this model.
SELENOO deletion increased complex-II activity in the tested melanoma model.
Experimental context and source evidence
- cell_type
- melanoma
- experimental_model
- Selenoo deletion
- limitations
- Does not isolate SDHA AMPylation as the sole cause.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 474–484
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Selenoo deletion · secondary_verified · secondary_verified
## selenoo-loss-increases-complex-ii-activity Removing SELENOO increased respiratory complex-II activity in this model. SELENOO deletion increased complex-II activity in the tested melanoma model. Organism: mouse Cell type: melanoma Experimental model: Selenoo deletion Limitations: Does not isolate SDHA AMPylation as the sole cause. Primary reference: [Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity](https://pubmed.ncbi.nlm.nih.gov/39700395/)
Complete structured claim and evidenceThe relay ends in peroxide removal.
PRDX3 consumes hydrogen peroxide, forming water within the mitochondrial thioredoxin circuit.
Experimental context and source evidence
- cell_type
- cardiac mitochondria
- experimental_model
- Peroxide and redox measurements
- limitations
- Other mitochondrial peroxide defenses also contribute.
- organism
- mouse and guinea pig
Selenium: literature corrections and mechanism additions · lines 630–640
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Peroxide and redox measurements · secondary_verified · secondary_verified
## prdx3-reduces-mitochondrial-peroxide The relay ends in peroxide removal. PRDX3 consumes hydrogen peroxide, forming water within the mitochondrial thioredoxin circuit. Organism: mouse and guinea pig Cell type: cardiac mitochondria Experimental model: Peroxide and redox measurements Limitations: Other mitochondrial peroxide defenses also contribute. Primary reference: [Thioredoxin Reductase-2 Is Essential for Keeping Low Levels of H2O2 Emission from Isolated Heart Mitochondria](https://pubmed.ncbi.nlm.nih.gov/21832082/)
Complete structured claim and evidenceA selenium enzyme restores mitochondrial thioredoxin's reducing power.
TXNRD2 uses NADPH-derived reducing equivalents to regenerate reduced TXN2.
Experimental context and source evidence
- cell_type
- cardiac mitochondria
- experimental_model
- Redox perturbation and peroxide-emission assays
- limitations
- Functional relay; not every chemical step isolated here.
- organism
- mouse and guinea pig
Selenium: literature corrections and mechanism additions · lines 606–616
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Redox perturbation and peroxide-emission assays · secondary_verified · secondary_verified
## txnrd2-reduces-txn2 A selenium enzyme restores mitochondrial thioredoxin's reducing power. TXNRD2 uses NADPH-derived reducing equivalents to regenerate reduced TXN2. Organism: mouse and guinea pig Cell type: cardiac mitochondria Experimental model: Redox perturbation and peroxide-emission assays Limitations: Functional relay; not every chemical step isolated here. Primary reference: [Thioredoxin Reductase-2 Is Essential for Keeping Low Levels of H2O2 Emission from Isolated Heart Mitochondria](https://pubmed.ncbi.nlm.nih.gov/21832082/)
Complete structured claim and evidenceThioredoxin recharges a mitochondrial peroxide-removal enzyme.
Reduced TXN2 regenerates the peroxide-reducing form of PRDX3.
Experimental context and source evidence
- cell_type
- cardiac mitochondria
- experimental_model
- Redox-state measurements
- limitations
- TXN2 and PRDX3 are not selenoproteins.
- organism
- mouse and guinea pig
Selenium: literature corrections and mechanism additions · lines 618–628
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Redox-state measurements · secondary_verified · secondary_verified
## txn2-regenerates-prdx3 Thioredoxin recharges a mitochondrial peroxide-removal enzyme. Reduced TXN2 regenerates the peroxide-reducing form of PRDX3. Organism: mouse and guinea pig Cell type: cardiac mitochondria Experimental model: Redox-state measurements Limitations: TXN2 and PRDX3 are not selenoproteins. Primary reference: [Thioredoxin Reductase-2 Is Essential for Keeping Low Levels of H2O2 Emission from Isolated Heart Mitochondria](https://pubmed.ncbi.nlm.nih.gov/21832082/)
Complete structured claim and evidenceLoss of neural SELENOI disrupted myelin formation.
Neural-lineage Selenoi deletion impaired myelination in mice.
Experimental context and source evidence
- cell_type
- neural lineage
- experimental_model
- Tuba1a-Cre conditional knockout
- limitations
- Does not identify one lipid species as the sole cause.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 762–772
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Tuba1a-Cre conditional knockout · secondary_verified · secondary_verified
## neural-selenoi-loss-impairs-myelin Loss of neural SELENOI disrupted myelin formation. Neural-lineage Selenoi deletion impaired myelination in mice. Organism: mouse Cell type: neural lineage Experimental model: Tuba1a-Cre conditional knockout Limitations: Does not identify one lipid species as the sole cause. Primary reference: [Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination](https://pubmed.ncbi.nlm.nih.gov/38582453/)
Complete structured claim and evidenceLoss of SELENOI increased lipid damage in this neural model.
Neural Selenoi deletion increased lipid-peroxidation readouts.
Experimental context and source evidence
- cell_type
- neural lineage
- experimental_model
- Conditional knockout
- limitations
- Indirect redox consequence does not establish SELENOI peroxidase activity.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 774–784
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Conditional knockout · secondary_verified · secondary_verified
## neural-selenoi-loss-increases-lipid-peroxidation Loss of SELENOI increased lipid damage in this neural model. Neural Selenoi deletion increased lipid-peroxidation readouts. Organism: mouse Cell type: neural lineage Experimental model: Conditional knockout Limitations: Indirect redox consequence does not establish SELENOI peroxidase activity. Primary reference: [Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination](https://pubmed.ncbi.nlm.nih.gov/38582453/)
Complete structured claim and evidenceThe regulatory lipid state changed ZDHHC6 activity.
C328-palmitoylated ZDHHC6 had higher acyltransferase activity than regulatory-unpalmitoylated forms in the tested system.
Experimental context and source evidence
- cell_type
- HeLa
- experimental_model
- Cysteine mutants and activity assays
- limitations
- Activity and turnover depend on the full site-occupancy state.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 906–916
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cysteine mutants and activity assays · secondary_verified · secondary_verified
## zdhhc6-c328-palmitoylation-increases-activity The regulatory lipid state changed ZDHHC6 activity. C328-palmitoylated ZDHHC6 had higher acyltransferase activity than regulatory-unpalmitoylated forms in the tested system. Organism: human Cell type: HeLa Experimental model: Cysteine mutants and activity assays Limitations: Activity and turnover depend on the full site-occupancy state. Primary reference: [Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade](https://elifesciences.org/articles/27826)
Complete structured claim and evidenceAPT2 can remove ZDHHC6's regulatory lipid groups.
APT2/LYPLA2 removes regulatory palmitoylation from ZDHHC6, with rapid turnover involving C328.
Experimental context and source evidence
- cell_type
- HeLa
- experimental_model
- Enzyme perturbation and pulse-chase
- limitations
- Not removal of the catalytic acyl intermediate.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 894–904
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Enzyme perturbation and pulse-chase · secondary_verified · secondary_verified
## apt2-depalmitoylates-zdhhc6 APT2 can remove ZDHHC6's regulatory lipid groups. APT2/LYPLA2 removes regulatory palmitoylation from ZDHHC6, with rapid turnover involving C328. Organism: human Cell type: HeLa Experimental model: Enzyme perturbation and pulse-chase Limitations: Not removal of the catalytic acyl intermediate. Primary reference: [Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade](https://elifesciences.org/articles/27826)
Complete structured claim and evidenceAnother enzyme adds regulatory lipid groups to ZDHHC6.
ZDHHC16 mediates regulatory ZDHHC6 palmitoylation at C328, C329 and C343.
Experimental context and source evidence
- cell_type
- HeLa and HAP1
- experimental_model
- Mutagenesis and enzyme perturbations
- limitations
- Distinct from catalytic DHHC self-acylation.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 882–892
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mutagenesis and enzyme perturbations · secondary_verified · secondary_verified
## zdhhc16-palmitoylates-zdhhc6-regulatory-sites Another enzyme adds regulatory lipid groups to ZDHHC6. ZDHHC16 mediates regulatory ZDHHC6 palmitoylation at C328, C329 and C343. Organism: human Cell type: HeLa and HAP1 Experimental model: Mutagenesis and enzyme perturbations Limitations: Distinct from catalytic DHHC self-acylation. Primary reference: [Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade](https://elifesciences.org/articles/27826)
Complete structured claim and evidenceMouse fat tissue had less OGT activity after SELENOV loss.
Selenov loss reduced adipose OGT activity in mice.
Experimental context and source evidence
- cell_type
- adipose tissue
- experimental_model
- Selenov knockout
- limitations
- Do not equate this perturbation with human dietary deficiency.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 822–832
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Selenov knockout · secondary_verified · secondary_verified
## selenov-loss-reduces-ogt-activity Mouse fat tissue had less OGT activity after SELENOV loss. Selenov loss reduced adipose OGT activity in mice. Organism: mouse Cell type: adipose tissue Experimental model: Selenov knockout Limitations: Do not equate this perturbation with human dietary deficiency. Primary reference: [Loss of Selenov predisposes mice to extra fat accumulation and attenuated energy expenditure](https://pubmed.ncbi.nlm.nih.gov/34167027/)
Complete structured claim and evidenceProtein sugar modification fell after SELENOV loss in this model.
Selenov loss reduced measured protein O-GlcNAcylation in adipose tissue.
Experimental context and source evidence
- cell_type
- adipose tissue
- experimental_model
- Selenov knockout
- limitations
- The extended AMPK pathway remains partly proposed.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 846–856
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Selenov knockout · secondary_verified · secondary_verified
## selenov-loss-reduces-o-glcnacylation Protein sugar modification fell after SELENOV loss in this model. Selenov loss reduced measured protein O-GlcNAcylation in adipose tissue. Organism: mouse Cell type: adipose tissue Experimental model: Selenov knockout Limitations: The extended AMPK pathway remains partly proposed. Primary reference: [Loss of Selenov predisposes mice to extra fat accumulation and attenuated energy expenditure](https://pubmed.ncbi.nlm.nih.gov/34167027/)
Complete structured claim and evidenceSELENOV was found to interact with the sugar-transfer enzyme OGT.
SELENOV physically associated with OGT in the reported interaction assays.
Experimental context and source evidence
- cell_type
- HEK293T assay system
- experimental_model
- Protein-interaction experiments
- limitations
- Binding does not establish a catalytic substrate relationship.
- organism
- mammalian proteins
Selenium: literature corrections and mechanism additions · lines 810–820
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Protein-interaction experiments · secondary_verified · secondary_verified
## selenov-binds-ogt SELENOV was found to interact with the sugar-transfer enzyme OGT. SELENOV physically associated with OGT in the reported interaction assays. Organism: mammalian proteins Cell type: HEK293T assay system Experimental model: Protein-interaction experiments Limitations: Binding does not establish a catalytic substrate relationship. Primary reference: [Loss of Selenov predisposes mice to extra fat accumulation and attenuated energy expenditure](https://pubmed.ncbi.nlm.nih.gov/34167027/)
Complete structured claim and evidenceMouse fat tissue contained less OGT protein after SELENOV loss.
Selenov loss reduced adipose OGT protein abundance in mice.
Experimental context and source evidence
- cell_type
- adipose tissue
- experimental_model
- Selenov knockout
- limitations
- Do not equate this perturbation with human dietary deficiency.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 834–844
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Selenov knockout · secondary_verified · secondary_verified
## selenov-loss-reduces-ogt-abundance Mouse fat tissue contained less OGT protein after SELENOV loss. Selenov loss reduced adipose OGT protein abundance in mice. Organism: mouse Cell type: adipose tissue Experimental model: Selenov knockout Limitations: Do not equate this perturbation with human dietary deficiency. Primary reference: [Loss of Selenov predisposes mice to extra fat accumulation and attenuated energy expenditure](https://pubmed.ncbi.nlm.nih.gov/34167027/)
Complete structured claim and evidenceSELENOO can attach an AMP group to a respiratory enzyme.
SELENOO transfers AMP from ATP onto SDHA in the reported AMPylation experiments.
Experimental context and source evidence
- cell_type
- melanoma-related assays
- experimental_model
- Biochemical substrate experiments
- limitations
- Keep this reaction separate from NAD hydrolysis.
- organism
- mammalian
Selenium: literature corrections and mechanism additions · lines 462–472
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical substrate experiments · secondary_verified · secondary_verified
## selenoo-ampylates-sdha SELENOO can attach an AMP group to a respiratory enzyme. SELENOO transfers AMP from ATP onto SDHA in the reported AMPylation experiments. Organism: mammalian Cell type: melanoma-related assays Experimental model: Biochemical substrate experiments Limitations: Keep this reaction separate from NAD hydrolysis. Primary reference: [Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity](https://pubmed.ncbi.nlm.nih.gov/39700395/)
Complete structured claim and evidenceSELENOO can modify the metabolic enzyme GLUD1 with AMP.
SELENOO catalyzes AMP attachment to GLUD1.
Experimental context and source evidence
- cell_type
- experimental cells
- experimental_model
- Biochemical AMPylation assays
- limitations
- Substrate identification does not establish every tissue context.
- organism
- mammalian
Selenium: literature corrections and mechanism additions · lines 486–496
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical AMPylation assays · secondary_verified · secondary_verified
## selenoo-ampylates-glud1 SELENOO can modify the metabolic enzyme GLUD1 with AMP. SELENOO catalyzes AMP attachment to GLUD1. Organism: mammalian Cell type: experimental cells Experimental model: Biochemical AMPylation assays Limitations: Substrate identification does not establish every tissue context. Primary reference: [A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism](https://www.nature.com/articles/s41467-025-63014-z)
Complete structured claim and evidenceThis cell line used a SCLY-independent recovery route.
Jurkat cells retained efficient SELENOP utilization without SCLY.
Experimental context and source evidence
- cell_type
- Jurkat
- experimental_model
- SCLY disruption
- limitations
- Alternative recovery chemistry is unresolved.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 582–592
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · SCLY disruption · secondary_verified · secondary_verified
## jurkat-selenop-use-persists-without-scly This cell line used a SCLY-independent recovery route. Jurkat cells retained efficient SELENOP utilization without SCLY. Organism: human Cell type: Jurkat Experimental model: SCLY disruption Limitations: Alternative recovery chemistry is unresolved. Primary reference: [An efficient selenium transport pathway of selenoprotein P utilizing a high-affinity ApoER2 receptor variant and being independent of selenocysteine lyase](https://pubmed.ncbi.nlm.nih.gov/37406814/)
Complete structured claim and evidenceThese rhabdomyosarcoma cells required SCLY for SELENOP selenium recovery.
RD cells used a lysosomal SELENOP recovery route dependent on SCLY.
Experimental context and source evidence
- cell_type
- RD rhabdomyosarcoma
- experimental_model
- Perturbation assays
- limitations
- Dependency does not locate SCLY catalysis inside lysosomes.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 570–580
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Perturbation assays · secondary_verified · secondary_verified
## rd-lysosomal-selenop-recovery-requires-scly These rhabdomyosarcoma cells required SCLY for SELENOP selenium recovery. RD cells used a lysosomal SELENOP recovery route dependent on SCLY. Organism: human Cell type: RD rhabdomyosarcoma Experimental model: Perturbation assays Limitations: Dependency does not locate SCLY catalysis inside lysosomes. Primary reference: [An efficient selenium transport pathway of selenoprotein P utilizing a high-affinity ApoER2 receptor variant and being independent of selenocysteine lyase](https://pubmed.ncbi.nlm.nih.gov/37406814/)
Complete structured claim and evidenceSCLY recovers selenium from free selenocysteine.
SCLY decomposes free L-selenocysteine, yielding L-alanine and released selenium.
Experimental context and source evidence
- cell_type
- liver-derived enzyme
- experimental_model
- Purified and recombinant enzyme
- limitations
- The original assay described elemental selenium; intracellular speciation remains separate.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 510–520
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Purified and recombinant enzyme · secondary_verified · secondary_verified
## scly-decomposes-selenocysteine SCLY recovers selenium from free selenocysteine. SCLY decomposes free L-selenocysteine, yielding L-alanine and released selenium. Organism: mouse Cell type: liver-derived enzyme Experimental model: Purified and recombinant enzyme Limitations: The original assay described elemental selenium; intracellular speciation remains separate. Primary reference: [cDNA cloning, purification, and characterization of mouse liver selenocysteine lyase. Candidate for selenium delivery protein in selenoprotein synthesis](https://pubmed.ncbi.nlm.nih.gov/10692412/)
Complete structured claim and evidenceThese cells needed SCLY for efficient selenium reuse.
SCLY knockdown reduced incorporation of SELENOP-derived selenium into newly synthesized selenoproteins in HeLa cells.
Experimental context and source evidence
- cell_type
- HeLa
- experimental_model
- 75Se-labeled SELENOP and RNA interference
- limitations
- Cell-specific dependency; not a universal uptake sequence.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 534–544
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · 75Se-labeled SELENOP and RNA interference · secondary_verified · secondary_verified
## scly-supports-selenop-selenium-reuse These cells needed SCLY for efficient selenium reuse. SCLY knockdown reduced incorporation of SELENOP-derived selenium into newly synthesized selenoproteins in HeLa cells. Organism: human Cell type: HeLa Experimental model: 75Se-labeled SELENOP and RNA interference Limitations: Cell-specific dependency; not a universal uptake sequence. Primary reference: [Mammalian Selenocysteine Lyase Is Involved in Selenoprotein Biosynthesis](https://www.jstage.jst.go.jp/article/jnsv/57/4/57_4_298/_article/-char/en)
Complete structured claim and evidenceA receptor variant improved SELENOP binding.
An ApoER2 variant containing its O-linked glycosylation domain bound SELENOP with high affinity in the tested system.
Experimental context and source evidence
- cell_type
- Jurkat
- experimental_model
- Receptor-variant assays
- limitations
- Do not generalize to all LRP8 variants.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 546–556
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Receptor-variant assays · secondary_verified · secondary_verified
## lrp8-variant-binds-selenop A receptor variant improved SELENOP binding. An ApoER2 variant containing its O-linked glycosylation domain bound SELENOP with high affinity in the tested system. Organism: human Cell type: Jurkat Experimental model: Receptor-variant assays Limitations: Do not generalize to all LRP8 variants. Primary reference: [An efficient selenium transport pathway of selenoprotein P utilizing a high-affinity ApoER2 receptor variant and being independent of selenocysteine lyase](https://pubmed.ncbi.nlm.nih.gov/37406814/)
Complete structured claim and evidenceCells processed SELENOP in acidified compartments.
Vesicle acidification was required for efficient selenium utilization from SELENOP.
Experimental context and source evidence
- cell_type
- Jurkat and RD
- experimental_model
- Acidification inhibition
- limitations
- Chemical recovery steps are incompletely resolved.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 558–568
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Acidification inhibition · secondary_verified · secondary_verified
## acidified-vesicles-enable-selenop-use Cells processed SELENOP in acidified compartments. Vesicle acidification was required for efficient selenium utilization from SELENOP. Organism: human Cell type: Jurkat and RD Experimental model: Acidification inhibition Limitations: Chemical recovery steps are incompletely resolved. Primary reference: [An efficient selenium transport pathway of selenoprotein P utilizing a high-affinity ApoER2 receptor variant and being independent of selenocysteine lyase](https://pubmed.ncbi.nlm.nih.gov/37406814/)
Complete structured claim and evidenceDisrupted selenium uptake hindered GPX4 production in these cancer cells.
LRP8 loss caused GPX4 UGA-associated ribosome stalling in the tested cancer cells.
Experimental context and source evidence
- cell_type
- cancer cell lines
- experimental_model
- Genetic disruption and ribosome analyses
- limitations
- Tumor-cell result; GPX4 priority is context dependent.
- organism
- human
Selenium: literature corrections and mechanism additions · lines 594–604
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Genetic disruption and ribosome analyses · secondary_verified · secondary_verified
## lrp8-loss-promotes-gpx4-stalling Disrupted selenium uptake hindered GPX4 production in these cancer cells. LRP8 loss caused GPX4 UGA-associated ribosome stalling in the tested cancer cells. Organism: human Cell type: cancer cell lines Experimental model: Genetic disruption and ribosome analyses Limitations: Tumor-cell result; GPX4 priority is context dependent. Primary reference: [Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability](https://pubmed.ncbi.nlm.nih.gov/35637349/)
Complete structured claim and evidenceSTAT5's inhibitory effect depended substantially on Blimp-1.
Blimp-1 deletion relieved STAT5-mediated inhibition of Tfh differentiation.
Experimental context and source evidence
- cell_type
- antigen-specific CD4 T cells
- experimental_model
- Conditional Prdm1 deletion with active STAT5
- limitations
- Dependency does not prove direct STAT5 induction of PRDM1.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 942–952
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Conditional Prdm1 deletion with active STAT5 · secondary_verified · secondary_verified
## blimp1-required-for-stat5-tfh-inhibition STAT5's inhibitory effect depended substantially on Blimp-1. Blimp-1 deletion relieved STAT5-mediated inhibition of Tfh differentiation. Organism: mouse Cell type: antigen-specific CD4 T cells Experimental model: Conditional Prdm1 deletion with active STAT5 Limitations: Dependency does not prove direct STAT5 induction of PRDM1. Primary reference: [STAT5 is a potent negative regulator of TFH cell differentiation](https://pmc.ncbi.nlm.nih.gov/articles/PMC3281266/)
Complete structured claim and evidenceMore STAT5 signaling reduced the Tfh cell fate.
Sustained STAT5 activity inhibited BCL6-associated Tfh differentiation in the studied model.
Experimental context and source evidence
- cell_type
- transferred antigen-specific CD4 T cells
- experimental_model
- LCMV infection
- limitations
- Not all IL-2 effects are inhibitory.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 930–940
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · LCMV infection · secondary_verified · secondary_verified
## stat5-inhibits-tfh-differentiation More STAT5 signaling reduced the Tfh cell fate. Sustained STAT5 activity inhibited BCL6-associated Tfh differentiation in the studied model. Organism: mouse Cell type: transferred antigen-specific CD4 T cells Experimental model: LCMV infection Limitations: Not all IL-2 effects are inhibitory. Primary reference: [STAT5 is a potent negative regulator of TFH cell differentiation](https://pmc.ncbi.nlm.nih.gov/articles/PMC3281266/)
Complete structured claim and evidenceIL-2 engages a signal that can oppose Tfh development.
IL-2 signaling activates STAT5 in the studied CD4 T-cell differentiation context.
Experimental context and source evidence
- cell_type
- antigen-specific CD4 T cells
- experimental_model
- LCMV infection and signaling perturbations
- limitations
- No selenium intervention in this study.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 918–928
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · LCMV infection and signaling perturbations · secondary_verified · secondary_verified
## il2-activates-stat5-tfh-context IL-2 engages a signal that can oppose Tfh development. IL-2 signaling activates STAT5 in the studied CD4 T-cell differentiation context. Organism: mouse Cell type: antigen-specific CD4 T cells Experimental model: LCMV infection and signaling perturbations Limitations: No selenium intervention in this study. Primary reference: [STAT5 is a potent negative regulator of TFH cell differentiation](https://pmc.ncbi.nlm.nih.gov/articles/PMC3281266/)
Complete structured claim and evidenceSELENOH can associate with DNA in a redox-sensitive manner.
SELENOH showed redox-responsive association with stress-responsive DNA sequences.
Experimental context and source evidence
- cell_type
- HT22
- experimental_model
- DNA-binding and expression assays
- limitations
- Not a universal genomic target map.
- organism
- human protein in mouse cells
Selenium: literature corrections and mechanism additions · lines 858–868
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · DNA-binding and expression assays · secondary_verified · secondary_verified
## selenoh-associates-with-stress-dna SELENOH can associate with DNA in a redox-sensitive manner. SELENOH showed redox-responsive association with stress-responsive DNA sequences. Organism: human protein in mouse cells Cell type: HT22 Experimental model: DNA-binding and expression assays Limitations: Not a universal genomic target map. Primary reference: [Selenoprotein H is a redox-sensing high mobility group family DNA-binding protein that up-regulates genes involved in glutathione synthesis and phase II detoxification](https://pubmed.ncbi.nlm.nih.gov/17526492/)
Complete structured claim and evidenceExtra SELENOH increased expression of glutathione-building genes in these cells.
Human SELENOH overexpression increased glutathione-synthesis gene expression in murine HT22 cells.
Experimental context and source evidence
- cell_type
- HT22 hippocampal cells
- experimental_model
- Overexpression
- limitations
- Does not prove an equivalent response to dietary selenium.
- organism
- human protein in mouse cells
Selenium: literature corrections and mechanism additions · lines 870–880
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Overexpression · secondary_verified · secondary_verified
## selenoh-increases-glutathione-gene-expression Extra SELENOH increased expression of glutathione-building genes in these cells. Human SELENOH overexpression increased glutathione-synthesis gene expression in murine HT22 cells. Organism: human protein in mouse cells Cell type: HT22 hippocampal cells Experimental model: Overexpression Limitations: Does not prove an equivalent response to dietary selenium. Primary reference: [Selenoprotein H is a redox-sensing high mobility group family DNA-binding protein that up-regulates genes involved in glutathione synthesis and phase II detoxification](https://pubmed.ncbi.nlm.nih.gov/17526492/)
Complete structured claim and evidenceGPX3 may help preserve nitric oxide's platelet-inhibitory signal.
Redox and platelet measurements support GPX3 preservation of NO-mediated platelet restraint.
Experimental context and source evidence
- cell_type
- plasma and platelets
- experimental_model
- Gpx3 knockout
- limitations
- Individual oxidant intermediates were not fully isolated.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 714–724
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Gpx3 knockout · secondary_verified · secondary_verified
## gpx3-supports-no-platelet-restraint GPX3 may help preserve nitric oxide's platelet-inhibitory signal. Redox and platelet measurements support GPX3 preservation of NO-mediated platelet restraint. Organism: mouse Cell type: plasma and platelets Experimental model: Gpx3 knockout Limitations: Individual oxidant intermediates were not fully isolated. Primary reference: [Glutathione Peroxidase-3 Deficiency Promotes Platelet-dependent Thrombosis in vivo](https://pmc.ncbi.nlm.nih.gov/articles/PMC3107543/)
Complete structured claim and evidenceGPX3-deficient mice formed more thrombus after vascular injury.
Gpx3 deficiency increased platelet-dependent thrombosis after experimental vascular provocation.
Experimental context and source evidence
- cell_type
- arterial injury model
- experimental_model
- Gpx3 knockout
- limitations
- Does not establish a human selenium cutoff.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 702–712
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Gpx3 knockout · secondary_verified · secondary_verified
## gpx3-loss-increases-provoked-thrombosis GPX3-deficient mice formed more thrombus after vascular injury. Gpx3 deficiency increased platelet-dependent thrombosis after experimental vascular provocation. Organism: mouse Cell type: arterial injury model Experimental model: Gpx3 knockout Limitations: Does not establish a human selenium cutoff. Primary reference: [Glutathione Peroxidase-3 Deficiency Promotes Platelet-dependent Thrombosis in vivo](https://pmc.ncbi.nlm.nih.gov/articles/PMC3107543/)
Complete structured claim and evidenceGPX3 loss made platelets more reactive in this model.
Gpx3-deficient mice showed increased platelet responsiveness.
Experimental context and source evidence
- cell_type
- platelets and plasma
- experimental_model
- Gpx3 knockout
- limitations
- Not a selenium-supplementation trial.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 690–700
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Gpx3 knockout · secondary_verified · secondary_verified
## gpx3-loss-increases-platelet-activation GPX3 loss made platelets more reactive in this model. Gpx3-deficient mice showed increased platelet responsiveness. Organism: mouse Cell type: platelets and plasma Experimental model: Gpx3 knockout Limitations: Not a selenium-supplementation trial. Primary reference: [Glutathione Peroxidase-3 Deficiency Promotes Platelet-dependent Thrombosis in vivo](https://pmc.ncbi.nlm.nih.gov/articles/PMC3107543/)
Complete structured claim and evidenceSCLY uses a vitamin B6-derived cofactor.
SCLY is a pyridoxal-phosphate-dependent enzyme.
Experimental context and source evidence
- cell_type
- liver-derived enzyme
- experimental_model
- Enzyme characterization
- limitations
- Not evidence that extra vitamin B6 improves selenium recycling.
- organism
- mouse
Selenium: literature corrections and mechanism additions · lines 522–532
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Enzyme characterization · secondary_verified · secondary_verified
## plp-supports-scly-catalysis SCLY uses a vitamin B6-derived cofactor. SCLY is a pyridoxal-phosphate-dependent enzyme. Organism: mouse Cell type: liver-derived enzyme Experimental model: Enzyme characterization Limitations: Not evidence that extra vitamin B6 improves selenium recycling. Primary reference: [cDNA cloning, purification, and characterization of mouse liver selenocysteine lyase. Candidate for selenium delivery protein in selenoprotein synthesis](https://pubmed.ncbi.nlm.nih.gov/10692412/)
Complete structured claim and evidenceSulforaphane-affinity beads captured APT2 from Huh-7 or transfected HEK293 lysates; C56S mutation attenuated binding in the reported assays.
Experimental context and source evidence
- evidence_cache
- artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a
- experimental_model
- Human Huh-7 and HEK293 cell lysates; endogenous or FLAG-tagged human APT2
- exposure
- Bead pulldown; free-sulforaphane competition at 100 micromolar for 30 minutes at 4 C. C56S and C2S constructs compared.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. Mutagenesis supports C56-dependent engagement; no binding affinity or substrate-specific catalytic inhibition constant was established.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figures 1 and 3, Results 3.1 and 3.3
- primary_references
- https://doi.org/10.1016/j.bbrc.2024.150244
- source_access
- Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 8–16
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human Huh-7 and HEK293 cell lysates; endogenous or FLAG-tagged human APT2 · source_derived_draft · unverified_draft
Sulforaphane-affinity beads captured APT2 from Huh-7 or transfected HEK293 lysates; C56S mutation attenuated binding in the reported assays. primary_references: https://doi.org/10.1016/j.bbrc.2024.150244 primary_locator: Figures 1 and 3, Results 3.1 and 3.3 source_access: Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a experimental_model: Human Huh-7 and HEK293 cell lysates; endogenous or FLAG-tagged human APT2 organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: Bead pulldown; free-sulforaphane competition at 100 micromolar for 30 minutes at 4 C. C56S and C2S constructs compared. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. Mutagenesis supports C56-dependent engagement; no binding affinity or substrate-specific catalytic inhibition constant was established.
Complete structured claim and evidenceSulforaphane reduced Alk14 labeling of immunoprecipitated APT2 in transfected HEK293 cells.
Experimental context and source evidence
- evidence_cache
- artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a
- experimental_model
- Human HEK293 expressing FLAG-tagged human APT2
- exposure
- 100 micromolar sulforaphane for 3 hours followed by 50 micromolar Alk14 for 5 hours; hydroxylamine control; three separate experiments.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The authors could not distinguish reduced palmitoylation from enhanced depalmitoylation. This assay does not measure GPX4 or ZDHHC6.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 4B; Methods 2.8
- primary_references
- https://doi.org/10.1016/j.bbrc.2024.150244
- source_access
- Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 19–27
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human HEK293 expressing FLAG-tagged human APT2 · source_derived_draft · unverified_draft
Sulforaphane reduced Alk14 labeling of immunoprecipitated APT2 in transfected HEK293 cells. primary_references: https://doi.org/10.1016/j.bbrc.2024.150244 primary_locator: Figure 4B; Methods 2.8 source_access: Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a experimental_model: Human HEK293 expressing FLAG-tagged human APT2 organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: 100 micromolar sulforaphane for 3 hours followed by 50 micromolar Alk14 for 5 hours; hydroxylamine control; three separate experiments. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The authors could not distinguish reduced palmitoylation from enhanced depalmitoylation. This assay does not measure GPX4 or ZDHHC6.
Complete structured claim and evidenceSulforaphane reduced the membrane-to-cytosol ratio of FLAG-tagged APT2 in HEK293 fractionation experiments.
Experimental context and source evidence
- evidence_cache
- artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a
- experimental_model
- Human HEK293 expressing FLAG-tagged human APT2
- exposure
- 100 micromolar sulforaphane for 3 hours; membrane and cytosol fractions with pan-cadherin and alpha-tubulin markers; three separate experiments.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The authors describe plasma-membrane localization, but fractionation is not an ER-specific or organelle-resolved measurement.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 4A; Results 3.4 and Methods 2.9
- primary_references
- https://doi.org/10.1016/j.bbrc.2024.150244
- source_access
- Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 30–38
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human HEK293 expressing FLAG-tagged human APT2 · source_derived_draft · unverified_draft
Sulforaphane reduced the membrane-to-cytosol ratio of FLAG-tagged APT2 in HEK293 fractionation experiments. primary_references: https://doi.org/10.1016/j.bbrc.2024.150244 primary_locator: Figure 4A; Results 3.4 and Methods 2.9 source_access: Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a experimental_model: Human HEK293 expressing FLAG-tagged human APT2 organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: 100 micromolar sulforaphane for 3 hours; membrane and cytosol fractions with pan-cadherin and alpha-tubulin markers; three separate experiments. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The authors describe plasma-membrane localization, but fractionation is not an ER-specific or organelle-resolved measurement.
Complete structured claim and evidenceSulforaphane did not significantly attenuate Alk14 labeling of APT2-C56S under the conditions that reduced labeling of wild-type APT2.
Experimental context and source evidence
- availability_state
- machinery_impairment Imported condition classification; unverified.
- evidence_cache
- artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a
- experimental_model
- Human HEK293 expressing FLAG-tagged APT2-C56S
- exposure
- 100 micromolar sulforaphane for 3 hours followed by 50 micromolar Alk14 for 5 hours; three separate experiments.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. C56S is a mutant-plus-exposure actor. Its baseline function must be assessed before using it as a selective pharmacological rescue.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Figure 4C
- primary_references
- https://doi.org/10.1016/j.bbrc.2024.150244
- source_access
- Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis.
- trigger_kind
- machinery_impairment Imported condition classification; unverified.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 41–49
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human HEK293 expressing FLAG-tagged APT2-C56S · source_derived_draft · unverified_draft
Sulforaphane did not significantly attenuate Alk14 labeling of APT2-C56S under the conditions that reduced labeling of wild-type APT2. primary_references: https://doi.org/10.1016/j.bbrc.2024.150244 primary_locator: Figure 4C source_access: Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a experimental_model: Human HEK293 expressing FLAG-tagged APT2-C56S organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: 100 micromolar sulforaphane for 3 hours followed by 50 micromolar Alk14 for 5 hours; three separate experiments. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. C56S is a mutant-plus-exposure actor. Its baseline function must be assessed before using it as a selective pharmacological rescue.
Complete structured claim and evidenceThe sulforaphane study reports no significant change in GAP-43 palmitoylation in the presence of sulforaphane.
Experimental context and source evidence
- evidence_cache
- artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a
- experimental_model
- Cell model and construct species not specified for this discussion-only result
- exposure
- Dose, timing and assay details for this null result are not separately reported.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. No plotted experiment or effect-size interval is provided. Preserve this author-reported null; it is not proof of equivalence.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Discussion, page 6
- primary_references
- https://doi.org/10.1016/j.bbrc.2024.150244
- source_access
- Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 52–60
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Cell model and construct species not specified for this discussion-only result · source_derived_draft · unverified_draft
The sulforaphane study reports no significant change in GAP-43 palmitoylation in the presence of sulforaphane. primary_references: https://doi.org/10.1016/j.bbrc.2024.150244 primary_locator: Discussion, page 6 source_access: Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a experimental_model: Cell model and construct species not specified for this discussion-only result organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: Dose, timing and assay details for this null result are not separately reported. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. No plotted experiment or effect-size interval is provided. Preserve this author-reported null; it is not proof of equivalence.
Complete structured claim and evidenceThe sulforaphane study reports no significant change in H-Ras palmitoylation in the presence of sulforaphane.
Experimental context and source evidence
- evidence_cache
- artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a
- experimental_model
- Cell model and construct species not specified for this discussion-only result
- exposure
- Dose, timing and assay details for this null result are not separately reported.
- limitations
- These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. No plotted experiment or effect-size interval is provided. This limits a universal APT2-substrate prediction.
- organism
- Human experimental cells; construct species unresolved where stated for discussion-only nulls
- primary_locator
- Discussion, page 6
- primary_references
- https://doi.org/10.1016/j.bbrc.2024.150244
- source_access
- Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis.
APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 63–71
Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Cell model and construct species not specified for this discussion-only result · source_derived_draft · unverified_draft
The sulforaphane study reports no significant change in H-Ras palmitoylation in the presence of sulforaphane. primary_references: https://doi.org/10.1016/j.bbrc.2024.150244 primary_locator: Discussion, page 6 source_access: Full six-page primary PDF, methods and discussion read; Figure 4 visually inspected. No raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/sulforaphane-apt2.pdf; SHA256 31e2993f88fe05eec199b9013173b29379b3346b9696ac766771173ddd0f181a experimental_model: Cell model and construct species not specified for this discussion-only result organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: Dose, timing and assay details for this null result are not separately reported. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. No plotted experiment or effect-size interval is provided. This limits a universal APT2-substrate prediction.
Complete structured claim and evidence
Availability and dependencies
Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.
Less selenium can constrain the Sec-tRNA supply
Condition: nutrient_deficiency · Selenium intake or availability becomes inadequate for the cellular context.
Normal role: Selenium metabolism supplies the selenium used to form Sec-tRNA, which delivers selenocysteine during UGA recoding.
Recorded consequence: Central selenium metabolism and Sec-tRNA supply can become constrained, affecting selenoprotein synthesis unevenly.
Scope: Biochemical pathway and experimental shortage model; effects depend on transcript and tissue.
GPX1 can lose both translation and its mRNA
Condition: nutrient_deficiency · Selenium restriction reduces recoding efficiency in an NMD-compatible GPX1 transcript context.
Normal role: Successful UGA recoding supports GPX1 translation; susceptible transcripts are subject to RNA quality control if translation terminates prematurely.
Recorded consequence: Less GPX1 can be produced while nonsense-mediated decay also lowers GPX1 mRNA abundance.
Scope: Transcript-specific mechanism supported by animal and cell experiments, including rat hepatocytes and cultured-cell GPX1 studies.
Palmitoylation-deficient APT2-C2S overexpression did not reproduce the significant reduction in ZDHHC6 palmitoylation caused by wild-type APT2.
Condition: machinery_impairment · 24-hour plasmid expression, then 2-hour tritiated-palmitate labeling; normalized to ZDHHC6 protein; n=6.
Normal role: APT2 regulates substrate depalmitoylation; relevant selenium-pathway proteins are separate actors. This scenario describes experimental machinery, not nutrient shortage.
Recorded consequence: Palmitoylation-deficient APT2-C2S overexpression did not reproduce the significant reduction in ZDHHC6 palmitoylation caused by wild-type APT2.
Scope: Human HeLa; tagged human APT2-C2S and ZDHHC6 constructs
Selenoproteins respond unevenly to restriction
Condition: nutrient_deficiency · Selenium supply is restricted for a defined tissue, species, and duration.
Normal role: Translation, tRNA modification, RNA stability, and tissue delivery jointly regulate the selenoprotein network.
Recorded consequence: GPX1 and SELENOW often respond strongly, while GPX4 can be relatively preserved; this is a schematic pattern rather than a fixed order.
Scope: Predominantly animal and cell models; ranking varies with tissue, species, development, duration, and measurement.
LYPLA2 silencing accelerated ZDHHC6 decay in HeLa pulse-chase experiments, shortening the reported apparent half-life from about 16 hours to about 3 hours.
Condition: machinery_impairment · 72-hour siRNA protocol; 2-hour metabolic protein pulse followed by chase. Reported apparent half-lives, not raw-data refits.
Normal role: APT2 regulates substrate depalmitoylation; relevant selenium-pathway proteins are separate actors. This scenario describes experimental machinery, not nutrient shortage.
Recorded consequence: LYPLA2 silencing accelerated ZDHHC6 decay in HeLa pulse-chase experiments, shortening the reported apparent half-life from about 16 hours to about 3 hours.
Scope: Human HeLa; LYPLA2 siRNA and tagged ZDHHC6
GPX4 loss weakens lipid defense; FSP1 can provide parallel protection
Condition: nutrient_deficiency · Selenium restriction becomes severe enough to compromise GPX4 function in a susceptible context.
Normal role: GPX4 reduces membrane phospholipid hydroperoxides. FSP1 regenerates reduced CoQ as a separate lipid-radical defense.
Recorded consequence: Phospholipid peroxide control can weaken, but ferroptosis susceptibility also depends on parallel defenses, including FSP1–CoQ10.
Scope: Cell and cancer-model evidence for parallel defenses; GPX4 may be relatively preserved during nutritional restriction.
APT2 shRNA increased GPX4 palmitoylation measured by acyl-biotin exchange in A375 cells.
Condition: machinery_impairment · ABE assay with and without hydroxylamine; representative of three independent experiments; exact shRNA exposure duration unresolved.
Normal role: APT2 regulates substrate depalmitoylation; relevant selenium-pathway proteins are separate actors. This scenario describes experimental machinery, not nutrient shortage.
Recorded consequence: APT2 shRNA increased GPX4 palmitoylation measured by acyl-biotin exchange in A375 cells.
Scope: Human A375 melanoma; lentiviral APT2 shRNA; exogenous GPX4
Restriction can change local thyroid-hormone metabolism
Condition: nutrient_deficiency · Selenium restriction affects deiodinase expression or activity in a particular tissue.
Normal role: DIO1, DIO2, and DIO3 regulate tissue thyroid-hormone activation and inactivation.
Recorded consequence: Local T4, T3, and rT3 metabolism can change without a universal relationship to a single circulating marker.
Scope: Mechanistic synthesis; deiodinase responses and clinical consequences are tissue- and context-dependent.
When thioredoxin reductase is built without selenium
Condition: nutrient_deficiency · Replacing the selenocysteine with cysteine, or truncating the C-terminal SeCys-Gly dipeptide as expected in selenium deficiency.
Normal role: Selenocysteine at position 498 forms the selenolthiol that reduces thioredoxin and hydroperoxides.
Recorded consequence: Catalytic turnover falls about a hundred-fold, the pH optimum shifts from 7 to 9, and hydroperoxidase activity is lost altogether.
Scope: Recombinant rat enzyme
When local thyroid hormone activation fails in brown fat
Condition: nutrient_deficiency · Targeted disruption of the Dio2 gene in mice.
Normal role: The selenoenzyme DIO2 converts thyroxine to T3 inside brown adipose tissue, saturating the thyroid hormone receptor alpha that the sympathetic response requires.
Recorded consequence: Cold-exposed animals become hypothermic despite normal plasma T3 and normal basal UCP1, and survive by shivering with acute weight loss; a single T3 injection reverses it completely.
Scope: Mouse brown adipose tissue
APT2 knockdown increased GPX4 protein stability in A375 cycloheximide-chase experiments.
Condition: machinery_impairment · Cycloheximide chase; three independent experiments; exact CHX concentration and time series not resolved from reviewed legend.
Normal role: APT2 regulates substrate depalmitoylation; relevant selenium-pathway proteins are separate actors. This scenario describes experimental machinery, not nutrient shortage.
Recorded consequence: APT2 knockdown increased GPX4 protein stability in A375 cycloheximide-chase experiments.
Scope: Human A375 melanoma; lentiviral APT2 shRNA
Severe deficiency can weaken thyroid peroxide defense
Condition: nutrient_deficiency · Severe selenium deficiency reduces selenium-dependent thyroid redox capacity.
Normal role: Thyroid-hormone synthesis uses locally generated H2O2; GPXs, thioredoxin reductases, and other systems limit peroxide spillover.
Recorded consequence: The thyroid can have less capacity to control peroxide used during hormone synthesis.
Scope: Biochemical redox mechanism in severe deficiency; autoimmune disease is a separate, multifactorial outcome.
APT2 knockdown did not significantly change GPX4 mRNA in the reported A375 and HT1080 RT-qPCR experiments.
Condition: machinery_impairment · RT-qPCR; three independent experiments; exposure timing unresolved.
Normal role: APT2 regulates substrate depalmitoylation; relevant selenium-pathway proteins are separate actors. This scenario describes experimental machinery, not nutrient shortage.
Recorded consequence: APT2 knockdown did not significantly change GPX4 mRNA in the reported A375 and HT1080 RT-qPCR experiments.
Scope: Human A375 and HT1080 cancer cells; lentiviral APT2 shRNA
SELENOP delivery and tissue retention respond differently
Condition: nutrient_deficiency · Dietary selenium availability declines.
Normal role: Liver-derived SELENOP carries selenium; ApoER2/LRP8 contributes to uptake in brain and testis.
Recorded consequence: Circulating SELENOP and delivery can fall while receptor biology helps brain and testis retain selenium relatively well in many models.
Scope: Tissue-selective distribution, largely from experimental models; relative retention differs from absolute protection.
APT2 knockdown reduced RSL3-induced cell death measured with SYTOX Green in A375 cells.
Condition: machinery_impairment · 4 micromolar RSL3 for 6 hours; SYTOX Green staining; three independent experiments.
Normal role: APT2 regulates substrate depalmitoylation; relevant selenium-pathway proteins are separate actors. This scenario describes experimental machinery, not nutrient shortage.
Recorded consequence: APT2 knockdown reduced RSL3-induced cell death measured with SYTOX Green in A375 cells.
Scope: Human A375 melanoma; lentiviral APT2 shRNA
Restricted selenium can impair sperm and fertility in animal models
Condition: nutrient_deficiency · Selenium restriction affects sperm biology; genetic disruption of delivery or GPX4 provides related but distinct evidence.
Normal role: SELENOP delivers selenium, and a structural GPX4 form contributes to the sperm mitochondrial sheath during maturation.
Recorded consequence: Animal studies link restriction to impaired fertility and disrupted delivery/GPX4 biology to sheath defects and reduced motility.
Scope: Animal dietary-restriction and genetic models; the experiments address related mechanisms with different perturbations.
Immune responses depend on cell-specific redox and lipid defenses
Condition: nutrient_deficiency · Selenium status changes in an immune context; GPX4 perturbation studies test specific downstream defenses.
Normal role: Selenium-dependent systems help regulate immune redox tone; GPX4-dependent lipid control can support T-cell survival and differentiation.
Recorded consequence: Immune redox tone and cell survival can shift, with different effects across cell populations.
Scope: Much of the detailed mechanism comes from cell and animal models; human immune findings are heterogeneous.
A deficient mouse host can favor more virulent viral variants
Condition: nutrient_deficiency · Experimental Coxsackievirus passage through selenium-deficient mice.
Normal role: The host nutritional and immune environment forms part of the conditions in which a virus replicates and variants are selected.
Recorded consequence: Genomic changes and increased virulence were observed; increased virulence could persist after transfer to nutritionally adequate mice.
Scope: Animal passage experiments; related influenza findings are reported, and vitamin E deficiency produced a similar Coxsackievirus effect.
Selenium shortage reduced a vitamin C recycling pathway and liver vitamin C in rats.
Condition: nutrient_deficiency · Dietary selenium deficiency
Normal role: Transport and recycling maintain available reduced vitamin C.
Recorded consequence: Selenium-deficient rats had 33% less liver ascorbate together with an 88% fall in thioredoxin-reductase activity; liver GSH content was unchanged.
Scope: Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver
SELENOK loss disrupts IP3R support and calcium signaling
Condition: machinery_impairment · Insufficient or absent SELENOK function; the reported phenotype comes from SELENOK-null mice.
Normal role: SELENOK supports the ZDHHC6 acyl-enzyme intermediate; ZDHHC6 palmitoylates IP3R, supporting a functional ER calcium channel.
Recorded consequence: The supplied immune draft reports failed receptor support and blunted immune-cell calcium flux after SELENOK loss.
Scope: SELENOK loss-of-function animal model and supplied biochemical mechanism, including T-cell context.
Selenium deficiency impaired radical recycling in the rat liver’s soluble fraction.
Condition: nutrient_deficiency · Dietary selenium depletion; isolated dialyzed cytosol
Normal role: Transport and recycling maintain available reduced vitamin C.
Recorded consequence: Dialyzed liver cytosol from selenium-deficient rats lost NADPH-dependent ascorbyl-radical reducing activity attributed to thioredoxin reductase.
Scope: Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats
FTSJ1 loss reduces efficient selenocysteine insertion
Condition: machinery_impairment · Experimental loss of FTSJ1-dependent tRNA modification.
Normal role: FTSJ1 supplies the Um34 ribose methylation of tRNA[Ser]Sec that helps efficient selenocysteine insertion.
Recorded consequence: Sec insertion becomes less efficient and experimental cells become more sensitive to oxidative stress.
Scope: Cell/biochemical studies and melanoma xenograft models reported in the 2024 FTSJ1 study.
A membrane-associated recycling route remained active despite selenium shortage.
Condition: nutrient_deficiency · Control and selenium-deficient rat liver microsome assays
Normal role: Transport and recycling maintain available reduced vitamin C.
Recorded consequence: Rat liver microsomes reduced ascorbyl radical using NADH, and this activity was insensitive to selenium depletion.
Scope: Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats
Tissue-selective response to selenium restriction
Condition: nutrient_deficiency · Twenty weeks on a basal diet containing 0.01 mg selenium/kg, compared with sodium-selenite-supplemented diets.
Normal role: Selenium supports selenoprotein production.
Recorded consequence: Liver type I deiodinase falls, while thyroid activity is maintained; thyroid glutathione peroxidase falls.
Scope: Male weanling Sprague-Dawley rats.
An IP3 message can be present while its calcium-release receptor fails
Condition: nutrient_deficiency · Low selenium in culture or loss of SELENOK machinery.
Normal role: SELENOK-linked palmitoylation helps sustain IP3R abundance and function.
Recorded consequence: IP3R palmitoylation and expression fall; receptor-induced IP3 production need not fall.
Scope: Cell and genetic models; no universal human selenium threshold.
SECISBP2 defects impair decoding despite dietary supply
Condition: machinery_impairment · Rare genetic SECISBP2 deficiency, distinct from inadequate dietary selenium.
Normal role: SECISBP2/SBP2 interacts with SECIS-dependent translation machinery to support selenocysteine insertion.
Recorded consequence: Failure of a required translation component is associated with abnormal thyroid-hormone profiles and multisystem phenotypes.
Scope: Rare human genetic disorder and biochemical role of SECIS-dependent recoding.
SEPSECS defects interrupt Sec-tRNA synthesis
Condition: machinery_impairment · Pathogenic SEPSECS impairment affecting Sec-tRNA synthesis.
Normal role: SEPSECS uses the phosphorylated serine-tRNA precursor in the pathway that produces Sec-tRNA.
Recorded consequence: Sec-tRNA synthesis is defective; the source associates pathogenic SEPSECS disorders with the pontocerebellar hypoplasia spectrum.
Scope: Rare human genetic disorders and the defined Sec-tRNA biosynthetic pathway.
Low circulating selenium during illness can have mixed causes
Condition: biomarker_context · Acute inflammation or severe illness changes hepatic priorities, protein distribution, losses, or intake.
Normal role: Plasma/serum selenium reflects several circulating pools; SELENOP reflects transport biology and is acute-phase sensitive.
Recorded consequence: Circulating selenium and SELENOP can fall without the measurement alone establishing dietary deficiency.
Scope: Inflammatory and acute-illness measurement context, including observational associations with illness severity.
SeMet enters both protein storage and functional selenium metabolism
Condition: biomarker_context · Selenomethionine contributes to measured selenium during exposure or repletion.
Normal role: Selenium forms enter different metabolic routes; total circulating selenium includes multiple pools.
Recorded consequence: SeMet can enter nonspecific protein incorporation and also supply functional selenium metabolism, so a total concentration does not identify its destination.
Scope: Selenium-form pharmacokinetics and interpretation of status markers.
A biomarker plateau does not locate a cellular failure or toxicity switch
Condition: biomarker_context · A selenium-responsive circulating biomarker approaches a plateau in a particular study or individual context.
Normal role: SELENOP concentration and GPX3 activity can respond to selenium supply and approach plateaus in dose-response studies.
Recorded consequence: Additional concentration changes become less informative for that endpoint; the plateau does not establish a universal treatment target or toxicity boundary.
Scope: Human intervention dose-response observations and biomarker interpretation.
Selenium alone lowered circulating T4 in this co-deficient population.
Condition: nutrient_deficiency · Severe selenium and iodine co-deficiency; selenium administered without a reported iodine-repletion regimen. Same co-deficient study population.
Normal role: Selenium-dependent hormone processing interacts with an iodine-dependent supply of thyroid hormones. Selenium-dependent processing and hormone synthesis require separate assessment. Different deiodination and feedback endpoints need not change together.
Recorded consequence: Mean serum total T4 fell from 73.1 ± 45.4 to 48.3 ± 23.7 nmol/L after two months of selenium treatment (P<0.001) in the iodine/selenium-deficient setting. Mean serum free T4 fell from 11.8 ± 6.7 to 8.4 ± 4.1 pmol/L after selenium treatment (P<0.01). Mean reverse T3 fell from 124 ± 115 to 90 ± 72 pmol/L after selenium treatment (P<0.05), while serum T3 and TSH did not change significantly.
Scope: Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire; Selenium 50 micrograms/day as selenomethionine or placebo for two months; no concurrent iodine-repletion regimen reported in the abstract.
Baseline selenium measurements helped identify different trial outcomes, but did not establish a safe supplement combination.
Condition: biomarker_context · Trial risk stratification by a cohort percentile of baseline toenail selenium.
Normal role: A baseline biomarker may modify observed supplement response without defining nutrient deficiency.
Recorded consequence: In the SELECT secondary analysis, vitamin E alone increased total prostate-cancer risk by 63% among men below the 40th percentile of baseline toenail selenium; a significant effect was not found above that split.
Scope: Secondary case-cohort analysis nested within SELECT; 1739 total cases and 3117 sampled cohort members; Trial supplementation analyzed by baseline toenail selenium; E-alone comparison used below versus at/above the 40th percentile.
Glutathione availability cannot replace selenium-dependent peroxidase
Condition: nutrient_deficiency · Dietary selenium deficiency followed by oxidant challenge of hemolyzates.
Normal role: Selenium-dependent glutathione peroxidase enables GSH-supported peroxide defense.
Recorded consequence: Added GSH did not prevent oxidative hemoglobin damage.
Scope: Rat erythrocyte hemolyzates.
The sources
Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.
- APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnoverTargeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · unverified_draftRead preserved source
- Diabetes cascade: targeted primary-source supplementSee claim-local references; curated paraphrases reviewed 2026-09-20. · unverified_draftRead preserved source
- Selenium deficiency: a mechanism-first referenceSupplied selenium deficiency reference · unverified_draftRead preserved source
- Selenium in immune cellsSelenium immune-cell mechanism draft · unverified_draftRead preserved source
- Selenium: literature corrections and mechanism additionsMetabolic Ledger literature curation, 17 September 2026; primary papers linked individually · secondary_verifiedRead preserved source
- Selenium: the molecular cascadeSelenium molecular cascade draft · unverified_draftRead preserved source
Recorded disagreements
Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.
Open questions in this collection
Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.
Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.