ZDHHC6

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"}

experimental_model

Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays

exposure

Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants

limitations

Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Mouse immune cells and mammalian cell models

plain_language

Impairing the modification enzyme weakened the calcium-release response.

primary_references

[ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

tissue_or_cell_type

ER-associated IP3 receptor machinery

trigger_kind

machinery_impairment Imported condition classification; unverified.

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1107–1118

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays · source_derived_draft · unverified_draft

### ino-dhhc6-flux DHHC6 knockdown reduced IP3R expression and IP3R-dependent calcium flux. Condition category: machinery_impairment nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: Impairing the modification enzyme weakened the calcium-release response. organism: Mouse immune cells and mammalian cell models tissue_or_cell_type: ER-associated IP3 receptor machinery experimental_model: Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays limitations: Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure. exposure: Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants evidence_span: {"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"} [ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

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.

availability_state

Insufficient or absent SELENOK function; the reported phenotype comes from SELENOK-null mice.

experimental_scope

SELENOK loss-of-function animal model and supplied biochemical mechanism, including T-cell context.

limitations

Dietary selenium restriction is not proven equivalent to SELENOK knockout. No selenium concentration is mapped to this phenotype, and this scenario does not invert every downstream normal-path arrow.

trigger_kind

machinery_impairment

Selenium in immune cells · lines 18–20

Selenium immune-cell mechanism draft · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

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 139–139

Selenium molecular cascade draft · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

**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.**

evidence_span

{"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"}

experimental_model

Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays

exposure

Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants

limitations

Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Mouse immune cells and mammalian cell models

plain_language

Two separately identifiable proteins cooperate in maintaining the receptor.

primary_references

[ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

tissue_or_cell_type

ER-associated IP3 receptor machinery

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1094–1105

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays · source_derived_draft · unverified_draft

### ino-selk-dhhc6 SELENOK and DHHC6 interacted at the ER membrane through SH3-related binding interactions. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: Two separately identifiable proteins cooperate in maintaining the receptor. organism: Mouse immune cells and mammalian cell models tissue_or_cell_type: ER-associated IP3 receptor machinery experimental_model: Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays limitations: Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure. exposure: Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants evidence_span: {"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"} [ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

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)

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)

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.

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.

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.

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.

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)