Component

Phosphodiesterase type 5 phosphorylated at serine 92

Phosphodiesterase type 5 phosphorylated at serine 92. Species, exposure and limitations are retained in each linked claim.

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

Read recorded mechanisms Open recursive mind map

How nutrients influence it

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

How nutrients reach it in more than one step

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

Tracing routes…

What it does

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

Recorded relationships

What it acts on

  1. There was no detectable difference between phosphorylated and unphosphorylated phosphodiesterase type 5 in the median inhibitory concentration for sildenafil, or for zaprinast or 3-isobutyl-1-methylxanthine.

    Phosphodiesterase type 5 phosphorylated at serine 92 → Sildenafil source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"}
    experimental_model
    Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement
    exposure
    Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP
    limitations
    Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Cattle enzyme
    plain_language
    Speeding the enzyme up does not make it any harder for the drug to block.
    primary_references
    [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
    tissue_or_cell_type
    Recombinant enzyme and lung extract

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 210–221

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement · source_derived_draft · unverified_draft

    ### sil-feedback-does-not-blunt-the-drug There was no detectable difference between phosphorylated and unphosphorylated phosphodiesterase type 5 in the median inhibitory concentration for sildenafil, or for zaprinast or 3-isobutyl-1-methylxanthine. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Speeding the enzyme up does not make it any harder for the drug to block. organism: Cattle enzyme tissue_or_cell_type: Recombinant enzyme and lung extract experimental_model: Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement limitations: Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug. exposure: Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP evidence_span: {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"} [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
    Complete structured claim and evidence

What acts on it

  1. Mutations affecting cyclic GMP binding to either one or both allosteric sites of phosphodiesterase type 5 do not influence cyclic GMP hydrolysis at the catalytic site under the conditions used, but the mutants defective in binding at either site require much higher cyclic GMP concentrations for allosteric stimulation of phosphorylation, while a mutant with higher binding affinity is phosphorylated at lower cyclic GMP concentrations, so binding to the allosteric sites does not directly affect catalysis but regulates phosphorylation of the enzyme.

    The two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 → Phosphodiesterase type 5 phosphorylated at serine 92 source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/9445376.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29", "start_char": 0, "end_char": 1541, "text_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29"}
    experimental_model
    Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5
    exposure
    D289A, D478A and D289A/D478A binding-site mutants, with phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase
    limitations
    Separates what the allosteric sites do from what the catalytic site does, using mutants that lose binding at one site, the other, or both.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Enzyme
    plain_language
    The second pair of binding sites does not change how fast the enzyme works; it decides when the enzyme gets switched up.
    primary_references
    [sil-p9445376] Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. (1998). https://pubmed.ncbi.nlm.nih.gov/9445376/ DOI: 10.1042/bj3290505
    tissue_or_cell_type
    Recombinant phosphodiesterase type 5

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 184–195

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 · source_derived_draft · unverified_draft

    ### sil-allosteric-sites-gate-phosphorylation Mutations affecting cyclic GMP binding to either one or both allosteric sites of phosphodiesterase type 5 do not influence cyclic GMP hydrolysis at the catalytic site under the conditions used, but the mutants defective in binding at either site require much higher cyclic GMP concentrations for allosteric stimulation of phosphorylation, while a mutant with higher binding affinity is phosphorylated at lower cyclic GMP concentrations, so binding to the allosteric sites does not directly affect catalysis but regulates phosphorylation of the enzyme. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The second pair of binding sites does not change how fast the enzyme works; it decides when the enzyme gets switched up. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 limitations: Separates what the allosteric sites do from what the catalytic site does, using mutants that lose binding at one site, the other, or both. exposure: D289A, D478A and D289A/D478A binding-site mutants, with phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase evidence_span: {"source_cache": "artifacts/sildenafil-research/9445376.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29", "start_char": 0, "end_char": 1541, "text_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29"} [sil-p9445376] Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. (1998). https://pubmed.ncbi.nlm.nih.gov/9445376/ DOI: 10.1042/bj3290505
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. Prior incubation of recombinant phosphodiesterase type 5 with protein kinase G, magnesium ATP and cyclic GMP, producing serine 92 phosphorylation, caused a 50 to 70% increase in enzyme activity and increased the affinity of cyclic GMP binding to the allosteric sites, reducing the concentration needed for half-maximum allosteric binding from 0.13 to 0.03 micromolar, with stimulation obtained at 0.2 to 0.5 micromolar kinase subunit which is approximately the cellular level in vascular smooth muscle, while considerably higher concentrations of protein kinase A were required.

    cGMP-dependent protein kinase I → Phosphodiesterase 5 family source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"}
    experimental_model
    Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement
    exposure
    Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP
    limitations
    Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Cattle enzyme
    plain_language
    The messenger switches on a kinase that speeds up the enzyme destroying it, which is a brake the cell applies to itself.
    primary_references
    [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
    tissue_or_cell_type
    Recombinant enzyme and lung extract

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 197–208

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement · source_derived_draft · unverified_draft

    ### sil-pkg-feedback-speeds-the-enzyme Prior incubation of recombinant phosphodiesterase type 5 with protein kinase G, magnesium ATP and cyclic GMP, producing serine 92 phosphorylation, caused a 50 to 70% increase in enzyme activity and increased the affinity of cyclic GMP binding to the allosteric sites, reducing the concentration needed for half-maximum allosteric binding from 0.13 to 0.03 micromolar, with stimulation obtained at 0.2 to 0.5 micromolar kinase subunit which is approximately the cellular level in vascular smooth muscle, while considerably higher concentrations of protein kinase A were required. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The messenger switches on a kinase that speeds up the enzyme destroying it, which is a brake the cell applies to itself. organism: Cattle enzyme tissue_or_cell_type: Recombinant enzyme and lung extract experimental_model: Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement limitations: Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug. exposure: Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP evidence_span: {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"} [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
    Complete structured claim and evidence

In the sources

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