The catalytic site of phosphodiesterase type 5: molecular mechanisms & dependencies

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.

Human evidence only

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 acts on it

Sildenafil and zaprinast are both competitive inhibitors of PDE5 and double-inhibition analysis shows they interact with the catalytic site in a mutually exclusive manner, with inhibition constants of 1 nanomolar for sildenafil, 5 nanomolar for UK-122764 and 130 nanomolar for zaprinast, and the affinity of each of these inhibitors for the enzyme is much higher than that of cyclic GMP itself whose Michaelis constant is 2000 nanomolar.
Sildenafil → The catalytic site of phosphodiesterase type 5 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"}
experimental_model
Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain
exposure
Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants
limitations
Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme.
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 drug holds the working part of the enzyme about two thousand times more tightly than the molecule the enzyme is meant to destroy.
primary_references
[sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124
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 158–169
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain · source_derived_draft · unverified_draft
### sil-two-thousand-fold-over-substrate Sildenafil and zaprinast are both competitive inhibitors of PDE5 and double-inhibition analysis shows they interact with the catalytic site in a mutually exclusive manner, with inhibition constants of 1 nanomolar for sildenafil, 5 nanomolar for UK-122764 and 130 nanomolar for zaprinast, and the affinity of each of these inhibitors for the enzyme is much higher than that of cyclic GMP itself whose Michaelis constant is 2000 nanomolar. 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 drug holds the working part of the enzyme about two thousand times more tightly than the molecule the enzyme is meant to destroy. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain limitations: Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme. exposure: Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants evidence_span: {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"} [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124
Complete structured claim and evidence

Where it participates (unsigned role)

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

The events it takes part in

A mechanism often involves more than two components. These are the full events, with every participant and its role.

Situations it appears in

Low-supply and faulty-machinery situations recorded in the chapters where this component plays a part.

In the sources

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

Open hypotheses

Proposed ideas that involve this component. They are labeled as hypotheses and do not change any recorded statement.

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

The catalytic site of phosphodiesterase type 5