Structural homology between phosphodiesterase type 5 and rod phosphodiesterase 6: molecular mechanisms & dependencies

How nutrients influence it

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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 it acts on

Early in development it was noted that besides its major inhibitory effect on the intended target, the vascular-associated PDE5, the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6 located in the retina, and for this reason preclinical evaluation included electroretinography plus postmortem histology and an extended eye examination was incorporated into clinical protocols, with data on the incidence, duration and type of colour vision defects observed at different doses.
Structural homology between phosphodiesterase type 5 and rod phosphodiesterase 6 → Transient colour vision disturbance and increased light sensitivity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10703120.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6", "start_char": 0, "end_char": 2146, "text_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6"}
experimental_model
Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance
exposure
Electroretinography and histology in preclinical evaluation, with extended eye examination in clinical protocols and registry surveillance
limitations
A methodological review of how the signal was tracked rather than a new measurement. It is useful because it records that the retinal effect was predicted before it was looked for.
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
Human and animal
plain_language
The visual effect was not a surprise; the homology between the two enzymes predicted it and the trials were designed to look for it.
primary_references
[sil-p10703120] Ocular safety of Viagra, (sildenafil citrate). (1999). https://pubmed.ncbi.nlm.nih.gov/10703120/
tissue_or_cell_type
Retina
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 496–507
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance · source_derived_draft · unverified_draft
### sil-the-off-target-was-predicted Early in development it was noted that besides its major inhibitory effect on the intended target, the vascular-associated PDE5, the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6 located in the retina, and for this reason preclinical evaluation included electroretinography plus postmortem histology and an extended eye examination was incorporated into clinical protocols, with data on the incidence, duration and type of colour vision defects observed at different doses. 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 visual effect was not a surprise; the homology between the two enzymes predicted it and the trials were designed to look for it. organism: Human and animal tissue_or_cell_type: Retina experimental_model: Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance limitations: A methodological review of how the signal was tracked rather than a new measurement. It is useful because it records that the retinal effect was predicted before it was looked for. exposure: Electroretinography and histology in preclinical evaluation, with extended eye examination in clinical protocols and registry surveillance evidence_span: {"source_cache": "artifacts/sildenafil-research/10703120.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6", "start_char": 0, "end_char": 2146, "text_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6"} [sil-p10703120] Ocular safety of Viagra, (sildenafil citrate). (1999). https://pubmed.ncbi.nlm.nih.gov/10703120/
Complete structured claim and evidence

Where it participates (unsigned role)

Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences.
Rod PDE6 complex → Phosphodiesterase 5 family source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"}
experimental_model
Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6
exposure
Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling
limitations
A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation.
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
plain_language
The retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other.
primary_references
[sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813
tissue_or_cell_type
Retinal rod outer segment
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 249–260
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 · source_derived_draft · unverified_draft
### sil-pde5-and-pde6-are-built-alike Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences. 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 retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other. organism: Cattle tissue_or_cell_type: Retinal rod outer segment experimental_model: Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 limitations: A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation. exposure: Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling evidence_span: {"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"} [sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813
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

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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.

Structural homology between phosphodiesterase type 5 and rod phosphodiesterase 6