{"id":"8a218113-e1d2-586d-8bd8-14ad365a350a","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-feedback-does-not-blunt-the-drug","predicate":"preserves_measured_pool","statement":"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.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"efed4a07-71a7-5af7-9beb-36a1165729d1","mechanism_event_label":"Speeding the enzyme up does not make it any harder for the drug to block.","subject":{"id":"c786e770-e988-5645-824d-0c1582036a85","slug":"phosphorylated-pde5","display_name":"Phosphodiesterase type 5 phosphorylated at serine 92","entity_type_key":"protein_state"},"object":{"id":"fe62cf8d-5f89-5e19-bc36-03ad3c9063b7","slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"},"evidence_count":1,"mechanism_event":{"id":"efed4a07-71a7-5af7-9beb-36a1165729d1","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-feedback-does-not-blunt-the-drug-event","event_type":"observed_intervention","label":"Speeding the enzyme up does not make it any harder for the drug to block.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"877abce1-0ce4-5782-acef-a5b9d5d8fdcb","slug":"pde5-ser92","display_name":"Serine 92 of phosphodiesterase type 5","entity_type_key":"protein_state"},"role":"modified_residue","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"9381d4a4-dd83-5d06-8ae4-f3a17ecbda8e","slug":"zaprinast","display_name":"Zaprinast","entity_type_key":"chemical_species"},"role":"co_tested_inhibitor","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c786e770-e988-5645-824d-0c1582036a85","slug":"phosphorylated-pde5","display_name":"Phosphodiesterase type 5 phosphorylated at serine 92","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"fe62cf8d-5f89-5e19-bc36-03ad3c9063b7","slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"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\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":{"slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Cattle enzyme","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Speeding the enzyme up does not make it any harder for the drug to block.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Recombinant enzyme and lung extract","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"3d9e9629-3c4a-5626-a4e2-1be3ccfc77d0","evidence_kind":"source_excerpt","locator":"Lines 210-221","start_line":210,"end_line":221,"excerpt":"### sil-feedback-does-not-blunt-the-drug\nThere 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.\nCondition category: normal\nnutrient_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.\nplain_language: Speeding the enzyme up does not make it any harder for the drug to block.\norganism: Cattle enzyme\ntissue_or_cell_type: Recombinant enzyme and lung extract\nexperimental_model: Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement\nlimitations: 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.\nexposure: Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP\nevidence_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\"}\n[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","model_system":"Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c6c2a590-1f8f-5fac-b2c7-3aae0440b9fd","stable_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","title":"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)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"bc81793d20d20d2eaad9cb530b70695d8d8778a3d7136e24715ac3369b939953","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}