{"id":"61dc2e22-b6bd-5669-abfa-73de0efbc848","stable_key":"b3c3f45a-50fb-5b79-98d7-5e5228df00db:cold-th-pterin-geometry","predicate":"binds","statement":"The pterin binds in the active-site cleft forming an aromatic stacking interaction with Phe300, which is itself hydroxylated in the meta position by an autocatalytic process and anchored by a hydrogen bond to the carbonyl of Gln310; the iron sits 5.6 angstrom from the pterin 4a carbon, and molecular oxygen could bind in a bridging position between the pterin and the iron before substrate hydroxylation.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"fe65a915-a6fd-575b-8c88-4dd842f22575","mechanism_event_label":"The oxygen molecule slots into the gap between the cofactor and the iron.","subject":{"id":"1c231b90-c106-507a-8766-870ecb40e368","slug":"tetrahydrobiopterin","display_name":"Tetrahydrobiopterin / BH4","entity_type_key":"small_molecule"},"object":{"id":"e4e0f24b-1e70-573d-b719-039a90191b90","slug":"human-tyrosine-hydroxylase","display_name":"Human tyrosine hydroxylase","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"fe65a915-a6fd-575b-8c88-4dd842f22575","stable_key":"b3c3f45a-50fb-5b79-98d7-5e5228df00db:cold-th-pterin-geometry-event","event_type":"biochemical_relationship","label":"The oxygen molecule slots into the gap between the cofactor and the iron.","description":"The pterin binds in the active-site cleft forming an aromatic stacking interaction with Phe300, which is itself hydroxylated in the meta position by an autocatalytic process and anchored by a hydrogen bond to the carbonyl of Gln310; the iron sits 5.6 angstrom from the pterin 4a carbon, and molecular oxygen could bind in a bridging position between the pterin and the iron before substrate hydroxylation.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"52e09bdf-3d54-52b2-b981-5879fc804ffe","slug":"th-phe300","display_name":"The self-hydroxylated Phe300 pterin-stacking residue of tyrosine hydroxylase","entity_type_key":"protein_state"},"role":"anchoring_residue","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"899c7ab0-6f81-5b38-a6bd-fbb33d66ac8d","slug":"oxygen","display_name":"Molecular oxygen","entity_type_key":"small_molecule"},"role":"bridging_substrate","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"89bcaf42-b4ab-5760-8c2e-44eace10cee0","slug":"iron","display_name":"Iron","entity_type_key":"nutrient_element"},"role":"required_metal","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"1c231b90-c106-507a-8766-870ecb40e368","slug":"tetrahydrobiopterin","display_name":"Tetrahydrobiopterin / BH4","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"e4e0f24b-1e70-573d-b719-039a90191b90","slug":"human-tyrosine-hydroxylase","display_name":"Human tyrosine hydroxylase","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/cold-research/9753429.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"3c76ec6d5dadb463c0a044175d5a78fbd02df4da7c339029c8c232e8878175b9\", \"start_char\": 0, \"end_char\": 1695, \"text_sha256\": \"3c76ec6d5dadb463c0a044175d5a78fbd02df4da7c339029c8c232e8878175b9\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Crystal structure of rat tyrosine hydroxylase with a cofactor analogue and iron at 2.3 angstrom","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Bound 7,8-dihydrobiopterin and iron","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Structural chemistry of the rate-limiting step. It is a rat enzyme structure with a cofactor analogue, not a measurement of iron status in an animal.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake.","comparator":null,"unit":null,"notes":"","entity":{"slug":"cold-water-immersion","display_name":"Cold water immersion","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Rat enzyme","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The oxygen molecule slots into the gap between the cofactor and the iron.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[cold-p9753429] Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site. (1998). https://pubmed.ncbi.nlm.nih.gov/9753429/ DOI: 10.1021/bi981462g","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Purified catalytic and tetramerization domains","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"104310c7-6bdf-5985-b60e-3a313139040b","evidence_kind":"source_excerpt","locator":"Lines 546-557","start_line":546,"end_line":557,"excerpt":"### cold-th-pterin-geometry\nThe pterin binds in the active-site cleft forming an aromatic stacking interaction with Phe300, which is itself hydroxylated in the meta position by an autocatalytic process and anchored by a hydrogen bond to the carbonyl of Gln310; the iron sits 5.6 angstrom from the pterin 4a carbon, and molecular oxygen could bind in a bridging position between the pterin and the iron before substrate hydroxylation.\nCondition category: normal\nnutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake.\nplain_language: The oxygen molecule slots into the gap between the cofactor and the iron.\norganism: Rat enzyme\ntissue_or_cell_type: Purified catalytic and tetramerization domains\nexperimental_model: Crystal structure of rat tyrosine hydroxylase with a cofactor analogue and iron at 2.3 angstrom\nlimitations: Structural chemistry of the rate-limiting step. It is a rat enzyme structure with a cofactor analogue, not a measurement of iron status in an animal.\nexposure: Bound 7,8-dihydrobiopterin and iron\nevidence_span: {\"source_cache\": \"artifacts/cold-research/9753429.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"3c76ec6d5dadb463c0a044175d5a78fbd02df4da7c339029c8c232e8878175b9\", \"start_char\": 0, \"end_char\": 1695, \"text_sha256\": \"3c76ec6d5dadb463c0a044175d5a78fbd02df4da7c339029c8c232e8878175b9\"}\n[cold-p9753429] Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site. (1998). https://pubmed.ncbi.nlm.nih.gov/9753429/ DOI: 10.1021/bi981462g","model_system":"Crystal structure of rat tyrosine hydroxylase with a cofactor analogue and iron at 2.3 angstrom","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [cold-p9753429] Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site. 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