{"corpus_id":11929689,"paper_sha":"71043e0f5c1aaa9995f0ef74b8bb48bccd920acd","doi":"10.1016/S0021-9258(18)60522-8","arxiv_id":null,"pmid":2722829,"pmcid":null,"mag_id":1485457766,"dblp_id":null,"acl_id":null,"title":"Stabilized isoporphyrin intermediates in the inactivation of horseradish peroxidase by alkylhydrazines.","year":1989,"publication_date":"1989-06-05","venue":"Journal of Biological Chemistry","journal":{"name":"The Journal of biological chemistry","pages":"\n          9250-7\n        ","volume":"264 16"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, U.S. Gov't, P.H.S."],"s2_fields_of_study":["Medicine","Chemistry"],"reference_count":27,"citation_count":24,"influential_citation_count":1,"is_open_access":false,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Alkylation","mj":false,"ui":"D000478"},{"d":"Catalysis","mj":false,"ui":"D002384"},{"d":"Enzyme Activation","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D004789"},{"d":"Enzyme Stability","mj":false,"ui":"D004795"},{"d":"Heme","mj":false,"ui":"D006418"},{"d":"Horseradish Peroxidase","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D006735"},{"d":"Hydrazines","mj":false,"qs":[{"q":"pharmacology","mj":true,"ui":"Q000494"}],"ui":"D006834"},{"d":"Hydrogen Peroxide","mj":false,"ui":"D006861"},{"d":"Hydrogen-Ion Concentration","mj":false,"ui":"D006863"},{"d":"Isomerism","mj":false,"ui":"D007536"},{"d":"Peroxidases","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D010544"},{"d":"Porphyrins","mj":true,"ui":"D011166"},{"d":"Potassium Cyanide","mj":false,"ui":"D011190"},{"d":"Spectrophotometry","mj":false,"ui":"D013053"}],"chemicals":[{"n":"Hydrazines","ui":"D006834","reg":"0"},{"n":"Porphyrins","ui":"D011166","reg":"0"},{"n":"Heme","ui":"D006418","reg":"42VZT0U6YR"},{"n":"Hydrogen Peroxide","ui":"D006861","reg":"BBX060AN9V"},{"n":"Horseradish Peroxidase","ui":"D006735","reg":"EC 1.11.1.-"},{"n":"Peroxidases","ui":"D010544","reg":"EC 1.11.1.-"},{"n":"Potassium Cyanide","ui":"D011190","reg":"MQD255M2ZO"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":null,"s2_open_access_landing_url":null,"s2_open_access_license":null,"s2_open_access_status":null,"pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"The reaction of horseradish peroxidase with alkylhydrazines results in delta-meso-alkylation of the prosthetic heme group and enzyme inactivation (Ator, M. A., David, S. K., and Ortiz de Montellano, P. R. (1987) J. Biol. Chem. 262, 14954-14960). As reported here, enzyme inactivation is associated with the accumulation of intermediates that absorb at approximately 835 nm. The properties of these intermediates, including their collapse to give meso-alkylhemes, identify them as isoporphyrins. The t1/2 values for inactivation and formation of the isoporphyrin intermediate at 25 degrees C are, respectively, 11.6 and 12.5 min for methylhydrazine (2.0 mM), 8.7 and 7.2 min for ethylhydrazine (1.0 mM), and 30 and 25 s for phenylethylhydrazine (50 microM). The isoporphyrin intermediates are surprisingly long-lived, with half-lives (35 degrees C, pH 7.0) of 9, 28, 96, and 450 min for, respectively, the phenylethyl, methyl, n-butyl, and ethyl analogues. pH studies show that protonation of a group with pKa = 5.0-6.5 accelerates isoporphyrin decay and decreases steady state isoporphyrin accumulation. Horseradish peroxidase reconstituted with delta-meso-methylheme, unlike horseradish peroxidase with a heme that has a larger meso-substituent, is catalytically active but is more sensitive to H2O2-mediated degradation of the prosthetic group than is the native enzyme. The delta-meso-methylheme prosthetic group is converted in the reaction with H2O2 to a biliverdin-like product. The results implicate highly stabilized isoporphyrin intermediates in the inactivation of horseradish peroxidase by alkylhydrazines and indicate that inactivation by the meso-alkyl groups is due to steric interference with electron delivery to the heme edge rather than to intrinsic electronic consequences of meso-alkylation. The structural features that stabilize the cationic isoporphyrins may also be involved in stabilization of the Compound I porphyrin radical cation.","claims":[{"public_id":"cl_d1f4dba2ac6177854a4d1e3de266796a","status":"active","text":"Enzyme inactivation by alkylhydrazines is associated with the accumulation of long-lived isoporphyrin intermediates that absorb at approximately 835 nm.","confidence":0.95,"contributors":[{"id":2,"public_id":"4715169a40","public_label":"AK (4715169a40)","roles":["extraction"],"url":"https://sah.borca.ai/u/4715169a40"},{"id":35,"public_id":"b2adb6bfad","public_label":"Anonymous (b2adb6bfad)","roles":["review"],"url":"https://sah.borca.ai/u/b2adb6bfad"},{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["review"],"url":"https://sah.borca.ai/u/12632b8b5f"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale 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