{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/22512"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/22512","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Halo enol lactone and protio enol lactone inhibitors of alpha-chymotrypsin: Mechanism and stereospecific behavior of inhibition","abstract":"A kinetic study of inactivation of $\\alpha$-chymotrypsin by enol lactones was performed. Halo enol lactones, 3-(1-naphthyl)-6(E)-(iodomethylene)tetrahydro-2-pyranone ($\\alpha$Np6I) and 3-phenyl-6(E)-(bromomethylene)tetrahydro-2-pyranone ($\\alpha$Ph6Br), showed burst kinetics in the inactivation of the enzyme, which requires a complicated kinetic scheme including partitioning of the first acyl enzyme between the covalent derivatization of the enzyme by the revealed halomethyl ketone reactive group (permanent inactivation) and formation of the second acyl enzyme by the hydrolysis of the halomethyl ketone of the first acyl enzyme to the non-reactive hydroxymethyl ketone group (transient inhibition). Deacylation of the second acyl enzyme leads to reactivation to free enzyme, which will be available for inactivation again. From the rate of the time-dependent irreversible inactivation and the rate of deacylation, a partition ratio between transient inhibition and permanent inactivation was calculated. A halo enol lactone with a small partition ratio showed a large burst. The efficiency of halo enol lactones as suicide inactivators is thus limited by the hydrolysis of the halomethyl reactive group.","abstract_html":"A kinetic study of inactivation of <span class=\"etd-inline-math\">&alpha;</span>-chymotrypsin by enol lactones was performed. Halo enol lactones, 3-(1-naphthyl)-6(E)-(iodomethylene)tetrahydro-2-pyranone (<span class=\"etd-inline-math\">&alpha;</span>Np6I) and 3-phenyl-6(E)-(bromomethylene)tetrahydro-2-pyranone (<span class=\"etd-inline-math\">&alpha;</span>Ph6Br), showed burst kinetics in the inactivation of the enzyme, which requires a complicated kinetic scheme including partitioning of the first acyl enzyme between the covalent derivatization of the enzyme by the revealed halomethyl ketone reactive group (permanent inactivation) and formation of the second acyl enzyme by the hydrolysis of the halomethyl ketone of the first acyl enzyme to the non-reactive hydroxymethyl ketone group (transient inhibition). Deacylation of the second acyl enzyme leads to reactivation to free enzyme, which will be available for inactivation again. From the rate of the time-dependent irreversible inactivation and the rate of deacylation, a partition ratio between transient inhibition and permanent inactivation was calculated. A halo enol lactone with a small partition ratio showed a large burst. The efficiency of halo enol lactones as suicide inactivators is thus limited by the hydrolysis of the halomethyl reactive group.","abstract_has_math":true,"creators":["Baek, Du-Jong"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-05-07T13:42:12Z","date_published":"2011-05-07T13:42:12Z","updated_at":"2026-07-22T22:25:20Z","subjects":["Chemistry, Biochemistry","Chemistry, Organic","Chemistry, Pharmaceutical"],"languages":["eng"],"rights":["Copyright 1989 Baek, Du-Jong"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["AAI8924762","(UMI)AAI8924762"],"render_values":[{"text":"AAI8924762","href":null,"code":true},{"text":"(UMI)AAI8924762","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/22512","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Baek, Du-Jong"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011-05-07T13:42:12Z","10000-01-01","1989"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Chemistry, Biochemistry","Chemistry, Organic","Chemistry, Pharmaceutical"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 1989 Baek, Du-Jong"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["AAI8924762","(UMI)AAI8924762","http://hdl.handle.net/2142/22512"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["A kinetic study of inactivation of $\\alpha$-chymotrypsin by enol lactones was performed. Halo enol lactones, 3-(1-naphthyl)-6(E)-(iodomethylene)tetrahydro-2-pyranone ($\\alpha$Np6I) and 3-phenyl-6(E)-(bromomethylene)tetrahydro-2-pyranone ($\\alpha$Ph6Br), showed burst kinetics in the inactivation of the enzyme, which requires a complicated kinetic scheme including partitioning of the first acyl enzyme between the covalent derivatization of the enzyme by the revealed halomethyl ketone reactive group (permanent inactivation) and formation of the second acyl enzyme by the hydrolysis of the halomethyl ketone of the first acyl enzyme to the non-reactive hydroxymethyl ketone group (transient inhibition). Deacylation of the second acyl enzyme leads to reactivation to free enzyme, which will be available for inactivation again. From the rate of the time-dependent irreversible inactivation and the rate of deacylation, a partition ratio between transient inhibition and permanent inactivation was calculated. A halo enol lactone with a small partition ratio showed a large burst. The efficiency of halo enol lactones as suicide inactivators is thus limited by the hydrolysis of the halomethyl reactive group.","The corresponding protio enol lactones showed only transient inhibition (not inactivation) due to the lack of halogen in the lactone molecule, but deacylation rates of 4-phenyl-6-methylenetetrahydro-2-pyranone ($\\beta$Ph6H) and 3-(1-naphthyl)-6-methylenetetrahydro-2-pyranone ($\\alpha$Np6H) were very slow, and they are thus still effective inhibitors by formation of stable acyl enzymes. In order to understand this slow deacylation and stereospecific behavior of inhibition, protio enol lactones were resolved into their two enantiomers, and the effects of the structure variation of the lactones on the inhibition kinetics were studied. This study shows that S enantiomer binds more strongly to the active site of the enzyme than R enantiomer, and the deacylation rates of the R enantiomers of $\\beta$Ph6H and $\\alpha$Np6H are very slow, with the half-lives of 4.0 h and 12.6 h at pH 7.2, respectively. The enantioselectivity of deacylation of these lactones is very large, with the R enantiomers having 60-70 fold slower deacylation rates than the S enantiomers. This slow deacylation could be explained by a twisted acyl enzyme model. Since deacylation is the rate-determining step, these lactones with very slow deacylation rates act as alternate substrate inhibitors.","Made available in DSpace on 2011-05-07T13:42:12Z (GMT). No. of bitstreams: 2 license.txt: 4922 bytes, checksum: 910b249b4beec47e7ab768910c8f966f (MD5) 8924762.pdf: 4550610 bytes, checksum: fd0ff34723999b7973a248abc670911c (MD5) Previous issue date: 1989","Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding (hding2@illinois.edu) on 2011-05-07T14:58:07Z Item is restricted indefinitely.","Restriction data tranferred 2014-07-01T11:27:19-05:00 Original Data Group with Access UIUC Users [automated] Release Date: none Reason: ETDs are only available to UIUC Users without author permission","ETDs are only available to UIUC Users without author permission","U of I Only"]},{"key":"dc:title","label":"Title","values":["Halo enol lactone and protio enol lactone inhibitors of alpha-chymotrypsin: Mechanism and stereospecific behavior of inhibition"]}]}],"canonical_facts":{"dc:creator":["Baek, Du-Jong"],"dc:date":["2011-05-07T13:42:12Z","10000-01-01","1989"],"dc:description":["A kinetic study of inactivation of $\\alpha$-chymotrypsin by enol lactones was performed. Halo enol lactones, 3-(1-naphthyl)-6(E)-(iodomethylene)tetrahydro-2-pyranone ($\\alpha$Np6I) and 3-phenyl-6(E)-(bromomethylene)tetrahydro-2-pyranone ($\\alpha$Ph6Br), showed burst kinetics in the inactivation of the enzyme, which requires a complicated kinetic scheme including partitioning of the first acyl enzyme between the covalent derivatization of the enzyme by the revealed halomethyl ketone reactive group (permanent inactivation) and formation of the second acyl enzyme by the hydrolysis of the halomethyl ketone of the first acyl enzyme to the non-reactive hydroxymethyl ketone group (transient inhibition). Deacylation of the second acyl enzyme leads to reactivation to free enzyme, which will be available for inactivation again. From the rate of the time-dependent irreversible inactivation and the rate of deacylation, a partition ratio between transient inhibition and permanent inactivation was calculated. A halo enol lactone with a small partition ratio showed a large burst. The efficiency of halo enol lactones as suicide inactivators is thus limited by the hydrolysis of the halomethyl reactive group.","The corresponding protio enol lactones showed only transient inhibition (not inactivation) due to the lack of halogen in the lactone molecule, but deacylation rates of 4-phenyl-6-methylenetetrahydro-2-pyranone ($\\beta$Ph6H) and 3-(1-naphthyl)-6-methylenetetrahydro-2-pyranone ($\\alpha$Np6H) were very slow, and they are thus still effective inhibitors by formation of stable acyl enzymes. In order to understand this slow deacylation and stereospecific behavior of inhibition, protio enol lactones were resolved into their two enantiomers, and the effects of the structure variation of the lactones on the inhibition kinetics were studied. This study shows that S enantiomer binds more strongly to the active site of the enzyme than R enantiomer, and the deacylation rates of the R enantiomers of $\\beta$Ph6H and $\\alpha$Np6H are very slow, with the half-lives of 4.0 h and 12.6 h at pH 7.2, respectively. The enantioselectivity of deacylation of these lactones is very large, with the R enantiomers having 60-70 fold slower deacylation rates than the S enantiomers. This slow deacylation could be explained by a twisted acyl enzyme model. Since deacylation is the rate-determining step, these lactones with very slow deacylation rates act as alternate substrate inhibitors.","Made available in DSpace on 2011-05-07T13:42:12Z (GMT). No. of bitstreams: 2 license.txt: 4922 bytes, checksum: 910b249b4beec47e7ab768910c8f966f (MD5) 8924762.pdf: 4550610 bytes, checksum: fd0ff34723999b7973a248abc670911c (MD5) Previous issue date: 1989","Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding (hding2@illinois.edu) on 2011-05-07T14:58:07Z Item is restricted indefinitely.","Restriction data tranferred 2014-07-01T11:27:19-05:00 Original Data Group with Access UIUC Users [automated] Release Date: none Reason: ETDs are only available to UIUC Users without author permission","ETDs are only available to UIUC Users without author permission","U of I Only"],"dc:identifier":["AAI8924762","(UMI)AAI8924762","http://hdl.handle.net/2142/22512"],"dc:language":["eng"],"dc:rights":["Copyright 1989 Baek, Du-Jong"],"dc:subject":["Chemistry, Biochemistry","Chemistry, Organic","Chemistry, Pharmaceutical"],"dc:title":["Halo enol lactone and protio enol lactone inhibitors of alpha-chymotrypsin: Mechanism and stereospecific behavior of inhibition"],"dc:type":["text"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:20Z"}