Inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: A simple model for kinetic interpretation of mechanism-based inhibitors
A simple mathematical model for studying mechanism-based inhibitors (MBIs) is presented. The mathematical equations are deduced for an experimental protocol consisting of a first incubation of the enzyme in the presence of MBI followed by a washing protocol to eliminate free MBI. Finally enzyme acti...
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todo:paper_0021924X_v129_n3_p383_Matkovic2023-10-03T14:22:52Z Inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: A simple model for kinetic interpretation of mechanism-based inhibitors Matkovic, L. Gomez-Sanchez, C.E. Cozza, E.N. 18-ethynyl-11-deoxycorticosterone Adrenal gland Aldosterone Mechanism-based inhibitors Suicide inhibitors 18 ethynyl 11 deoxycorticosterone aldosterone deoxycorticosterone suicide substrate unclassified drug adrenal gland animal cell animal tissue article controlled study enzyme activity enzyme mechanism enzyme substrate mathematical model mitochondrion nonhuman rat Animalia A simple mathematical model for studying mechanism-based inhibitors (MBIs) is presented. The mathematical equations are deduced for an experimental protocol consisting of a first incubation of the enzyme in the presence of MBI followed by a washing protocol to eliminate free MBI. Finally enzyme activity (initial velocity) is measured with specific substrate. The representation of the final equation obtained is a straight line, and the MBI-specific association constant of velocity (k) can be calculated from its slope. The mathematical model was then challenged with the effect of 18-ethynyl-11-deoxycorticosterone (18-EtDOC) as an MBI on aldosterone biosynthesis from 11-deoxycorticosterone (DOC) in rat adrenal mitochondria. The last step of the mitochondrial biosynthesis of aldosterone consists of the conversion of DOC into corticosterone (B) or 18-hydroxy-11-deoxycorticosterone (18-OHDOC), and both steroids can then be transformed into aldosterone. The k (mM-1·min-1) values obtained for 18-EtDOC were: 451 ± 36 for DOC to aldosterone; 177 ± 16 for B to aldosterone; 175 ± 15 for 18-OHDOC to aldosterone; and 2.7 ± 0.2 for DOC to B. These results show that this MBI practically does not affect the metabolism of DOC to B in our enzyme preparation and that conversions of B and 18-OHDOC into aldosterone are catalyzed by the same enzyme. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_0021924X_v129_n3_p383_Matkovic |
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Universidad de Buenos Aires |
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I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
18-ethynyl-11-deoxycorticosterone Adrenal gland Aldosterone Mechanism-based inhibitors Suicide inhibitors 18 ethynyl 11 deoxycorticosterone aldosterone deoxycorticosterone suicide substrate unclassified drug adrenal gland animal cell animal tissue article controlled study enzyme activity enzyme mechanism enzyme substrate mathematical model mitochondrion nonhuman rat Animalia |
| spellingShingle |
18-ethynyl-11-deoxycorticosterone Adrenal gland Aldosterone Mechanism-based inhibitors Suicide inhibitors 18 ethynyl 11 deoxycorticosterone aldosterone deoxycorticosterone suicide substrate unclassified drug adrenal gland animal cell animal tissue article controlled study enzyme activity enzyme mechanism enzyme substrate mathematical model mitochondrion nonhuman rat Animalia Matkovic, L. Gomez-Sanchez, C.E. Cozza, E.N. Inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: A simple model for kinetic interpretation of mechanism-based inhibitors |
| topic_facet |
18-ethynyl-11-deoxycorticosterone Adrenal gland Aldosterone Mechanism-based inhibitors Suicide inhibitors 18 ethynyl 11 deoxycorticosterone aldosterone deoxycorticosterone suicide substrate unclassified drug adrenal gland animal cell animal tissue article controlled study enzyme activity enzyme mechanism enzyme substrate mathematical model mitochondrion nonhuman rat Animalia |
| description |
A simple mathematical model for studying mechanism-based inhibitors (MBIs) is presented. The mathematical equations are deduced for an experimental protocol consisting of a first incubation of the enzyme in the presence of MBI followed by a washing protocol to eliminate free MBI. Finally enzyme activity (initial velocity) is measured with specific substrate. The representation of the final equation obtained is a straight line, and the MBI-specific association constant of velocity (k) can be calculated from its slope. The mathematical model was then challenged with the effect of 18-ethynyl-11-deoxycorticosterone (18-EtDOC) as an MBI on aldosterone biosynthesis from 11-deoxycorticosterone (DOC) in rat adrenal mitochondria. The last step of the mitochondrial biosynthesis of aldosterone consists of the conversion of DOC into corticosterone (B) or 18-hydroxy-11-deoxycorticosterone (18-OHDOC), and both steroids can then be transformed into aldosterone. The k (mM-1·min-1) values obtained for 18-EtDOC were: 451 ± 36 for DOC to aldosterone; 177 ± 16 for B to aldosterone; 175 ± 15 for 18-OHDOC to aldosterone; and 2.7 ± 0.2 for DOC to B. These results show that this MBI practically does not affect the metabolism of DOC to B in our enzyme preparation and that conversions of B and 18-OHDOC into aldosterone are catalyzed by the same enzyme. |
| format |
JOUR |
| author |
Matkovic, L. Gomez-Sanchez, C.E. Cozza, E.N. |
| author_facet |
Matkovic, L. Gomez-Sanchez, C.E. Cozza, E.N. |
| author_sort |
Matkovic, L. |
| title |
Inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: A simple model for kinetic interpretation of mechanism-based inhibitors |
| title_short |
Inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: A simple model for kinetic interpretation of mechanism-based inhibitors |
| title_full |
Inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: A simple model for kinetic interpretation of mechanism-based inhibitors |
| title_fullStr |
Inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: A simple model for kinetic interpretation of mechanism-based inhibitors |
| title_full_unstemmed |
Inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: A simple model for kinetic interpretation of mechanism-based inhibitors |
| title_sort |
inhibition of aldosterone production in rat adrenal mitochondria by 18-ethynyl-11-deoxycorticosterone: a simple model for kinetic interpretation of mechanism-based inhibitors |
| url |
http://hdl.handle.net/20.500.12110/paper_0021924X_v129_n3_p383_Matkovic |
| work_keys_str_mv |
AT matkovicl inhibitionofaldosteroneproductioninratadrenalmitochondriaby18ethynyl11deoxycorticosteroneasimplemodelforkineticinterpretationofmechanismbasedinhibitors AT gomezsanchezce inhibitionofaldosteroneproductioninratadrenalmitochondriaby18ethynyl11deoxycorticosteroneasimplemodelforkineticinterpretationofmechanismbasedinhibitors AT cozzaen inhibitionofaldosteroneproductioninratadrenalmitochondriaby18ethynyl11deoxycorticosteroneasimplemodelforkineticinterpretationofmechanismbasedinhibitors |
| _version_ |
1807323875361423360 |