THE USE OF DEUTERIUM ISOTOPE EFFECTS TO PROBE THE ACTIVE SITE PROPERTIES, MECHANISM OF CYTOCHROME P450-CATALYZED REACTIONS, AND MECHANISMS OF METABOLICALLY DEPENDENT TOXICITY
Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (k H /k D )obs, of most enzymatically mediated reactions to be much smaller than the âtrueâ or intrinsic primary deuterium isotope effect, k H /k D ,...
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| Published in: | Drug metabolism and disposition Vol. 31; no. 12; pp. 1481 - 1498 |
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| Main Authors: | , |
| Format: | Journal Article |
| Language: | English |
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Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01-12-2003
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| Abstract | Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium
isotope effect, (k H /k D )obs, of most enzymatically mediated reactions to be much smaller than the âtrueâ or intrinsic primary deuterium isotope effect,
k H /k D , for the reaction are presented. This new understanding has provided a unique and powerful tool for probing the catalytic
and active site properties of enzymes, particularly the cytochromes P450 (P450). Examples are presented that illustrate how
the technique has been used to determine k H /k D , and properties such as the catalytic nature of the reactive oxenoid intermediate, prochiral selectivity, the chemical and
enzymatic mechanisms of cytochrome P450-catalyzed reactions, and the relative active site size of different P450 isoforms.
Examples are also presented of how deuterium isotope effects have been used to probe mechanisms of the formation of reactive
metabolites that can cause toxic effects. |
|---|---|
| AbstractList | Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium
isotope effect, (k H /k D )obs, of most enzymatically mediated reactions to be much smaller than the âtrueâ or intrinsic primary deuterium isotope effect,
k H /k D , for the reaction are presented. This new understanding has provided a unique and powerful tool for probing the catalytic
and active site properties of enzymes, particularly the cytochromes P450 (P450). Examples are presented that illustrate how
the technique has been used to determine k H /k D , and properties such as the catalytic nature of the reactive oxenoid intermediate, prochiral selectivity, the chemical and
enzymatic mechanisms of cytochrome P450-catalyzed reactions, and the relative active site size of different P450 isoforms.
Examples are also presented of how deuterium isotope effects have been used to probe mechanisms of the formation of reactive
metabolites that can cause toxic effects. Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (k sub(H)/k sub(D))obs, of most enzymatically mediated reactions to be much smaller than the "true" or intrinsic primary deuterium isotope effect, k sub(H)/k sub(D), for the reaction are presented. This new understanding has provided a unique and powerful tool for probing the catalytic and active site properties of enzymes, particularly the cytochromes P450 (P450). Examples are presented that illustrate how the technique has been used to determine k sub(H)/k sub(D), and properties such as the catalytic nature of the reactive oxenoid intermediate, prochiral selectivity, the chemical and enzymatic mechanisms of cytochrome P450-catalyzed reactions, and the relative active site size of different P450 isoforms. Examples are also presented of how deuterium isotope effects have been used to probe mechanisms of the formation of reactive metabolites that can cause toxic effects. Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (kH/kD)obs, of most enzymatically mediated reactions to be much smaller than the "true" or intrinsic primary deuterium isotope effect, kH/kD, for the reaction are presented. This new understanding has provided a unique and powerful tool for probing the catalytic and active site properties of enzymes, particularly the cytochromes P450 (P450). Examples are presented that illustrate how the technique has been used to determine kH/kD, and properties such as the catalytic nature of the reactive oxenoid intermediate, prochiral selectivity, the chemical and enzymatic mechanisms of cytochrome P450-catalyzed reactions, and the relative active site size of different P450 isoforms. Examples are also presented of how deuterium isotope effects have been used to probe mechanisms of the formation of reactive metabolites that can cause toxic effects. |
| Author | William F. Trager Sidney D. Nelson |
| Author_xml | – sequence: 1 givenname: Sidney D surname: NELSON fullname: NELSON, Sidney D organization: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, United States – sequence: 2 givenname: William F surname: TRAGER fullname: TRAGER, William F organization: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, United States |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15322095$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/14625345$$D View this record in MEDLINE/PubMed |
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| Keywords | Deuterium Isotope effect Investigation method Isozyme Metabolite Toxicity Cytochrome P450 Active site Reagents Reaction mechanism Review Mechanism of action |
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| Snippet | Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium
isotope effect, (k H /k D... Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (kH/kD)obs,... Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (k sub(H)/k... |
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| SubjectTerms | Analytical, structural and metabolic biochemistry Animals Binding Sites Biological and medical sciences Catalysis Cytochrome P-450 Enzyme System - metabolism Deuterium - chemistry Drug-Related Side Effects and Adverse Reactions Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Humans Isotope Labeling - methods Kinetics Lyases Pharmaceutical Preparations - chemistry Pharmaceutical Preparations - metabolism Structure-Activity Relationship |
| Title | THE USE OF DEUTERIUM ISOTOPE EFFECTS TO PROBE THE ACTIVE SITE PROPERTIES, MECHANISM OF CYTOCHROME P450-CATALYZED REACTIONS, AND MECHANISMS OF METABOLICALLY DEPENDENT TOXICITY |
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