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Emma Lloyd Raven - One of the best experts on this subject based on the ideXlab platform.
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Heme-Containing Dioxygenases
Inorganic Bioinorganic Reaction Mechanisms, 2012Co-Authors: Igor Efimov, Jaswir Basran, Sarah J. Thackray, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:Abstract The heme dioxygenase enzymes involved in tryptophan oxidation catalyse the first and rate-limiting step in the kynurenine pathway—the O 2 -dependent oxidation of l-tryptophan to N -formylkynurenine. In the past 10 years, there have been substantial new developments, including new structural information, bacterial expression systems for a number of dioxygenases, contributions from computational chemistry, and emerging mechanistic data from site-directed mutagenesis. This review summarizes these recent contributions.
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The mechanism of formation of N-Formylkynurenine by heme dioxygenases.
Journal of the American Chemical Society, 2011Co-Authors: Jaswir Basran, Nishma Chauhan, Igor Efimov, Sarah J. Thackray, James L. Krupa, Graham Eaton, Gerry A. Griffith, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:Heme dioxygenases catalyze the oxidation of L-tryptophan to N-Formylkynurenine (NFK), the first and rate-limiting step in tryptophan catabolism. Although recent progress has been made on early stages in the mechanism, there is currently no experimental data on the mechanism of product (NFK) formation. In this work, we have used mass spectrometry to examine product formation in a number of dioxygenases. In addition to NFK formation (m/z = 237), the data identify a species (m/z = 221) that is consistent with insertion of a single atom of oxygen into the substrate during O(2)-driven turnover. The fragmentation pattern for this m/z = 221 species is consistent with a cyclic amino acetal structure; independent chemical synthesis of the 3a-hydroxypyrroloindole-2-carboxylic acid compound is in agreement with this assignment. Labeling experiments with (18)O(2) confirm the origin of the oxygen atom as arising from O(2)-dependent turnover. These data suggest that the dioxygenases use a ring-opening mechanism during NFK formation, rather than Criegee or dioxetane mechanisms as previously proposed.
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Structure and Reaction Mechanism in the Heme Dioxygenases
Biochemistry, 2011Co-Authors: Igor Efimov, Jaswir Basran, Sarah J. Thackray, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:As members of the family of heme-dependent enzymes, the heme dioxygenases are differentiated by virtue of their ability to catalyze the oxidation of l-tryptophan to N-Formylkynurenine, the first and rate-limiting step in tryptophan catabolism. In the past several years, there have been a number of important developments that have meant that established proposals for the reaction mechanism in the heme dioxygenases have required reassessment. This focused review presents a summary of these recent advances, written from a structural and mechanistic perspective. It attempts to present answers to some of the long-standing questions, to highlight as yet unresolved issues, and to explore the similarities and differences of other well-known catalytic heme enzymes such as the cytochromes P450, NO synthase, and peroxidases.
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Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase.
Biochemical Society transactions, 2009Co-Authors: Sara A Rafice, Jaswir Basran, Nishma Chauhan, Igor Efimov, Emma Lloyd RavenAbstract:The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-Formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.
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a kinetic spectroscopic and redox study of human tryptophan 2 3 dioxygenase
Biochemistry, 2008Co-Authors: Jaswir Basran, Sara A Rafice, Nishma Chauhan, Igor Efimov, Myles R Cheesman, Lila Ghamsari, Emma Lloyd RavenAbstract:The family of heme dioxygenases, as exemplified by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase, catalyzes the oxidative cleavage of l-tryptophan to N-Formylkynurenine. Here, we describe a bacterial expression system for human tryptophan 2,3-dioxygenase (rhTDO) together with spectroscopic, kinetic, and redox analyses. We find unexpected differences between human tryptophan 2,3-dioxygenase and human indoleamine 2,3-dioxygenase [Chauhan et al. (2008) Biochemistry 47, 4761−4769]. Thus, in contrast to indoleamine 2,3-dioxygenase, the catalytic ferrous−oxy complex of rhTDO is not observed, nor does the enzyme discriminate against substrate binding to the ferric derivative. In addition, we show that the rhTDO is also catalytically active in the ferric form. These new findings illustrate that significant mechanistic differences exist across the heme dioxygenase family, and the data are discussed within this broader framework.
Jaswir Basran - One of the best experts on this subject based on the ideXlab platform.
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Heme-Containing Dioxygenases
Inorganic Bioinorganic Reaction Mechanisms, 2012Co-Authors: Igor Efimov, Jaswir Basran, Sarah J. Thackray, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:Abstract The heme dioxygenase enzymes involved in tryptophan oxidation catalyse the first and rate-limiting step in the kynurenine pathway—the O 2 -dependent oxidation of l-tryptophan to N -formylkynurenine. In the past 10 years, there have been substantial new developments, including new structural information, bacterial expression systems for a number of dioxygenases, contributions from computational chemistry, and emerging mechanistic data from site-directed mutagenesis. This review summarizes these recent contributions.
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The mechanism of formation of N-Formylkynurenine by heme dioxygenases.
Journal of the American Chemical Society, 2011Co-Authors: Jaswir Basran, Nishma Chauhan, Igor Efimov, Sarah J. Thackray, James L. Krupa, Graham Eaton, Gerry A. Griffith, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:Heme dioxygenases catalyze the oxidation of L-tryptophan to N-Formylkynurenine (NFK), the first and rate-limiting step in tryptophan catabolism. Although recent progress has been made on early stages in the mechanism, there is currently no experimental data on the mechanism of product (NFK) formation. In this work, we have used mass spectrometry to examine product formation in a number of dioxygenases. In addition to NFK formation (m/z = 237), the data identify a species (m/z = 221) that is consistent with insertion of a single atom of oxygen into the substrate during O(2)-driven turnover. The fragmentation pattern for this m/z = 221 species is consistent with a cyclic amino acetal structure; independent chemical synthesis of the 3a-hydroxypyrroloindole-2-carboxylic acid compound is in agreement with this assignment. Labeling experiments with (18)O(2) confirm the origin of the oxygen atom as arising from O(2)-dependent turnover. These data suggest that the dioxygenases use a ring-opening mechanism during NFK formation, rather than Criegee or dioxetane mechanisms as previously proposed.
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Structure and Reaction Mechanism in the Heme Dioxygenases
Biochemistry, 2011Co-Authors: Igor Efimov, Jaswir Basran, Sarah J. Thackray, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:As members of the family of heme-dependent enzymes, the heme dioxygenases are differentiated by virtue of their ability to catalyze the oxidation of l-tryptophan to N-Formylkynurenine, the first and rate-limiting step in tryptophan catabolism. In the past several years, there have been a number of important developments that have meant that established proposals for the reaction mechanism in the heme dioxygenases have required reassessment. This focused review presents a summary of these recent advances, written from a structural and mechanistic perspective. It attempts to present answers to some of the long-standing questions, to highlight as yet unresolved issues, and to explore the similarities and differences of other well-known catalytic heme enzymes such as the cytochromes P450, NO synthase, and peroxidases.
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Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase.
Biochemical Society transactions, 2009Co-Authors: Sara A Rafice, Jaswir Basran, Nishma Chauhan, Igor Efimov, Emma Lloyd RavenAbstract:The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-Formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.
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a kinetic spectroscopic and redox study of human tryptophan 2 3 dioxygenase
Biochemistry, 2008Co-Authors: Jaswir Basran, Sara A Rafice, Nishma Chauhan, Igor Efimov, Myles R Cheesman, Lila Ghamsari, Emma Lloyd RavenAbstract:The family of heme dioxygenases, as exemplified by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase, catalyzes the oxidative cleavage of l-tryptophan to N-Formylkynurenine. Here, we describe a bacterial expression system for human tryptophan 2,3-dioxygenase (rhTDO) together with spectroscopic, kinetic, and redox analyses. We find unexpected differences between human tryptophan 2,3-dioxygenase and human indoleamine 2,3-dioxygenase [Chauhan et al. (2008) Biochemistry 47, 4761−4769]. Thus, in contrast to indoleamine 2,3-dioxygenase, the catalytic ferrous−oxy complex of rhTDO is not observed, nor does the enzyme discriminate against substrate binding to the ferric derivative. In addition, we show that the rhTDO is also catalytically active in the ferric form. These new findings illustrate that significant mechanistic differences exist across the heme dioxygenase family, and the data are discussed within this broader framework.
Igor Efimov - One of the best experts on this subject based on the ideXlab platform.
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Heme-Containing Dioxygenases
Inorganic Bioinorganic Reaction Mechanisms, 2012Co-Authors: Igor Efimov, Jaswir Basran, Sarah J. Thackray, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:Abstract The heme dioxygenase enzymes involved in tryptophan oxidation catalyse the first and rate-limiting step in the kynurenine pathway—the O 2 -dependent oxidation of l-tryptophan to N -formylkynurenine. In the past 10 years, there have been substantial new developments, including new structural information, bacterial expression systems for a number of dioxygenases, contributions from computational chemistry, and emerging mechanistic data from site-directed mutagenesis. This review summarizes these recent contributions.
-
The mechanism of formation of N-Formylkynurenine by heme dioxygenases.
Journal of the American Chemical Society, 2011Co-Authors: Jaswir Basran, Nishma Chauhan, Igor Efimov, Sarah J. Thackray, James L. Krupa, Graham Eaton, Gerry A. Griffith, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:Heme dioxygenases catalyze the oxidation of L-tryptophan to N-Formylkynurenine (NFK), the first and rate-limiting step in tryptophan catabolism. Although recent progress has been made on early stages in the mechanism, there is currently no experimental data on the mechanism of product (NFK) formation. In this work, we have used mass spectrometry to examine product formation in a number of dioxygenases. In addition to NFK formation (m/z = 237), the data identify a species (m/z = 221) that is consistent with insertion of a single atom of oxygen into the substrate during O(2)-driven turnover. The fragmentation pattern for this m/z = 221 species is consistent with a cyclic amino acetal structure; independent chemical synthesis of the 3a-hydroxypyrroloindole-2-carboxylic acid compound is in agreement with this assignment. Labeling experiments with (18)O(2) confirm the origin of the oxygen atom as arising from O(2)-dependent turnover. These data suggest that the dioxygenases use a ring-opening mechanism during NFK formation, rather than Criegee or dioxetane mechanisms as previously proposed.
-
Structure and Reaction Mechanism in the Heme Dioxygenases
Biochemistry, 2011Co-Authors: Igor Efimov, Jaswir Basran, Sarah J. Thackray, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:As members of the family of heme-dependent enzymes, the heme dioxygenases are differentiated by virtue of their ability to catalyze the oxidation of l-tryptophan to N-Formylkynurenine, the first and rate-limiting step in tryptophan catabolism. In the past several years, there have been a number of important developments that have meant that established proposals for the reaction mechanism in the heme dioxygenases have required reassessment. This focused review presents a summary of these recent advances, written from a structural and mechanistic perspective. It attempts to present answers to some of the long-standing questions, to highlight as yet unresolved issues, and to explore the similarities and differences of other well-known catalytic heme enzymes such as the cytochromes P450, NO synthase, and peroxidases.
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Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase.
Biochemical Society transactions, 2009Co-Authors: Sara A Rafice, Jaswir Basran, Nishma Chauhan, Igor Efimov, Emma Lloyd RavenAbstract:The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-Formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.
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a kinetic spectroscopic and redox study of human tryptophan 2 3 dioxygenase
Biochemistry, 2008Co-Authors: Jaswir Basran, Sara A Rafice, Nishma Chauhan, Igor Efimov, Myles R Cheesman, Lila Ghamsari, Emma Lloyd RavenAbstract:The family of heme dioxygenases, as exemplified by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase, catalyzes the oxidative cleavage of l-tryptophan to N-Formylkynurenine. Here, we describe a bacterial expression system for human tryptophan 2,3-dioxygenase (rhTDO) together with spectroscopic, kinetic, and redox analyses. We find unexpected differences between human tryptophan 2,3-dioxygenase and human indoleamine 2,3-dioxygenase [Chauhan et al. (2008) Biochemistry 47, 4761−4769]. Thus, in contrast to indoleamine 2,3-dioxygenase, the catalytic ferrous−oxy complex of rhTDO is not observed, nor does the enzyme discriminate against substrate binding to the ferric derivative. In addition, we show that the rhTDO is also catalytically active in the ferric form. These new findings illustrate that significant mechanistic differences exist across the heme dioxygenase family, and the data are discussed within this broader framework.
Nishma Chauhan - One of the best experts on this subject based on the ideXlab platform.
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The mechanism of formation of N-Formylkynurenine by heme dioxygenases.
Journal of the American Chemical Society, 2011Co-Authors: Jaswir Basran, Nishma Chauhan, Igor Efimov, Sarah J. Thackray, James L. Krupa, Graham Eaton, Gerry A. Griffith, Christopher G. Mowat, Sandeep Handa, Emma Lloyd RavenAbstract:Heme dioxygenases catalyze the oxidation of L-tryptophan to N-Formylkynurenine (NFK), the first and rate-limiting step in tryptophan catabolism. Although recent progress has been made on early stages in the mechanism, there is currently no experimental data on the mechanism of product (NFK) formation. In this work, we have used mass spectrometry to examine product formation in a number of dioxygenases. In addition to NFK formation (m/z = 237), the data identify a species (m/z = 221) that is consistent with insertion of a single atom of oxygen into the substrate during O(2)-driven turnover. The fragmentation pattern for this m/z = 221 species is consistent with a cyclic amino acetal structure; independent chemical synthesis of the 3a-hydroxypyrroloindole-2-carboxylic acid compound is in agreement with this assignment. Labeling experiments with (18)O(2) confirm the origin of the oxygen atom as arising from O(2)-dependent turnover. These data suggest that the dioxygenases use a ring-opening mechanism during NFK formation, rather than Criegee or dioxetane mechanisms as previously proposed.
-
Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase.
Biochemical Society transactions, 2009Co-Authors: Sara A Rafice, Jaswir Basran, Nishma Chauhan, Igor Efimov, Emma Lloyd RavenAbstract:The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-Formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.
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a kinetic spectroscopic and redox study of human tryptophan 2 3 dioxygenase
Biochemistry, 2008Co-Authors: Jaswir Basran, Sara A Rafice, Nishma Chauhan, Igor Efimov, Myles R Cheesman, Lila Ghamsari, Emma Lloyd RavenAbstract:The family of heme dioxygenases, as exemplified by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase, catalyzes the oxidative cleavage of l-tryptophan to N-Formylkynurenine. Here, we describe a bacterial expression system for human tryptophan 2,3-dioxygenase (rhTDO) together with spectroscopic, kinetic, and redox analyses. We find unexpected differences between human tryptophan 2,3-dioxygenase and human indoleamine 2,3-dioxygenase [Chauhan et al. (2008) Biochemistry 47, 4761−4769]. Thus, in contrast to indoleamine 2,3-dioxygenase, the catalytic ferrous−oxy complex of rhTDO is not observed, nor does the enzyme discriminate against substrate binding to the ferric derivative. In addition, we show that the rhTDO is also catalytically active in the ferric form. These new findings illustrate that significant mechanistic differences exist across the heme dioxygenase family, and the data are discussed within this broader framework.
Sara A Rafice - One of the best experts on this subject based on the ideXlab platform.
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Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase.
Biochemical Society transactions, 2009Co-Authors: Sara A Rafice, Jaswir Basran, Nishma Chauhan, Igor Efimov, Emma Lloyd RavenAbstract:The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-Formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.
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a kinetic spectroscopic and redox study of human tryptophan 2 3 dioxygenase
Biochemistry, 2008Co-Authors: Jaswir Basran, Sara A Rafice, Nishma Chauhan, Igor Efimov, Myles R Cheesman, Lila Ghamsari, Emma Lloyd RavenAbstract:The family of heme dioxygenases, as exemplified by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase, catalyzes the oxidative cleavage of l-tryptophan to N-Formylkynurenine. Here, we describe a bacterial expression system for human tryptophan 2,3-dioxygenase (rhTDO) together with spectroscopic, kinetic, and redox analyses. We find unexpected differences between human tryptophan 2,3-dioxygenase and human indoleamine 2,3-dioxygenase [Chauhan et al. (2008) Biochemistry 47, 4761−4769]. Thus, in contrast to indoleamine 2,3-dioxygenase, the catalytic ferrous−oxy complex of rhTDO is not observed, nor does the enzyme discriminate against substrate binding to the ferric derivative. In addition, we show that the rhTDO is also catalytically active in the ferric form. These new findings illustrate that significant mechanistic differences exist across the heme dioxygenase family, and the data are discussed within this broader framework.
