The Reaction Mechanism of Phenylalanine Hydroxylase. – A Question of Coordination
Phenylalanine hydroxylase (PAH) is a non-heme iron and tetrahydrobiopterin-dependent enzyme that catalyzes the hydroxylation of L-phenylalanine to L-tyrosine using dioxygen as additional substrate. The cofactor tetrahydrobiopterin accepts one of the oxygen atoms of dioxygen during catalysis and also...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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De Gruyter
2005-02-01
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| Series: | Pteridines |
| Subjects: | |
| Online Access: | https://doi.org/10.1515/pteridines.2005.16.1.27 |
| _version_ | 1819031302235488256 |
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| author | Teigen Knut Jensen Vidar R. Martinez Aurora |
| author_facet | Teigen Knut Jensen Vidar R. Martinez Aurora |
| author_sort | Teigen Knut |
| collection | DOAJ |
| description | Phenylalanine hydroxylase (PAH) is a non-heme iron and tetrahydrobiopterin-dependent enzyme that catalyzes the hydroxylation of L-phenylalanine to L-tyrosine using dioxygen as additional substrate. The cofactor tetrahydrobiopterin accepts one of the oxygen atoms of dioxygen during catalysis and also seems to be involved in prereduction of the active site iron from the ferric to the activated ferrous form. Structures of the truncated form of PAH in complex with substrate and cofactor are available, but the oxygen binding site and the actual mechanism of electron transfer are uncertain. It is believed that dioxygen binds directly to the metal, where it is activated, and several reaction mechanisms involving end-on binding of 0 2 have been proposed based on both experimental studies and quantum mechanical calculations. However, in this work we aimed to investigate the possibility of side-on binding of dioxygen to the iron. Furthermore, NMR and recent high-resolution crystallographic studies also place the cofactor in closer proximity to the iron, challenging the mechanistic conclusions from earlier crystallographic and computational studies. In this paper we report preliminary results from a density functional theory (DFT) study of the coordination of dioxygen to a structural model of PAH based on a recent crystallographic structure. These results are compared with existing computational and experimental data and their implications for the mechanism of the PAH-reaction are discussed. Particular attention is paid to the binding-mode of dioxygen and the iron-cofactor distance. |
| first_indexed | 2024-12-21T06:43:53Z |
| format | Article |
| id | doaj.art-d75c2e0b427e4632866b3e21cb8e9e7e |
| institution | Directory Open Access Journal |
| issn | 0933-4807 2195-4720 |
| language | English |
| last_indexed | 2024-12-21T06:43:53Z |
| publishDate | 2005-02-01 |
| publisher | De Gruyter |
| record_format | Article |
| series | Pteridines |
| spelling | doaj.art-d75c2e0b427e4632866b3e21cb8e9e7e2022-12-21T19:12:39ZengDe GruyterPteridines0933-48072195-47202005-02-01161273410.1515/pteridines.2005.16.1.27The Reaction Mechanism of Phenylalanine Hydroxylase. – A Question of CoordinationTeigen Knut0Jensen Vidar R.1Martinez Aurora2Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009-Bergen, NorwayDepartment of Chemistry, University of Bergen, Allégaten 41, 5007-Bergen, NorwayDepartment of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009-Bergen, NorwayPhenylalanine hydroxylase (PAH) is a non-heme iron and tetrahydrobiopterin-dependent enzyme that catalyzes the hydroxylation of L-phenylalanine to L-tyrosine using dioxygen as additional substrate. The cofactor tetrahydrobiopterin accepts one of the oxygen atoms of dioxygen during catalysis and also seems to be involved in prereduction of the active site iron from the ferric to the activated ferrous form. Structures of the truncated form of PAH in complex with substrate and cofactor are available, but the oxygen binding site and the actual mechanism of electron transfer are uncertain. It is believed that dioxygen binds directly to the metal, where it is activated, and several reaction mechanisms involving end-on binding of 0 2 have been proposed based on both experimental studies and quantum mechanical calculations. However, in this work we aimed to investigate the possibility of side-on binding of dioxygen to the iron. Furthermore, NMR and recent high-resolution crystallographic studies also place the cofactor in closer proximity to the iron, challenging the mechanistic conclusions from earlier crystallographic and computational studies. In this paper we report preliminary results from a density functional theory (DFT) study of the coordination of dioxygen to a structural model of PAH based on a recent crystallographic structure. These results are compared with existing computational and experimental data and their implications for the mechanism of the PAH-reaction are discussed. Particular attention is paid to the binding-mode of dioxygen and the iron-cofactor distance.https://doi.org/10.1515/pteridines.2005.16.1.27phenylalanine hydroxylase. reaction mechanism5,6,7,8-tetrahydrobiopterindensity functional theory |
| spellingShingle | Teigen Knut Jensen Vidar R. Martinez Aurora The Reaction Mechanism of Phenylalanine Hydroxylase. – A Question of Coordination Pteridines phenylalanine hydroxylase. reaction mechanism 5,6,7,8-tetrahydrobiopterin density functional theory |
| title | The Reaction Mechanism of Phenylalanine Hydroxylase. – A Question of Coordination |
| title_full | The Reaction Mechanism of Phenylalanine Hydroxylase. – A Question of Coordination |
| title_fullStr | The Reaction Mechanism of Phenylalanine Hydroxylase. – A Question of Coordination |
| title_full_unstemmed | The Reaction Mechanism of Phenylalanine Hydroxylase. – A Question of Coordination |
| title_short | The Reaction Mechanism of Phenylalanine Hydroxylase. – A Question of Coordination |
| title_sort | reaction mechanism of phenylalanine hydroxylase a question of coordination |
| topic | phenylalanine hydroxylase. reaction mechanism 5,6,7,8-tetrahydrobiopterin density functional theory |
| url | https://doi.org/10.1515/pteridines.2005.16.1.27 |
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