Theoretical Studies of Cytochrome P450
(2007)- Abstract
- The cytochromes P450 are a large enzyme family that is found in all living organisms and takes part in both endogenous and exogenous metabolism. They are primarily mono-oxygenases and perform a wide range of reactions. In contrast to many other enzymes, they have been optimised to react with a wide range of substrates instead of having high reaction rates. In the active site, these enzymes have a haem group, a porphyrin ring with an iron ion in the centre, and a cysteine amino acid bound to the iron. During the reaction cycle, this complex is turned into a highly oxidative complex, which enables the enzyme to oxidise even aliphatic carbons.
We study various aspects of the functionality of these enzymes and other related... (More) - The cytochromes P450 are a large enzyme family that is found in all living organisms and takes part in both endogenous and exogenous metabolism. They are primarily mono-oxygenases and perform a wide range of reactions. In contrast to many other enzymes, they have been optimised to react with a wide range of substrates instead of having high reaction rates. In the active site, these enzymes have a haem group, a porphyrin ring with an iron ion in the centre, and a cysteine amino acid bound to the iron. During the reaction cycle, this complex is turned into a highly oxidative complex, which enables the enzyme to oxidise even aliphatic carbons.
We study various aspects of the functionality of these enzymes and other related haem-containing proteins with theoretical methods. For example, we discuss how nature has tuned the functionality of different haem proteins by using different axial ligands, and go into depth on the elusive properties of a mobile proton in haem peroxidases.
Furthermore, we study the transition state in aliphatic hydroxylation, nitrogen oxidation, sulphur oxidation, and sulphoxide oxidation in cytochrome P450 with density functional theory and suggest a qualitative model to predict the activation energy of the aliphatic hydroxylation reaction. By constructing a transition-state force field and combining it with the qualitative model, we study the hydroxylation reactivity of two drugs in two cytochrome P450 isoforms.
Finally, using molecular dynamics, we provide the first calculation of the free energy for moving a substrate molecule from bulk water solution into the active site of a cytochrome P450, and we also study the dynamics of water molecules in the active-site cavity. (Less) - Abstract (Swedish)
- Popular Abstract in Swedish
Cytokrom P450 är en stor enzymfamilj som finns i alla levande organismer och tar del i både endogen och exogen metabolism. De är primärt mono-oxygenaser och utför en stor mängd reaktioner. Till skillnad från många andra enzymer har de blivit optimerade för att kunna reagera med många olika substrat, istället för att ha höga reaktionshastigheter. I det aktiva sätet har dessa enzymer en hemgrupp, bestående av en porfyrinring med en järnjon i mitten och en cystein-aminosyra bunden till järnjonen. Under reaktionscykeln omvandlas detta komplex till ett väldigt reaktivt komplex, vilket gör det möjligt för enzymet att oxidera även alifatiska kolatomer.
Med teoretiska metoder har vi... (More) - Popular Abstract in Swedish
Cytokrom P450 är en stor enzymfamilj som finns i alla levande organismer och tar del i både endogen och exogen metabolism. De är primärt mono-oxygenaser och utför en stor mängd reaktioner. Till skillnad från många andra enzymer har de blivit optimerade för att kunna reagera med många olika substrat, istället för att ha höga reaktionshastigheter. I det aktiva sätet har dessa enzymer en hemgrupp, bestående av en porfyrinring med en järnjon i mitten och en cystein-aminosyra bunden till järnjonen. Under reaktionscykeln omvandlas detta komplex till ett väldigt reaktivt komplex, vilket gör det möjligt för enzymet att oxidera även alifatiska kolatomer.
Med teoretiska metoder har vi studerat olika aspekter av funktionaliteten hos dessa enzymer och andra relaterade enzymer som också innehåller hemgrupper. Till exempel har vi undersökt hur naturen har ändrat funktionaliteten hos olika hem-innehållande proteiner genom att använda olika axiala ligander och speciellt de gäckande egenskaperna hos en mobil proton i hemperoxidaser.
Dessutom har vi studerat övergångstillstånd i alifatisk hydroxylering, kväveoxiderinng, svaveloxidering och sulfoxidoxidering i cytokrom P450 med täthetsfunktionalteori och vi föreslår en kvalitativ modell som kan förutsäga aktiveringsenergin för reaktionstypen alifatisk hydroxylering. Genom att konstruera ett kraftfält för övergångstillstånd och kombinera det med den kvalitativa modellen har vi studerat reaktiviteten för två olika läkemedel i två olika cytokrom P450 med avseende på alifatisk hydroxylering.
Slutligen har vi med hjälp av molekyldynamik gjort den första beräkningen av den fria energin för att flytta en substratmolekyl från vattenlösning in till det aktiva sätet i ett cytokrom P450 och vi har också studerat dynamiken hos vattenmolekyler i kaviteten kring det aktiva sätet. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/548761
- author
- Rydberg, Patrik LU
- supervisor
-
- Ulf Ryde LU
- opponent
-
- Professor Thiel, Walter, Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany
- organization
- publishing date
- 2007
- type
- Thesis
- publication status
- published
- subject
- keywords
- quantum chemistry, Proteins, enzymology, Proteiner, enzymologi, Theoretical chemistry, transition-state force field, peroxidase, theoretical chemistry, molecular dynamics, density functional theory, cytochrome P450, porphyrin, haem, heme, kvantkemi, Teoretisk kemi
- pages
- 152 pages
- publisher
- Department of Theoretical Chemistry, Lund University
- defense location
- Auditorium B Chemical Center Lund
- defense date
- 2007-06-07 10:15:00
- ISBN
- 978-91-7422-161-9
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
- id
- b888d12f-feba-437f-9ada-f2c98675778f (old id 548761)
- date added to LUP
- 2016-04-04 10:08:24
- date last changed
- 2018-11-21 20:56:59
@phdthesis{b888d12f-feba-437f-9ada-f2c98675778f,
abstract = {{The cytochromes P450 are a large enzyme family that is found in all living organisms and takes part in both endogenous and exogenous metabolism. They are primarily mono-oxygenases and perform a wide range of reactions. In contrast to many other enzymes, they have been optimised to react with a wide range of substrates instead of having high reaction rates. In the active site, these enzymes have a haem group, a porphyrin ring with an iron ion in the centre, and a cysteine amino acid bound to the iron. During the reaction cycle, this complex is turned into a highly oxidative complex, which enables the enzyme to oxidise even aliphatic carbons.<br/><br>
<br/><br>
We study various aspects of the functionality of these enzymes and other related haem-containing proteins with theoretical methods. For example, we discuss how nature has tuned the functionality of different haem proteins by using different axial ligands, and go into depth on the elusive properties of a mobile proton in haem peroxidases.<br/><br>
<br/><br>
Furthermore, we study the transition state in aliphatic hydroxylation, nitrogen oxidation, sulphur oxidation, and sulphoxide oxidation in cytochrome P450 with density functional theory and suggest a qualitative model to predict the activation energy of the aliphatic hydroxylation reaction. By constructing a transition-state force field and combining it with the qualitative model, we study the hydroxylation reactivity of two drugs in two cytochrome P450 isoforms.<br/><br>
<br/><br>
Finally, using molecular dynamics, we provide the first calculation of the free energy for moving a substrate molecule from bulk water solution into the active site of a cytochrome P450, and we also study the dynamics of water molecules in the active-site cavity.}},
author = {{Rydberg, Patrik}},
isbn = {{978-91-7422-161-9}},
keywords = {{quantum chemistry; Proteins; enzymology; Proteiner; enzymologi; Theoretical chemistry; transition-state force field; peroxidase; theoretical chemistry; molecular dynamics; density functional theory; cytochrome P450; porphyrin; haem; heme; kvantkemi; Teoretisk kemi}},
language = {{eng}},
publisher = {{Department of Theoretical Chemistry, Lund University}},
school = {{Lund University}},
title = {{Theoretical Studies of Cytochrome P450}},
year = {{2007}},
}