Coordinatore | UNIVERSITY OF NORTHUMBRIA AT NEWCASTLE.
Organization address
address: "Ellison Place, Ellison Building" contact info |
Nazionalità Coordinatore | United Kingdom [UK] |
Totale costo | 334˙689 € |
EC contributo | 334˙689 € |
Programma | FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
Code Call | FP7-PEOPLE-2009-IOF |
Funding Scheme | MC-IOF |
Anno di inizio | 2011 |
Periodo (anno-mese-giorno) | 2011-05-16 - 2014-07-31 |
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UNIVERSITY OF NORTHUMBRIA AT NEWCASTLE.
Organization address
address: "Ellison Place, Ellison Building" contact info |
UK (NEWCASTLE UPON TYNE) | coordinator | 334˙689.80 |
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'Metalloenzymes play crucial role in neurobiology and therefore they are very important target for drug design for treatment neuropathological processes. In order to make new specific and effective drugs it is crucially important to understand the structure and functions of their drug targets. In this Outgoing Marie Curie Fellowship application we propose combined computational/spectroscopic investigation of the enzyme mechanism of tryptophan hydroxylase – a pterin-dependent non-heme containing iron enzyme in crucial importance for the nervous system. Accurate insight in the mechanism of such a complicated enzyme can not be received using solely computational or experimental methods therefore we will apply integrated combination of state-of-the-art computational methods with most modern spectroscopy methods (e.g. K edge X-ray Absorption Spectroscopy, Magnetic Circular Dichroism and variable-temperature variable-field MCD, and EPR). The results will provide understanding of the structure-functions relationships of this enzyme and will be used in drug design.'
Metalloenzymes play a crucial role in neurobiology and are potential targets for drug design in the treatment of nervous system diseases. Understanding the structure and function of targets is important for making new, effective drugs.
One third of the known enzyme catalysis reactions use metal, either as a cofactor, or incorporated into the enzyme molecule. Metals, such as iron, copper, zinc and magnesium participate in electronic transfer and empower numerous essential reactions.
The EU-funded Marie Curie fellowship ICSTH (An integrated computational and spectroscopic investigation of the enzyme mechanism of tryptophan hydroxylase) was dedicated to metalloenzymes. In the course of the project, the initial focus shifted from tryptophan hydroxylase, an enzyme involved in the synthesis of serotonin, to binuclear copper enzymes. Peptidylglycine ?-hydroxylating monooxygenase (PAM) and dopamine ?-monooxygenase (D?M) catalyse hydroxylation of substrates crucial for functioning of the nervous system. Catalysis in both PAM and D?M is initiated by copper reduction and oxygen activation, but the mechanism of the reactions remains unknown.
The project aimed to understand the mechanisms of oxygen activation, hydrogen abstraction, water binding and direct hydroxylation reactions catalysed by PAM and D?M. The complexity of copper catalytic centres required using a variety of the state-of-the art computational chemistry and spectroscopy methods.
Defining the electronic structure of the initial enzymatic complex included determining the oxidation state of copper and the chemical nature of the oxygen adduct. The performed analysis of the hydroxylation mechanism explored the reaction paths, refined the transition states and possible reaction intermediates of each step. Combined quantum mechanical, molecular mechanical and molecular dynamics simulations helped study the effects of multiple mutations. This in turn allowed the exploration of the conformational effects on the reaction mechanism.
The results of ICSTH enhanced our understanding of the crucial steps of hydroxylation mechanism of non-coupled di-copper containing enzymes. Such understanding is needed for advanced applications in drug design, protein engineering and biotechnology.
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