OXMEDIAT · Molecular Enzymology of Eicosanoid synthesizing Enzymes: from mechanistic studies to rational drug design
6РП — Действия „Мария Кюри“
- Период
- 2006-05-01 → 2008-04-30
- Финансиране от ЕС
- 202 778 €
- Участници
- 1
- Схема
- IIF
Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.
Накратко на български
Ензимите, синтезиращи ейкозаноиди, се анализират чрез компютърно моделиране и химия, за да се разбере структурата им (например при 12/15-липоксигеназата). Познаването на тези процеси помага при разработването на лекарства срещу рак, възпаления и сърдечно-съдови заболявания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - OXMEDIAT (Molecular Enzymology of Eicosanoid synthesising enzymes:
Eicosanoids and eicosanoid synthesising enzymes have been implicated in the pathogenesis of various diseases (atherosclerosis, inflammation, osteoporosis, cancer), which are of major health political relevance for all industrialised countries. In most cases these disorders are chronic, gradually crippling and often fatal. The costs, that society has to pay for treatment of these disorders and for the losses in working time, are enormous. In fact, ischemic cardiovascular disorders, which frequently lead to heart attack and stroke, are the major causes of premature lethality in Europe. Hence, these illness cause immense human suffering, shorten life-span and pose an ever increasing burden on the European healthcare system. The present project was aimed at increasing our knowledge about the structural biology of eicosanoid synthesising enzymes, which are potential targets for drug therapy of these diseases. To achieve our goals we applied an integrated strategy, which involves elements of synthetic organic chemistry, molecular enzymology (recombinant expression and targeted modification of eicosanoid synthesising enzymes by site-directed mutagenesis) and computer-assisted modelling (structural and kinetic modelling and simulation of molecular dynamics). Special attention has been paid to conformational changes of protein matrix (inter domain movement of 12/15-lipoxygenase) in solution and molecular dynamics of oxygen as second lipoxygenase substrate. Our major finding suggests that mutual interaction of the two domains appears to be crucial for protein stability and its biological function. N-terminal beta-barrel domain of LOXs may serve as built-in modulator of the enzymatic activity and membrane binding. Regarding oxygen movement we obtained strong evidence that the main route for oxygen access to the active site of the enzyme follows a transiently interconnected cavities whereby the opening and closure is governed by side chain dynamics. This path is not conserved and appears to be individual for each particular protein. These data prompt the conclusion that similar structures might exist for many other oxygen-consuming enzymes. This methodology can also be applied to other small hydrophobic molecules.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
In recent years functional genomics of eicosanoid synthesizing enzymes and molecular enzymology of these biocatalysts have become a hotspot in eicosanoid research. One reason for this switch in interest is the fact that rational drug development requires detailed knowledge on structural biology of enzymes and receptors to effectively prevent their interactions with the natural ligands.The present research project is aimed at assembling a comprehensive picture of lipoxygenase/cyclooxygenase catalysis employing dynamic models. To understand the fundamental principles of the enzymatic reaction we will combine biochemical and molecular biological approaches and use them for investigation of elementary steps of the reaction cascades with particular emphasis on the substrate binding and intra-enzyme oxygen movement.Structurally, the project can be divided into three subprojects:i) substrate binding of mammalian LOX/COX-isoforms;ii) investigations of solution structure of LOX/COX-isoforms; inter-domain movement in LOXs and its regulatory relevance;iii) structural identification of oxygen access channel(s) applying an integrated research strategy that involves molecular modelling (structural modelling and molecular dynamics) and site-directed mutagenesis.Eicosan oids and eicosanoid synthesizing enzymes have been implicated in the pathogenesis of atherosclerosis, inflammation, osteoporosis and cancer, which are of major health political relevance for all industrialized countries. Our results are expected to open new perspectives in regulation of catalytic activity of LOX/COX-isoforms providing an improved structural basis for the development of novel therapeutics.
Оригинален текст от CORDIS (на английски).
Участници
- CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN · BERLINКоординаторНиво градГермания
Връзки
Данни: CORDIS, © Европейски съюз