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| Project leader: |
Assistant Professor Aleksandra Maršavelski |
| Project co-leader: |
Professor Lynn Kamerlin |
| Administering organization: |
Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia, http://www.pmf.unizg.hr, OIB: 28163265527,
Dean prof. dr. sc. Aleksandra Čizmešija, dekanat@dekanat.pmf.hr |
| Partner Institution/Company: |
Department of Chemistry, Biomedicinska Centrum (BMC), Uppsala University, Uppsala |
| Grant type: |
2A |
| Project title: |
Catalytic selectivity toward fluorinated compounds |
| Project summary: |
Fluorinated molecules are important bioactive compounds used for a broad range of applications. The most important fluorinated pharmaceuticals include the antidepressant fluoxetine (Prozac), antipsychotic haloperidol (Haldol) and the cholesterol-lowering drug atorvastatin (Lipitor). Site-specific fluorination has proved to be an important strategy for drug metabolic stability. However, other implications that fluorine brings are yet to be understood. Therefore, there is a strong interest in gaining detailed insights into how fluorine substituent affects the selectivity and reactivity of these compounds. Fluoroacetyl-CoA thioesterase from the organofluorine-producing bacteria Streptomyces cattleya is an excellent example of a naturally evolved enzyme that demonstrates high discrimination between fluoroacetyl-CoA and acetyl-CoA. Although experimental studies have demonstrated that a 106-fold selectivity against fluoroacetyl-CoA can be attributed to a different catalytic mechanism and entropically driven recognition that favors fluorinated over nonfluorinated compound, many aspects of this selectivity are left unexplained. The aim of this project is, therefore, to elucidate mechanistic differences in the hydrolysis of fluoroacetyl-CoA and acetyl-CoA by fluoroacetyl-CoA thioesterase by applying empirical valence bond simulations. The expected outcome includes detailed insight into the reaction mechanisms of hydrolysis of both compounds, by mapping all intermediates and transitions states along the reaction pathways, which is essential to understanding the catalytic effects of fluorine-containing compounds. The project will allow the establishment of a long-term collaboration with the host laboratory, which has impressive experience in studying enzyme’s reactivity. The host laboratory will, besides expertise, provide access to extensive computing power for simulations, not available in Croatia. Altogether, this will contribute to the quality and international visibility of Croatian research results. |
| Hrvatski sažetak: |
Fluorirane molekule su važni bioaktivni spojevi koji imaju široku primjenu. Najvažniji fluorirani lijekovi uključuju antidepresiv fluoksetin (Prozac), antipsihotik haloperidol (Haldol) i lijek za snižavanje kolesterola atorvastatin (Lipitor). Specifično fluoriranje pokazalo se kao važna strategija za dobivanje metabolički stabilnih lijekova, međutim ostale implikacije koje fluor donosi tek trebaju biti razjašnjene. Stoga postoji snažan interes za razumijavnje utjecaja fluoro supstituenata na selektivnost i reaktivnost ovih spojeva. Fluoroacetil-CoA tioesteraza iz bakterije Streptomyces cattleya koja proizvodi organofluorirane spojeve izvrstan je primjer prirodno evoluiranog enzima koji pokazuje visoki stupanj diskriminacije između fluoroacetil-CoA i acetil-CoA. Iako su eksperimentalna istraživanja pokazala da se selektivnost prema fluoroacetil-CoA u odnosu na acetil-CoA u iznosu od šest redova veličine može pripisati specifičnom katalitičkom mehanizmu i entropijski vođenim prepoznavanjem koje favorizira fluorirani umjesto nefluorirani spoj, mnogi aspekti ove selektivnosti ostali su nerazjašnjeni. Cilj ovog projekta je, dakle, pojasniti mehanističke razlike u hidrolizi fluoroacetil-CoA i acetil-CoA fluoroacetil-CoA tioesterazom primjenom simulacija empirijskih valentnih veza (engl. empirical valence bond simulations). Očekivani ishodi uključuju detaljan uvid u reakcijske mehanizme hidrolize oba spoja, mapiranjem svih međuprodukata i prijelaznih stanja duž reakcijskog puta, što je nužno za razumijevanje katalitičkih učinaka spojeva koji sadrže fluor. Projekt će omogućiti uspostavu dugoročne suradnje s partnerskim laboratorijem koji ima impresivno iskustvo u proučavanju reaktivnosti enzima. Partnerski laboratorij će, osim ekspertize, omogućiti pristup računalnim resursima neophodnim za opsežne simulacije, a koji nisu dostupni u Hrvatskoj. Sve navedeno doprinijet će kvaliteti i međunarodnoj vidljivosti hrvatskh istraživačkih rezultata. |
| Amount requested from UKF: |
26.000,00 |
| Amount of matching funding: |
5.200,00 |
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