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Young Researchers and Professionals
| Project leader |
Majeric Elenkov Maja |
| Administering organization: |
Ruđer Bošković Institute
Bijenička c. 54
10002 Zagreb
Croatia |
| Partner Institution/Company: |
Chirallica d.o.o., University of Zagreb |
| Grant type: |
3A |
| Project title: |
Biocatalytic application of halohydrin dehalogenases for production of chiral building blocks |
| Project summary: |
The ability of enzymes to catalyse conversion of non-natural substrates has been used in synthetic organic chemistry, especially for synthesis of chiral molecules, and to date over 300 processes have been implemented in industry. However, the lack of suitable biocatalyst often makes a desirable biotransformation impossible. Recently, halohydrin dehalogenases have been discovered to catalyse several very attractive non-natural reactions. They can catalyse ring-opening of epoxides by using nucleophiles such as azide, cyanide, nitrite, cyanate and thiocyanate. These reactions represent an excellent method to furnish enantiopure building blocks. The access to such products by means of enzyme-catalysis is of great interest to the chemical and pharmaceutical industry. Target synthesis of the respective active enantiomer can improve the economics of the process and lead to reduced quantities applied thus reducing environmental impact.There are only several halohydrin dehalogenases discovered till now and only one has been sufficiently biocatalytically characterised. Now we want to expand the biocatalytic toolbox of halohydrin dehalogenases with a new enzyme from this class, an enzyme from Arthrobacter sp. On the basis of docking simulations and molecular modeling studies and with subsequent experimental synthesis and testing we expect to reveal the relationship between substrate structure, enzyme activity and enantioselectivity. Testing of a range of substrates and reaction conditions will deliver candidates for further development into preparative reactions with relevance to industrial application. Furthermore, it is to expect that this research besides revealing biocatalytic properties and applications of novel halohydrin dehalogenase will lay solid foundations for the protein engineering and design of improved enzyme variants in the future. |
| Hrvatski sažetak: |
Sposobnost enzima da katalizira transformacije neprirodnih supstrata koristi se u sintetskoj organskoj kemiji posebno za sintezu kiralnih molekula, a do danas je preko 300 postupaka našlo primjenu u industriji. Međutim, zbog nepostojanja odgovarajućeg biokatalizatora često je željenu biotransformaciju nemoguće provesti. Nedavno je otkriveno da halogenhidrin dehalogenaze kataliziraju nekoliko vrlo atraktivnih neprirodnih reakcija, otvaranje epoksida koristeći nukleofile poput azida, cijanida, cijanata, nitrita i tiocijanata. Ove reakcije predstavljaju izvrsnu metodu za pripravu enantiomerno čistih građevnih blokova, a dostupnost ovakvih produkata putem enzimske katalize je od velikog značenja za kemijsku i farmaceutsku industriju. Ciljana sinteza aktivnog enantiomera može poboljšati ekonomičnost industrijskih procesa jer se koristi manja količina skupih polaznih materijala, a s druge strane se smanjuje količina otpadnih produkata kemijske sinteze. Sve to ima pozitivan ekonomski i ekološki utjecaj.
U prirodi je do danas otkriveno svega nekoliko halogenhidrin dehalogenaza, a samo je jedna dostatno biokatalitički karakterizirana. Projekt predviđa ispitivanje nove halogenhidrin dehalogenaze, enzima iz Arthrobacter sp., s ciljem proširenja njihove biokatalitičke primjene. Na osnovu molekulskog modeliranja, te s narednom sintezom i testiranjem očekujemo da će se otkriti odnos između strukture supstrata, enzimske aktivnosti te enantioselektivnosti. Ispitivanjem niza supstrata i reakcijskih uvjeta očekujemo da ćemo doći do kandidata od važnosti za industrijsku primjenu. Nadalje, za očekivati je da će ova istraživanja osim što će razotkriti biokatalitička svojstva i primjenu nove halogenhidrin dehalogenaze, postaviti čvrste temelje za dizajn poboljšanih varijanti enzima metodama genetičkog inženjerstva.
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| Amount requested from UKF: |
350.000 HRK |
| Amount of matching funding: |
122.500 HRK |
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