Mechanism-Based Discovery of Novel Substrates of Haloalkane
Dehalogenases using in Silico Screening

J 2015

Mechanism-Based Discovery of Novel Substrates of Haloalkane Dehalogenases using in Silico Screening

DANIEL, Lukáš, Tomáš BURYŠKA, Zbyněk PROKOP, Jiří DAMBORSKÝ, Jan BREZOVSKÝ et. al.

Základní údaje

Originální název

Mechanism-Based Discovery of Novel Substrates of Haloalkane Dehalogenases using in Silico Screening

Autoři

DANIEL, Lukáš (203 Česká republika, domácí), Tomáš BURYŠKA (203 Česká republika, domácí), Zbyněk PROKOP (203 Česká republika, domácí), Jiří DAMBORSKÝ (203 Česká republika, domácí) a Jan BREZOVSKÝ (203 Česká republika, garant, domácí)

Vydání

Journal of Chemical Information and Modeling, 2015, 1549-9596

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.657

Kód RIV

RIV/00216224:14310/15:00081404

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1021/ci500486y

UT WoS

000348619400005

Klíčová slova anglicky

in Silico Screening;Haloalkane Dehalogenases

Štítky

AKR, rivok

Změněno: 7. 4. 2016 10:10, Ing. Andrea Mikešková

Anotace

V originále

The substrate specificity is a key feature of enzymes determining their applicability in biomaterials and biotechnologies. Experimental testing of activities with novel substrates is a time-consuming and inefficient process, typically resulting in many failures. Here, we present an experimentally validated in silico method for the discovery of novel substrates of enzymes with known reaction mechanism. The method was developed for a model system of biotechnologically relevant enzymes, haloalkane dehalogenases. Based on the parameterization of six different haloalkane dehalogenases with 30 halogenated substrates, mechanism-based geometric criteria for reactivity approximation were defined. These criteria were subsequently applied to the previously experimentally uncharacterized haloalkane dehalogenase DmmA. The enzyme was computationally screened against 42,000 compounds, yielding 548 structurally unique compounds as potential substrates. Eight out of sixteen experimentally tested top-ranking compounds were active with DmmA, indicating a 50% success rate for the prediction of substrates. The remaining eight compounds were able to bind to the active site and inhibit enzymatic activity. These results confirmed good applicability of the method for prioritizing active compounds – true substrates and binders – for experimental testing.

Návaznosti

EE2.3.30.0037, projekt VaV

Název: Zaměstnáním nejlepších mladých vědců k rozvoji mezinárodní spolupráce

GAP503/12/0572, projekt VaV

Název: Konstrukce syntetické metabolické dráhy pro degradaci důležitého environmentálního polutantu proteinovým a metabolickým inženýrstvím

Investor: Grantová agentura ČR, Konstrukce syntetické metabolické dráhy pro degradaci důležitého environmentlního polutantu proteinovým a metabolickým inženýrstvím

LO1214, projekt VaV

Název: Centrum pro výzkum toxických látek v prostředí (Akronym: RECETOX)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Centrum pro výzkum toxických látek v prostředí

Citovat

DANIEL, Lukáš, Tomáš BURYŠKA, Zbyněk PROKOP, Jiří DAMBORSKÝ a Jan BREZOVSKÝ. Mechanism-Based Discovery of Novel Substrates of Haloalkane Dehalogenases using in Silico Screening. Journal of Chemical Information and Modeling. 2015, roč. 55, č. 1, s. 54-62. ISSN 1549-9596. Dostupné z: https://dx.doi.org/10.1021/ci500486y.

@article{1323004,
   author = {Daniel, Lukáš and Buryška, Tomáš and Prokop, Zbyněk and Damborský, Jiří and Brezovský, Jan},
   article_number = {1},
   doi = {http://dx.doi.org/10.1021/ci500486y},
   keywords = {in Silico Screening;Haloalkane Dehalogenases},
   language = {eng},
   issn = {1549-9596},
   journal = {Journal of Chemical Information and Modeling},
   title = {Mechanism-Based Discovery of Novel Substrates of Haloalkane Dehalogenases using in Silico Screening},
   url = {http://loschmidt.chemi.muni.cz/peg/wp-content/uploads/2015/01/jcim15.pdf},
   volume = {55},
   year = {2015}
}

TY  - JOUR
ID  - 1323004
AU  - Daniel, Lukáš - Buryška, Tomáš - Prokop, Zbyněk - Damborský, Jiří - Brezovský, Jan
PY  - 2015
TI  - Mechanism-Based Discovery of Novel Substrates of Haloalkane Dehalogenases using in Silico Screening
JF  - Journal of Chemical Information and Modeling
VL  - 55
IS  - 1
SP  - 54-62
EP  - 54-62
SN  - 15499596
KW  - in Silico Screening;Haloalkane Dehalogenases
UR  - http://loschmidt.chemi.muni.cz/peg/wp-content/uploads/2015/01/jcim15.pdf
L2  - http://loschmidt.chemi.muni.cz/peg/wp-content/uploads/2015/01/jcim15.pdf
N2  - The substrate specificity is a key feature of enzymes determining their applicability in biomaterials and biotechnologies. Experimental testing of activities with novel substrates is a time-consuming and inefficient process, typically resulting in many failures. Here, we present an experimentally validated in silico method for the discovery of novel substrates of enzymes with known reaction mechanism. The method was developed for a model system of biotechnologically relevant enzymes, haloalkane dehalogenases. Based on the parameterization of six different haloalkane dehalogenases with 30 halogenated substrates, mechanism-based geometric criteria for reactivity approximation were defined. These criteria were subsequently applied to the previously experimentally uncharacterized haloalkane dehalogenase DmmA. The enzyme was computationally screened against 42,000 compounds, yielding 548 structurally unique compounds as potential substrates. Eight out of sixteen experimentally tested top-ranking compounds were active with DmmA, indicating a 50% success rate for the prediction of substrates. The remaining eight compounds were able to bind to the active site and inhibit enzymatic activity. These results confirmed good applicability of the method for prioritizing active compounds – true substrates and binders – for experimental testing.
ER  -

DANIEL, Lukáš, Tomáš BURYŠKA, Zbyněk PROKOP, Jiří DAMBORSKÝ a Jan BREZOVSKÝ. Mechanism-Based Discovery of Novel Substrates of Haloalkane Dehalogenases using in Silico Screening. \textit{Journal of Chemical Information and Modeling}. 2015, roč.~55, č.~1, s.~54-62. ISSN~1549-9596. Dostupné z: https://dx.doi.org/10.1021/ci500486y.

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