Discovery of Novel Haloalkane Dehalogenase Inhibitors

J 2016

Discovery of Novel Haloalkane Dehalogenase Inhibitors

BURYŠKA, Tomáš, Lukáš DANIEL, Antonín KUNKA, Jan BREZOVSKÝ, Jiří DAMBORSKÝ et. al.

Základní údaje

Originální název

Discovery of Novel Haloalkane Dehalogenase Inhibitors

Autoři

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

Vydání

Applied and Environmental Microbiology, WASHINGTON, DC (USA), AMER SOC MICROBIOLOGY, 2016, 0099-2240

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: 3.807

Kód RIV

RIV/00216224:14310/16:00087944

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1128/AEM.03916-15

UT WoS

000373339400032

Klíčová slova anglicky

SPHINGOMONAS-PAUCIMOBILIS UT26; AMBER FORCE-FIELD; MYCOBACTERIUM-TUBERCULOSIS; GENERALIZED BORN; SCORING FUNCTION; GAMMA-HEXACHLOROCYCLOHEXANE; BRADYRHIZOBIUM-JAPONICUM; CRYSTAL-STRUCTURE; PURIFICATION; SEQUENCE

Štítky

AKR, rivok

Změněno: 3. 4. 2017 12:24, Ing. Andrea Mikešková

Anotace

V originále

Haloalkane dehalogenases (HLDs) have recently been discovered in a number of bacteria, including symbionts and pathogens of both plants and humans. However, the biological roles of HLDs in these organisms are unclear. The development of efficient HLD inhibitors serving as molecular probes to explore their function would represent an important step toward a better understanding of these interesting enzymes. Here we report the identification of inhibitors for this enzyme family using two different approaches. The first builds on the structures of the enzymes' known substrates and led to the discovery of less potent nonspecific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of an HLD from the human pathogen Mycobacterium tuberculosis H37Rv. The best inhibitor exhibited high specificity for the target structure, with an inhibition constant of 3 mu M and a molecular architecture that clearly differs from those of all known HLD substrates. The new inhibitors will be used to study the natural functions of HLDs in bacteria, to probe their mechanisms, and to achieve their stabilization.

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

LH14027, projekt VaV

Název: Nové koncepty a nástroje pro racionální design enzymů

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Nové koncepty a nástroje pro racionální design enzymů

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

BURYŠKA, Tomáš, Lukáš DANIEL, Antonín KUNKA, Jan BREZOVSKÝ, Jiří DAMBORSKÝ a Zbyněk PROKOP. Discovery of Novel Haloalkane Dehalogenase Inhibitors. Applied and Environmental Microbiology. WASHINGTON, DC (USA): AMER SOC MICROBIOLOGY, 2016, roč. 82, č. 6, s. 1958-1965. ISSN 0099-2240. Dostupné z: https://dx.doi.org/10.1128/AEM.03916-15.

@article{1345850,
   author = {Buryška, Tomáš and Daniel, Lukáš and Kunka, Antonín and Brezovský, Jan and Damborský, Jiří and Prokop, Zbyněk},
   article_location = {WASHINGTON, DC (USA)},
   article_number = {6},
   doi = {http://dx.doi.org/10.1128/AEM.03916-15},
   keywords = {SPHINGOMONAS-PAUCIMOBILIS UT26; AMBER FORCE-FIELD; MYCOBACTERIUM-TUBERCULOSIS; GENERALIZED BORN; SCORING FUNCTION; GAMMA-HEXACHLOROCYCLOHEXANE; BRADYRHIZOBIUM-JAPONICUM; CRYSTAL-STRUCTURE; PURIFICATION; SEQUENCE},
   language = {eng},
   issn = {0099-2240},
   journal = {Applied and Environmental Microbiology},
   title = {Discovery of Novel Haloalkane Dehalogenase Inhibitors},
   url = {https://loschmidt.chemi.muni.cz/peg/publications/discovery-of-novel-haloalkane-dehalogenase-inhibitors/},
   volume = {82},
   year = {2016}
}

TY  - JOUR
ID  - 1345850
AU  - Buryška, Tomáš - Daniel, Lukáš - Kunka, Antonín - Brezovský, Jan - Damborský, Jiří - Prokop, Zbyněk
PY  - 2016
TI  - Discovery of Novel Haloalkane Dehalogenase Inhibitors
JF  - Applied and Environmental Microbiology
VL  - 82
IS  - 6
SP  - 1958-1965
EP  - 1958-1965
PB  - AMER SOC MICROBIOLOGY
SN  - 00992240
KW  - SPHINGOMONAS-PAUCIMOBILIS UT26
KW  - AMBER FORCE-FIELD
KW  - MYCOBACTERIUM-TUBERCULOSIS
KW  - GENERALIZED BORN
KW  - SCORING FUNCTION
KW  - GAMMA-HEXACHLOROCYCLOHEXANE
KW  - BRADYRHIZOBIUM-JAPONICUM
KW  - CRYSTAL-STRUCTURE
KW  - PURIFICATION
KW  - SEQUENCE
UR  - https://loschmidt.chemi.muni.cz/peg/publications/discovery-of-novel-haloalkane-dehalogenase-inhibitors/
L2  - https://loschmidt.chemi.muni.cz/peg/publications/discovery-of-novel-haloalkane-dehalogenase-inhibitors/
N2  - Haloalkane dehalogenases (HLDs) have recently been discovered in a number of bacteria, including symbionts and pathogens of both plants and humans. However, the biological roles of HLDs in these organisms are unclear. The development of efficient HLD inhibitors serving as molecular probes to explore their function would represent an important step toward a better understanding of these interesting enzymes. Here we report the identification of inhibitors for this enzyme family using two different approaches. The first builds on the structures of the enzymes' known substrates and led to the discovery of less potent nonspecific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of an HLD from the human pathogen Mycobacterium tuberculosis H37Rv. The best inhibitor exhibited high specificity for the target structure, with an inhibition constant of 3 mu M and a molecular architecture that clearly differs from those of all known HLD substrates. The new inhibitors will be used to study the natural functions of HLDs in bacteria, to probe their mechanisms, and to achieve their stabilization.
ER  -

BURYŠKA, Tomáš, Lukáš DANIEL, Antonín KUNKA, Jan BREZOVSKÝ, Jiří DAMBORSKÝ a Zbyněk PROKOP. Discovery of Novel Haloalkane Dehalogenase Inhibitors. \textit{Applied and Environmental Microbiology}. WASHINGTON, DC (USA): AMER SOC MICROBIOLOGY, 2016, roč.~82, č.~6, s.~1958-1965. ISSN~0099-2240. Dostupné z: https://dx.doi.org/10.1128/AEM.03916-15.

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