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.

Basic information

Original name

Discovery of Novel Haloalkane Dehalogenase Inhibitors

Authors

BURYŠKA, Tomáš (203 Czech Republic, belonging to the institution), Lukáš DANIEL (203 Czech Republic, belonging to the institution), Antonín KUNKA (203 Czech Republic, belonging to the institution), Jan BREZOVSKÝ (203 Czech Republic, belonging to the institution), Jiří DAMBORSKÝ (203 Czech Republic, guarantor, belonging to the institution) and Zbyněk PROKOP (203 Czech Republic, belonging to the institution)

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10600 1.6 Biological sciences

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 3.807

RIV identification code

RIV/00216224:14310/16:00087944

Organization unit

Faculty of Science

DOI

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

UT WoS

000373339400032

Keywords in English

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

Abstract

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.

Links

EE2.3.30.0037, research and development project

Name: Zaměstnáním nejlepších mladých vědců k rozvoji mezinárodní spolupráce

GAP503/12/0572, research and development project

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

Investor: Czech Science Foundation

LH14027, research and development project

Name: Nové koncepty a nástroje pro racionální design enzymů

Investor: Ministry of Education, Youth and Sports of the CR

LO1214, research and development project

Name: Centrum pro výzkum toxických látek v prostředí (Acronym: RECETOX)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

BURYŠKA, Tomáš, Lukáš DANIEL, Antonín KUNKA, Jan BREZOVSKÝ, Jiří DAMBORSKÝ and Zbyněk PROKOP. Discovery of Novel Haloalkane Dehalogenase Inhibitors. Applied and Environmental Microbiology. WASHINGTON, DC (USA): AMER SOC MICROBIOLOGY, 2016, vol. 82, No 6, p. 1958-1965. ISSN 0099-2240. Available from: 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 and Zbyněk PROKOP. Discovery of Novel Haloalkane Dehalogenase Inhibitors. \textit{Applied and Environmental Microbiology}. WASHINGTON, DC (USA): AMER SOC MICROBIOLOGY, 2016, vol.~82, No~6, p.~1958-1965. ISSN~0099-2240. Available from: https://dx.doi.org/10.1128/AEM.03916-15.

Detailed Information on Publication Record