The crystal structure of mycobacterial epoxide hydrolase A

TY - JOUR

T1 - The crystal structure of mycobacterial epoxide hydrolase A

AU - Schulz, Eike C

AU - Henderson, Sara R

AU - Illarionov, Boris

AU - Crosskey, Thomas

AU - Southall, Stacey M

AU - Krichel, Boris

AU - Uetrecht, Charlotte

AU - Fischer, Markus

AU - Wilmanns, Matthias

PY - 2020/10/6

Y1 - 2020/10/6

N2 - The human pathogen Mycobacterium tuberculosis is the causative agent of tuberculosis resulting in over 1 million fatalities every year, despite decades of research into the development of new anti-TB compounds. Unlike most other organisms M. tuberculosis has six putative genes for epoxide hydrolases (EH) of the α/β-hydrolase family with little known about their individual substrates, suggesting functional significance for these genes to the organism. Due to their role in detoxification, M. tuberculosis EH's have been identified as potential drug targets. Here, we demonstrate epoxide hydrolase activity of M. thermoresistibile epoxide hydrolase A (Mth-EphA) and report its crystal structure in complex with the inhibitor 1,3-diphenylurea at 2.0 Å resolution. Mth-EphA displays high sequence similarity to its orthologue from M. tuberculosis and generally high structural similarity to α/β-hydrolase EHs. The structure of the inhibitor bound complex reveals the geometry of the catalytic residues and the conformation of the inhibitor. Comparison to other EHs from mycobacteria allows insight into the active site plasticity with respect to substrate specificity. We speculate that mycobacterial EHs may have a narrow substrate specificity providing a potential explanation for the genetic repertoire of epoxide hydrolase genes in M. tuberculosis.

AB - The human pathogen Mycobacterium tuberculosis is the causative agent of tuberculosis resulting in over 1 million fatalities every year, despite decades of research into the development of new anti-TB compounds. Unlike most other organisms M. tuberculosis has six putative genes for epoxide hydrolases (EH) of the α/β-hydrolase family with little known about their individual substrates, suggesting functional significance for these genes to the organism. Due to their role in detoxification, M. tuberculosis EH's have been identified as potential drug targets. Here, we demonstrate epoxide hydrolase activity of M. thermoresistibile epoxide hydrolase A (Mth-EphA) and report its crystal structure in complex with the inhibitor 1,3-diphenylurea at 2.0 Å resolution. Mth-EphA displays high sequence similarity to its orthologue from M. tuberculosis and generally high structural similarity to α/β-hydrolase EHs. The structure of the inhibitor bound complex reveals the geometry of the catalytic residues and the conformation of the inhibitor. Comparison to other EHs from mycobacteria allows insight into the active site plasticity with respect to substrate specificity. We speculate that mycobacterial EHs may have a narrow substrate specificity providing a potential explanation for the genetic repertoire of epoxide hydrolase genes in M. tuberculosis.

KW - Carbanilides

KW - Crystallization

KW - Epoxide Hydrolases/chemistry

KW - Genes, Bacterial/genetics

KW - Inactivation, Metabolic/genetics

KW - Mycobacterium tuberculosis/enzymology

KW - Substrate Specificity

U2 - 10.1038/s41598-020-73452-y

DO - 10.1038/s41598-020-73452-y

M3 - SCORING: Journal article

C2 - 33024154

VL - 10

SP - 16539

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -