Mycobacterial Epoxide Hydrolase EphD Is Inhibited by Urea and Thiourea Derivatives

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Apr 3

PMID 33809178

Citations 5

Authors

Jan Madacki

Martin Kopal

Mary Jackson

Jana Kordulakova

Affiliations

Soon will be listed here.

Abstract

The genome of the human intracellular pathogen encodes an unusually large number of epoxide hydrolases, which are thought to be involved in lipid metabolism and detoxification reactions needed to endure the hostile environment of host macrophages. These enzymes therefore represent suitable targets for compounds such as urea derivatives, which are known inhibitors of soluble epoxide hydrolases. In this work, we studied in vitro the effect of the thiourea drug isoxyl on six epoxide hydrolases of using a fatty acid substrate. We show that one of the proteins inhibited by isoxyl is EphD, an enzyme involved in the metabolism of mycolic acids, key components of the mycobacterial cell wall. By analyzing mycolic acid profiles, we demonstrate the inhibition of EphD epoxide hydrolase activity by isoxyl and two other urea-based inhibitors, thiacetazone and AU1235, inside the mycobacterial cell.

Citing Articles

Synthesis and Structure-Activity Relationship of Thiourea Derivatives Against .

Viana G, Cunha-Junior E, Assumpcao P, Rezende M, Emiliano Y, Soares L Pharmaceuticals (Basel). 2025; 17(12.

PMID: 39770415 PMC: 11677126. DOI: 10.3390/ph17121573.

Impact of the elderly lung mucosa on transcriptional adaptation during infection of alveolar epithelial cells.

M Olmo-Fontanez A, Allue-Guardia A, Garcia-Vilanova A, Glenn J, Wang S, Merritt R Microbiol Spectr. 2024; :e0179024.

PMID: 39513699 PMC: 11619525. DOI: 10.1128/spectrum.01790-24.

Gut microbiome-derived hydrolases-an underrated target of natural product metabolism.

He J, Liu X, Zhang J, Wang R, Cao X, Liu G Front Cell Infect Microbiol. 2024; 14:1392249.

PMID: 38915922 PMC: 11194327. DOI: 10.3389/fcimb.2024.1392249.

Uncovering the roles of in redox and bioenergetic homeostasis: implications for antitubercular therapy.

Chen Y, Yang X, Wang N, Sampson N mSphere. 2024; 9(4):e0006124.

PMID: 38564709 PMC: 11036813. DOI: 10.1128/msphere.00061-24.

Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery.

de Melo Milani V, Silva M, Camargo P, Bispo M Curr Med Chem. 2024; 31(29):4703-4724.

PMID: 38375848 DOI: 10.2174/0109298673276076231124104513.

References

Imig J, Hammock B . Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov. 2009; 8(10):794-805. PMC: 3021468. DOI: 10.1038/nrd2875. View

Carrere-Kremer S, Blaise M, Singh V, Alibaud L, Tuaillon E, Halloum I . A new dehydratase conferring innate resistance to thiacetazone and intra-amoebal survival of Mycobacterium smegmatis. Mol Microbiol. 2015; 96(5):1085-102. DOI: 10.1111/mmi.12992. View

Zuber B, Chami M, Houssin C, Dubochet J, Griffiths G, Daffe M . Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J Bacteriol. 2008; 190(16):5672-80. PMC: 2519390. DOI: 10.1128/JB.01919-07. View

Grzegorzewicz A, Eynard N, Quemard A, North E, Margolis A, Lindenberger J . Covalent modification of the FAS-II dehydratase by Isoxyl and Thiacetazone. ACS Infect Dis. 2015; 1(2):91-97. PMC: 4401429. DOI: 10.1021/id500032q. View

Johansson P, Unge T, Cronin A, Arand M, Bergfors T, Jones T . Structure of an atypical epoxide hydrolase from Mycobacterium tuberculosis gives insights into its function. J Mol Biol. 2005; 351(5):1048-56. DOI: 10.1016/j.jmb.2005.06.055. View

Coxon G, Craig D, Corrales R, Vialla E, Gannoun-Zaki L, Kremer L . Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues. PLoS One. 2013; 8(1):e53162. PMC: 3536773. DOI: 10.1371/journal.pone.0053162. View

Hoffmann C, Leis A, Niederweis M, Plitzko J, Engelhardt H . Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc Natl Acad Sci U S A. 2008; 105(10):3963-7. PMC: 2268800. DOI: 10.1073/pnas.0709530105. View

Phetsuksiri B, Jackson M, Scherman H, McNeil M, Besra G, Baulard A . Unique mechanism of action of the thiourea drug isoxyl on Mycobacterium tuberculosis. J Biol Chem. 2003; 278(52):53123-30. PMC: 4747054. DOI: 10.1074/jbc.M311209200. View

Muller F, Arand M, Frank H, Seidel A, Hinz W, Winkler L . Visualization of a covalent intermediate between microsomal epoxide hydrolase, but not cholesterol epoxide hydrolase, and their substrates. Eur J Biochem. 1997; 245(2):490-6. DOI: 10.1111/j.1432-1033.1997.00490.x. View

10.

Morisseau C, Goodrow M, Dowdy D, Zheng J, Greene J, Sanborn J . Potent urea and carbamate inhibitors of soluble epoxide hydrolases. Proc Natl Acad Sci U S A. 1999; 96(16):8849-54. PMC: 17696. DOI: 10.1073/pnas.96.16.8849. View

11.

Dover L, Alahari A, Gratraud P, Gomes J, Bhowruth V, Reynolds R . EthA, a common activator of thiocarbamide-containing drugs acting on different mycobacterial targets. Antimicrob Agents Chemother. 2007; 51(3):1055-63. PMC: 1803108. DOI: 10.1128/AAC.01063-06. View

12.

Banerjee A, DUBNAU E, Quemard A, Balasubramanian V, Um K, Wilson T . inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994; 263(5144):227-30. DOI: 10.1126/science.8284673. View

13.

Argiriadi M, Morisseau C, Goodrow M, Dowdy D, Hammock B, Christianson D . Binding of alkylurea inhibitors to epoxide hydrolase implicates active site tyrosines in substrate activation. J Biol Chem. 2000; 275(20):15265-70. DOI: 10.1074/jbc.M000278200. View

14.

Triccas J, Parish T, Britton W, Gicquel B . An inducible expression system permitting the efficient purification of a recombinant antigen from Mycobacterium smegmatis. FEMS Microbiol Lett. 1998; 167(2):151-6. DOI: 10.1111/j.1574-6968.1998.tb13221.x. View

15.

Phetsuksiri B, Baulard A, Cooper A, Minnikin D, Douglas J, Besra G . Antimycobacterial activities of isoxyl and new derivatives through the inhibition of mycolic acid synthesis. Antimicrob Agents Chemother. 1999; 43(5):1042-51. PMC: 89109. DOI: 10.1128/AAC.43.5.1042. View

16.

Huszar S, Chibale K, Singh V . The quest for the holy grail: new antitubercular chemical entities, targets and strategies. Drug Discov Today. 2020; 25(4):772-780. PMC: 7215093. DOI: 10.1016/j.drudis.2020.02.003. View

17.

Grzegorzewicz A, Kordulakova J, Jones V, Born S, Belardinelli J, Vaquie A . A common mechanism of inhibition of the Mycobacterium tuberculosis mycolic acid biosynthetic pathway by isoxyl and thiacetazone. J Biol Chem. 2012; 287(46):38434-41. PMC: 3493888. DOI: 10.1074/jbc.M112.400994. View

18.

Daffe M, Marrakchi H . Unraveling the Structure of the Mycobacterial Envelope. Microbiol Spectr. 2019; 7(4). PMC: 10957186. DOI: 10.1128/microbiolspec.GPP3-0027-2018. View

19.

Rengarajan J, Bloom B, Rubin E . Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proc Natl Acad Sci U S A. 2005; 102(23):8327-32. PMC: 1142121. DOI: 10.1073/pnas.0503272102. View

20.

Schulz E, Henderson S, Illarionov B, Crosskey T, Southall S, Krichel B . The crystal structure of mycobacterial epoxide hydrolase A. Sci Rep. 2020; 10(1):16539. PMC: 7538969. DOI: 10.1038/s41598-020-73452-y. View