Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone

Anna E. Grzegorzewicz, Nathalie Eynard, Annaïk Quémard, E. Jeffrey North, Alyssa Margolis, Jared J. Lindenberger, Victoria Jones, Jana Korduláková, Patrick J. Brennan, Richard E. Lee, Donald R. Ronning, Michael R. McNeil, Mary Jackson

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs formerly used in the clinical treatment of tuberculosis. Although both prodrugs have recently been shown to kill Mycobacterium tuberculosis through the inhibition of the dehydration step of the type II fatty acid synthase pathway, their detailed mechanism of inhibition, the precise number of enzymes involved in their activation, and the nature of their activated forms remained unknown. This paper demonstrates that both ISO and TAC specifically and covalently react with a cysteine residue (Cys61) of the HadA subunit of the dehydratase, thereby inhibiting HadAB activity. The results unveil for the first time the nature of the active forms of ISO and TAC and explain the basis for the structure-activity relationship of and resistance to these thiourea prodrugs. The results further indicate that the flavin-containing monooxygenase EthA is most likely the only enzyme required for the activation of ISO and TAC in mycobacteria.

Original languageEnglish
Pages (from-to)91-97
Number of pages7
JournalACS Infectious Diseases
Volume1
Issue number2
DOIs
StatePublished - Jan 8 2016
Externally publishedYes

Fingerprint

Thioacetazone
Hydro-Lyases
Mycobacterium tuberculosis
Prodrugs
dimethylaniline monooxygenase (N-oxide forming)
Type II Fatty Acid Synthase
Thiourea
Enzyme Activation
Structure-Activity Relationship
Mycobacterium
Dehydration
Cysteine
Tuberculosis
thiocarlide
Enzymes

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

Cite this

Grzegorzewicz, A. E., Eynard, N., Quémard, A., North, E. J., Margolis, A., Lindenberger, J. J., ... Jackson, M. (2016). Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone. ACS Infectious Diseases, 1(2), 91-97. https://doi.org/10.1021/id500032q

Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone. / Grzegorzewicz, Anna E.; Eynard, Nathalie; Quémard, Annaïk; North, E. Jeffrey; Margolis, Alyssa; Lindenberger, Jared J.; Jones, Victoria; Korduláková, Jana; Brennan, Patrick J.; Lee, Richard E.; Ronning, Donald R.; McNeil, Michael R.; Jackson, Mary.

In: ACS Infectious Diseases, Vol. 1, No. 2, 08.01.2016, p. 91-97.

Research output: Contribution to journalArticle

Grzegorzewicz, AE, Eynard, N, Quémard, A, North, EJ, Margolis, A, Lindenberger, JJ, Jones, V, Korduláková, J, Brennan, PJ, Lee, RE, Ronning, DR, McNeil, MR & Jackson, M 2016, 'Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone', ACS Infectious Diseases, vol. 1, no. 2, pp. 91-97. https://doi.org/10.1021/id500032q
Grzegorzewicz, Anna E. ; Eynard, Nathalie ; Quémard, Annaïk ; North, E. Jeffrey ; Margolis, Alyssa ; Lindenberger, Jared J. ; Jones, Victoria ; Korduláková, Jana ; Brennan, Patrick J. ; Lee, Richard E. ; Ronning, Donald R. ; McNeil, Michael R. ; Jackson, Mary. / Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone. In: ACS Infectious Diseases. 2016 ; Vol. 1, No. 2. pp. 91-97.
@article{bafbf149c78d4245bf8a0d99fb2f580d,
title = "Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone",
abstract = "Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs formerly used in the clinical treatment of tuberculosis. Although both prodrugs have recently been shown to kill Mycobacterium tuberculosis through the inhibition of the dehydration step of the type II fatty acid synthase pathway, their detailed mechanism of inhibition, the precise number of enzymes involved in their activation, and the nature of their activated forms remained unknown. This paper demonstrates that both ISO and TAC specifically and covalently react with a cysteine residue (Cys61) of the HadA subunit of the dehydratase, thereby inhibiting HadAB activity. The results unveil for the first time the nature of the active forms of ISO and TAC and explain the basis for the structure-activity relationship of and resistance to these thiourea prodrugs. The results further indicate that the flavin-containing monooxygenase EthA is most likely the only enzyme required for the activation of ISO and TAC in mycobacteria.",
author = "Grzegorzewicz, {Anna E.} and Nathalie Eynard and Anna{\"i}k Qu{\'e}mard and North, {E. Jeffrey} and Alyssa Margolis and Lindenberger, {Jared J.} and Victoria Jones and Jana Kordul{\'a}kov{\'a} and Brennan, {Patrick J.} and Lee, {Richard E.} and Ronning, {Donald R.} and McNeil, {Michael R.} and Mary Jackson",
year = "2016",
month = "1",
day = "8",
doi = "10.1021/id500032q",
language = "English",
volume = "1",
pages = "91--97",
journal = "ACS Infectious Diseases",
issn = "2373-8227",
publisher = "American Chemical Society",
number = "2",

}

TY - JOUR

T1 - Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone

AU - Grzegorzewicz, Anna E.

AU - Eynard, Nathalie

AU - Quémard, Annaïk

AU - North, E. Jeffrey

AU - Margolis, Alyssa

AU - Lindenberger, Jared J.

AU - Jones, Victoria

AU - Korduláková, Jana

AU - Brennan, Patrick J.

AU - Lee, Richard E.

AU - Ronning, Donald R.

AU - McNeil, Michael R.

AU - Jackson, Mary

PY - 2016/1/8

Y1 - 2016/1/8

N2 - Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs formerly used in the clinical treatment of tuberculosis. Although both prodrugs have recently been shown to kill Mycobacterium tuberculosis through the inhibition of the dehydration step of the type II fatty acid synthase pathway, their detailed mechanism of inhibition, the precise number of enzymes involved in their activation, and the nature of their activated forms remained unknown. This paper demonstrates that both ISO and TAC specifically and covalently react with a cysteine residue (Cys61) of the HadA subunit of the dehydratase, thereby inhibiting HadAB activity. The results unveil for the first time the nature of the active forms of ISO and TAC and explain the basis for the structure-activity relationship of and resistance to these thiourea prodrugs. The results further indicate that the flavin-containing monooxygenase EthA is most likely the only enzyme required for the activation of ISO and TAC in mycobacteria.

AB - Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs formerly used in the clinical treatment of tuberculosis. Although both prodrugs have recently been shown to kill Mycobacterium tuberculosis through the inhibition of the dehydration step of the type II fatty acid synthase pathway, their detailed mechanism of inhibition, the precise number of enzymes involved in their activation, and the nature of their activated forms remained unknown. This paper demonstrates that both ISO and TAC specifically and covalently react with a cysteine residue (Cys61) of the HadA subunit of the dehydratase, thereby inhibiting HadAB activity. The results unveil for the first time the nature of the active forms of ISO and TAC and explain the basis for the structure-activity relationship of and resistance to these thiourea prodrugs. The results further indicate that the flavin-containing monooxygenase EthA is most likely the only enzyme required for the activation of ISO and TAC in mycobacteria.

UR - http://www.scopus.com/inward/record.url?scp=84969151001&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969151001&partnerID=8YFLogxK

U2 - 10.1021/id500032q

DO - 10.1021/id500032q

M3 - Article

AN - SCOPUS:84969151001

VL - 1

SP - 91

EP - 97

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

SN - 2373-8227

IS - 2

ER -