An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism
Abstract
Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis. One-fourth of the global population is estimated to be infected with Mtb, accounting for ~1.3 million deaths in 2017. As part of the immune response to Mtb infection, macrophages produce metabolites with the purpose of inhibiting or killing the bacterial cell. Itaconate is an abundant host metabolite thought to be both an antimicrobial agent and a modulator of the host inflammatory response. However, the exact mode of action of itaconate remains unclear. Here, we show that Mtb has an itaconate dissimilation pathway and that the last enzyme in this pathway, Rv2498c, also participates in l-leucine catabolism. Our results from phylogenetic analysis, in vitro enzymatic assays, X-ray crystallography, and in vivo Mtb experiments, identified Mtb Rv2498c as a bifunctional β-hydroxyacyl-CoA lyase and that deletion of the rv2498c gene from the Mtb genome resulted in attenuation in a mouse infection model. Altogether, this report describes an itaconate resistance mechanism in Mtb and an l-leucine catabolic pathway that proceeds via an unprecedented (R)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) stereospecific route in nature.
- Authors:
-
- Francis Crick Institute (United Kingdom)
- Albert Einstein College of Medicine, Bronx, NY (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1557314
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 116; Journal Issue: 32; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; biological sciences; biochemistry; enzyme function; carbon-carbon bond lyase; mycobacterium tuberculosis; itaconate catabolism; leucine catabolism
Citation Formats
Wang, Hua, Fedorov, Alexander A., Fedorov, Elena V., Hunt, Debbie M., Rodgers, Angela, Douglas, Holly L., Garza-Garcia, Acely, Bonanno, Jeffrey B., Almo, Steven C., and de Carvalho, Luiz Sório. An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism. United States: N. p., 2019.
Web. doi:10.1073/pnas.1906606116.
Wang, Hua, Fedorov, Alexander A., Fedorov, Elena V., Hunt, Debbie M., Rodgers, Angela, Douglas, Holly L., Garza-Garcia, Acely, Bonanno, Jeffrey B., Almo, Steven C., & de Carvalho, Luiz Sório. An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism. United States. https://doi.org/10.1073/pnas.1906606116
Wang, Hua, Fedorov, Alexander A., Fedorov, Elena V., Hunt, Debbie M., Rodgers, Angela, Douglas, Holly L., Garza-Garcia, Acely, Bonanno, Jeffrey B., Almo, Steven C., and de Carvalho, Luiz Sório. Thu .
"An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism". United States. https://doi.org/10.1073/pnas.1906606116. https://www.osti.gov/servlets/purl/1557314.
@article{osti_1557314,
title = {An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism},
author = {Wang, Hua and Fedorov, Alexander A. and Fedorov, Elena V. and Hunt, Debbie M. and Rodgers, Angela and Douglas, Holly L. and Garza-Garcia, Acely and Bonanno, Jeffrey B. and Almo, Steven C. and de Carvalho, Luiz Sório},
abstractNote = {Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis. One-fourth of the global population is estimated to be infected with Mtb, accounting for ~1.3 million deaths in 2017. As part of the immune response to Mtb infection, macrophages produce metabolites with the purpose of inhibiting or killing the bacterial cell. Itaconate is an abundant host metabolite thought to be both an antimicrobial agent and a modulator of the host inflammatory response. However, the exact mode of action of itaconate remains unclear. Here, we show that Mtb has an itaconate dissimilation pathway and that the last enzyme in this pathway, Rv2498c, also participates in l-leucine catabolism. Our results from phylogenetic analysis, in vitro enzymatic assays, X-ray crystallography, and in vivo Mtb experiments, identified Mtb Rv2498c as a bifunctional β-hydroxyacyl-CoA lyase and that deletion of the rv2498c gene from the Mtb genome resulted in attenuation in a mouse infection model. Altogether, this report describes an itaconate resistance mechanism in Mtb and an l-leucine catabolic pathway that proceeds via an unprecedented (R)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) stereospecific route in nature.},
doi = {10.1073/pnas.1906606116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 32,
volume = 116,
place = {United States},
year = {Thu Jul 18 00:00:00 EDT 2019},
month = {Thu Jul 18 00:00:00 EDT 2019}
}
Web of Science
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Works referencing / citing this record:
Crystal structure of cis -aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis
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