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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 15907-15913 |
| Number of pages | 7 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 116 |
| Issue number | 32 |
| DOIs | |
| State | Published - Aug 6 2019 |
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Keywords
- Carbon–carbon bond lyase
- Enzyme function
- Itaconate catabolism
- Leucine catabolism
- Mycobacterium
- Tuberculosis
ASJC Scopus subject areas
- General
Cite this
An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism. / 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 Pedro Sório.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 32, 06.08.2019, p. 15907-15913.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism
AU - Wang, Hua
AU - Fedorov, Alexander A.
AU - Fedorov, Elena V.
AU - Hunt, Debbie M.
AU - Rodgers, Angela
AU - Douglas, Holly L.
AU - Garza-Garcia, Acely
AU - Bonanno, Jeffrey B.
AU - Almo, Steven C.
AU - de Carvalho, Luiz Pedro Sório
PY - 2019/8/6
Y1 - 2019/8/6
N2 - 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.
AB - 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.
KW - Carbon–carbon bond lyase
KW - Enzyme function
KW - Itaconate catabolism
KW - Leucine catabolism
KW - Mycobacterium
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85070207022&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070207022&partnerID=8YFLogxK
U2 - 10.1073/pnas.1906606116
DO - 10.1073/pnas.1906606116
M3 - Article
C2 - 31320588
AN - SCOPUS:85070207022
VL - 116
SP - 15907
EP - 15913
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 32
ER -