Abstract
Although small molecules shed from pathogens are widely used to diagnose infection, such tests have not been widely implemented for tuberculosis. Here we show that the recently identified compound, 1-tuberculosinyladenosine (1-TbAd), accumulates to comprise >1% of all Mycobacterium tuberculosis lipid. In vitro and in vivo, two isomers of TbAd were detected that might serve as infection markers. Using mass spectrometry and nuclear magnetic resonance, we established the structure of the previously unknown molecule, N6-tuberculosinyladenosine (N6-TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N6-TbAd via the Dimroth rearrangement. Intact biosynthetic genes are observed only within M. tuberculosis complex bacteria, and TbAd was not detected among other medically important pathogens, environmental bacteria, and vaccine strains. With no substantially similar known molecules in nature, the discovery and in vivo detection of two abundant terpene nucleosides support their development as specific diagnostic markers of tuberculosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 516-526 |
| Number of pages | 11 |
| Journal | Chemistry and Biology |
| Volume | 22 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 23 2015 |
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ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Molecular Biology
- Clinical Biochemistry
- Molecular Medicine
- Pharmacology
Cite this
In vivo biosynthesis of terpene nucleosides provides unique chemical markers of mycobacterium tuberculosis infection. / Young, David C.; Layre, Emilie; Pan, Shih Jung; Tapley, Asa; Adamson, John; Seshadri, Chetan; Wu, Zhongtao; Buter, Jeffrey; Minnaard, Adriaan J.; Coscolla, Mireia; Gagneux, Sebastien; Copin, Richard; Ernst, Joel D.; Bishai, William Ramses; Snider, Barry B.; Moody, D. Branch.
In: Chemistry and Biology, Vol. 22, No. 4, 23.04.2015, p. 516-526.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In vivo biosynthesis of terpene nucleosides provides unique chemical markers of mycobacterium tuberculosis infection
AU - Young, David C.
AU - Layre, Emilie
AU - Pan, Shih Jung
AU - Tapley, Asa
AU - Adamson, John
AU - Seshadri, Chetan
AU - Wu, Zhongtao
AU - Buter, Jeffrey
AU - Minnaard, Adriaan J.
AU - Coscolla, Mireia
AU - Gagneux, Sebastien
AU - Copin, Richard
AU - Ernst, Joel D.
AU - Bishai, William Ramses
AU - Snider, Barry B.
AU - Moody, D. Branch
PY - 2015/4/23
Y1 - 2015/4/23
N2 - Although small molecules shed from pathogens are widely used to diagnose infection, such tests have not been widely implemented for tuberculosis. Here we show that the recently identified compound, 1-tuberculosinyladenosine (1-TbAd), accumulates to comprise >1% of all Mycobacterium tuberculosis lipid. In vitro and in vivo, two isomers of TbAd were detected that might serve as infection markers. Using mass spectrometry and nuclear magnetic resonance, we established the structure of the previously unknown molecule, N6-tuberculosinyladenosine (N6-TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N6-TbAd via the Dimroth rearrangement. Intact biosynthetic genes are observed only within M. tuberculosis complex bacteria, and TbAd was not detected among other medically important pathogens, environmental bacteria, and vaccine strains. With no substantially similar known molecules in nature, the discovery and in vivo detection of two abundant terpene nucleosides support their development as specific diagnostic markers of tuberculosis.
AB - Although small molecules shed from pathogens are widely used to diagnose infection, such tests have not been widely implemented for tuberculosis. Here we show that the recently identified compound, 1-tuberculosinyladenosine (1-TbAd), accumulates to comprise >1% of all Mycobacterium tuberculosis lipid. In vitro and in vivo, two isomers of TbAd were detected that might serve as infection markers. Using mass spectrometry and nuclear magnetic resonance, we established the structure of the previously unknown molecule, N6-tuberculosinyladenosine (N6-TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N6-TbAd via the Dimroth rearrangement. Intact biosynthetic genes are observed only within M. tuberculosis complex bacteria, and TbAd was not detected among other medically important pathogens, environmental bacteria, and vaccine strains. With no substantially similar known molecules in nature, the discovery and in vivo detection of two abundant terpene nucleosides support their development as specific diagnostic markers of tuberculosis.
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U2 - 10.1016/j.chembiol.2015.03.015
DO - 10.1016/j.chembiol.2015.03.015
M3 - Article
VL - 22
SP - 516
EP - 526
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 4
ER -