In vivo biosynthesis of terpene nucleosides provides unique chemical markers of mycobacterium tuberculosis infection

David C. Young, Emilie Layre, Shih Jung Pan, Asa Tapley, John Adamson, Chetan Seshadri, Zhongtao Wu, Jeffrey Buter, Adriaan J. Minnaard, Mireia Coscolla, Sebastien Gagneux, Richard Copin, Joel D. Ernst, William Ramses Bishai, Barry B. Snider, D. Branch Moody

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)516-526
Number of pages11
JournalChemistry and Biology
Volume22
Issue number4
DOIs
StatePublished - Apr 23 2015

Fingerprint

Mycobacterium Infections
Biosynthesis
Terpenes
Mycobacterium tuberculosis
Nucleosides
Tuberculosis
Pathogens
Bacteria
Molecules
Infection
Mass Spectrometry
Magnetic Resonance Spectroscopy
Vaccines
Lipids
Isomers
Mass spectrometry
Genes
Nuclear magnetic resonance
1-tuberculosinyladenosine
In Vitro Techniques

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 journalArticle

Young, DC, Layre, E, Pan, SJ, Tapley, A, Adamson, J, Seshadri, C, Wu, Z, Buter, J, Minnaard, AJ, Coscolla, M, Gagneux, S, Copin, R, Ernst, JD, Bishai, WR, Snider, BB & Moody, DB 2015, 'In vivo biosynthesis of terpene nucleosides provides unique chemical markers of mycobacterium tuberculosis infection', Chemistry and Biology, vol. 22, no. 4, pp. 516-526. https://doi.org/10.1016/j.chembiol.2015.03.015
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 vivo biosynthesis of terpene nucleosides provides unique chemical markers of mycobacterium tuberculosis infection. In: Chemistry and Biology. 2015 ; Vol. 22, No. 4. pp. 516-526.
@article{12d96c8387424118969ab46b7e44ee16,
title = "In vivo biosynthesis of terpene nucleosides provides unique chemical markers of mycobacterium tuberculosis infection",
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.",
author = "Young, {David C.} and Emilie Layre and Pan, {Shih Jung} and Asa Tapley and John Adamson and Chetan Seshadri and Zhongtao Wu and Jeffrey Buter and Minnaard, {Adriaan J.} and Mireia Coscolla and Sebastien Gagneux and Richard Copin and Ernst, {Joel D.} and Bishai, {William Ramses} and Snider, {Barry B.} and Moody, {D. Branch}",
year = "2015",
month = "4",
day = "23",
doi = "10.1016/j.chembiol.2015.03.015",
language = "English (US)",
volume = "22",
pages = "516--526",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "4",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84928398396&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928398396&partnerID=8YFLogxK

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 -