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 R. Bishai; Barry B. Snider; D. Branch Moody

doi:10.1016/j.chembiol.2015.03.015

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 R. Bishai, Barry B. Snider, D. Branch Moody

Johns Hopkins Hospital

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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	https://doi.org/10.1016/j.chembiol.2015.03.015
State	Published - Apr 23 2015

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

Access to Document

10.1016/j.chembiol.2015.03.015

Cite this

Young, D. C., Layre, E., Pan, S. J., Tapley, A., Adamson, J., Seshadri, C., Wu, Z., Buter, J., Minnaard, A. J., Coscolla, M., Gagneux, S., Copin, R., Ernst, J. D., Bishai, W. R., Snider, B. B., & Moody, D. B. (2015). In vivo biosynthesis of terpene nucleosides provides unique chemical markers of mycobacterium tuberculosis infection. Chemistry and Biology, 22(4), 516-526. https://doi.org/10.1016/j.chembiol.2015.03.015

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

@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 R.} and Snider, {Barry B.} and Moody, {D. Branch}",

year = "2015",

month = apr,

day = "23",

doi = "10.1016/j.chembiol.2015.03.015",

language = "English (US)",

volume = "22",

pages = "516--526",

journal = "Chemistry and Biology",

issn = "1074-5521",

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 R.

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

C2 - 25910243

AN - SCOPUS:84928398396

SN - 1074-5521

VL - 22

SP - 516

EP - 526

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 4

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this