dc.contributor.author | Layre, Emilie | |
dc.contributor.author | Lee, Ho Jun | |
dc.contributor.author | Young, David C. | |
dc.contributor.author | Martinot, Amanda Jezek | |
dc.contributor.author | Buter, Jeffrey | |
dc.contributor.author | Minnaard, Adriaan J. | |
dc.contributor.author | Annand, John W. | |
dc.contributor.author | Fortune, Sarah M. | |
dc.contributor.author | Snider, Barry B. | |
dc.contributor.author | Matsunaga, Isamu | |
dc.contributor.author | Rubin, Eric J. | |
dc.contributor.author | Alber, Tom | |
dc.contributor.author | Moody, D. Branch | |
dc.date.accessioned | 2019-10-15T18:22:14Z | |
dc.date.issued | 2014 | |
dc.identifier.citation | Layre, E., H. J. Lee, D. C. Young, A. Jezek Martinot, J. Buter, A. J. Minnaard, J. W. Annand, et al. 2014. “Molecular Profiling of Mycobacterium Tuberculosis Identifies Tuberculosinyl Nucleoside Products of the Virulence-Associated Enzyme Rv3378c.” Proceedings of the National Academy of Sciences 111 (8): 2978–83. https://doi.org/10.1073/pnas.1315883111. | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.issn | 0744-2831 | |
dc.identifier.issn | 1091-6490 | |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:41552031 | * |
dc.description.abstract | To identify lipids with roles in tuberculosis disease, we systematically compared the lipid content of virulent Mycobacterium tuberculosis with the attenuated vaccine strain Mycobacterium bovis bacillus Calmette-Guerin. Comparative lipidomics analysis identified more than 1,000 molecular differences, including a previously unknown, Mycobacterium tuberculosis-specific lipid that is composed of a diterpene unit linked to adenosine. We established the complete structure of the natural product as 1-tuberculosiny-ladenosine (1-TbAd) using mass spectrometry and NMR spectroscopy. A screen for 1-TbAd mutants, complementation studies, and gene transfer identified Rv3378c as necessary for 1-TbAd biosynthesis. Whereas Rv3378c was previously thought to function as a phosphatase, these studies establish its role as a tuberculosinyl transferase and suggest a revised biosynthetic pathway for the sequential action of Rv3377c-Rv3378c. In agreement with this model, recombinant Rv3378c protein produced 1-TbAd, and its crystal structure revealed a cis-prenyl transferase fold with hydrophobic residues for isoprenoid binding and a second binding pocket suitable for the nucleoside substrate. The dual-substrate pocket distinguishes Rv3378c from classical cis-prenyl transferases, providing a unique model for the prenylation of diverse metabolites. Terpene nucleosides are rare in nature, and 1-TbAd is known only in Mycobacterium tuberculosis. Thus, this intersection of nucleoside and terpene pathways likely arose late in the evolution of the Mycobacterium tuberculosis complex; 1-TbAd serves as an abundant chemical marker of Mycobacterium tuberculosis, and the extracellular export of this amphipathic molecule likely accounts for the known virulence-promoting effects of the Rv3378c enzyme. | |
dc.language.iso | en_US | |
dc.publisher | National Academy of Sciences | |
dash.license | LAA | |
dc.title | Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c | |
dc.type | Journal Article | |
dc.description.version | Version of Record | |
dc.relation.journal | Proceedings of the National Academy of Sciences of the United States of America | |
dash.depositing.author | Rubin, Eric J.::2ccf3691d766f02c048797e00c06cc44::600 | |
dc.date.available | 2019-10-15T18:22:14Z | |
dash.workflow.comments | 1Science Serial ID 91184 | |
dc.identifier.doi | 10.1073/pnas.1315883111 | |
dash.source.volume | 111;8 | |
dash.source.page | 2978 | |