Academic Journal
Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c
| العنوان: | Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c |
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| المؤلفون: | Layre, Emilie, Lee, Ho Jun, Young, David C., Martinot, Amanda Jezek, Buter, Jeffrey, Minnaard, Adriaan J., Annand, John W., Fortune, Sarah M., Snider, Barry B., Matsunaga, Isamu, Rubin, Eric J., Alber, Tom, Moody, D. Branch |
| المصدر: | Layre , E , Lee , H J , Young , D C , Martinot , A J , Buter , J , Minnaard , A J , Annand , J W , Fortune , S M , Snider , B B , Matsunaga , I , Rubin , E J , Alber , T & Moody , D B 2014 , ' Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 111 , no. 8 , .... |
| سنة النشر: | 2014 |
| المجموعة: | University of Groningen research database |
| مصطلحات موضوعية: | TbAd, terpenyl transferase, UNDECAPRENYL PYROPHOSPHATE SYNTHASE, DITERPENE CYCLASE, PHAGOSOME MATURATION, BIOSYNTHESIS, GENOME, C-35-TERPENE, PROTEINS, ANALOGS, MMPL8, BCG |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1073/pnas.1315883111 |
| الاتاحة: | https://hdl.handle.net/11370/5775a801-6093-432a-8b07-a49f6bd5e1ae https://research.rug.nl/en/publications/5775a801-6093-432a-8b07-a49f6bd5e1ae https://doi.org/10.1073/pnas.1315883111 |
| Rights: | info:eu-repo/semantics/closedAccess |
| رقم الانضمام: | edsbas.5082DADA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1073/pnas.1315883111 |
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