Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides.
Mycobacterium tuberculosis (Mtb) releases the unusual terpene nucleoside 1-tuberculosinyladenosine (1-TbAd) to block lysosomal function and promote survival in human macrophages. Using conventional approaches, we found that genes Rv3377c and Rv3378c, but not Rv3376, were necessary for 1-TbAd biosynt...
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Public Library of Science (PLoS)
2024-09-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3002813 |
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| author | Jacob A Mayfield Sahadevan Raman Alexandrea K Ramnarine Vivek K Mishra Annie D Huang Sandrine Dudoit Jeffrey Buter Tan-Yun Cheng David C Young Yashodhan M Nair Isobel G Ouellet Braden T Griebel Shuyi Ma David R Sherman Ludovic Mallet Kyu Y Rhee Adriaan J Minnaard D Branch Moody |
| author_facet | Jacob A Mayfield Sahadevan Raman Alexandrea K Ramnarine Vivek K Mishra Annie D Huang Sandrine Dudoit Jeffrey Buter Tan-Yun Cheng David C Young Yashodhan M Nair Isobel G Ouellet Braden T Griebel Shuyi Ma David R Sherman Ludovic Mallet Kyu Y Rhee Adriaan J Minnaard D Branch Moody |
| author_sort | Jacob A Mayfield |
| collection | DOAJ |
| description | Mycobacterium tuberculosis (Mtb) releases the unusual terpene nucleoside 1-tuberculosinyladenosine (1-TbAd) to block lysosomal function and promote survival in human macrophages. Using conventional approaches, we found that genes Rv3377c and Rv3378c, but not Rv3376, were necessary for 1-TbAd biosynthesis. Here, we introduce linear models for mass spectrometry (limms) software as a next-generation lipidomics tool to study the essential functions of lipid biosynthetic enzymes on a whole-cell basis. Using limms, whole-cell lipid profiles deepened the phenotypic landscape of comparative mass spectrometry experiments and identified a large family of approximately 100 terpene nucleoside metabolites downstream of Rv3378c. We validated the identity of previously unknown adenine-, adenosine-, and lipid-modified tuberculosinol-containing molecules using synthetic chemistry and collisional mass spectrometry, including comprehensive profiling of bacterial lipids that fragment to adenine. We tracked terpene nucleoside genotypes and lipid phenotypes among Mycobacterium tuberculosis complex (MTC) species that did or did not evolve to productively infect either human or nonhuman mammals. Although 1-TbAd biosynthesis genes were thought to be restricted to the MTC, we identified the locus in unexpected species outside the MTC. Sequence analysis of the locus showed nucleotide usage characteristic of plasmids from plant-associated bacteria, clarifying the origin and timing of horizontal gene transfer to a pre-MTC progenitor. The data demonstrated correlation between high level terpene nucleoside biosynthesis and mycobacterial competence for human infection, and 2 mechanisms of 1-TbAd biosynthesis loss. Overall, the selective gain and evolutionary retention of tuberculosinyl metabolites in modern species that cause human TB suggest a role in human TB disease, and the newly discovered molecules represent candidate disease-specific biomarkers. |
| format | Article |
| id | doaj-art-ebb47c13ec454405ad6a796ddd4a62ef |
| institution | DOAJ |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Biology |
| spelling | doaj-art-ebb47c13ec454405ad6a796ddd4a62ef2025-08-20T02:46:54ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852024-09-01229e300281310.1371/journal.pbio.3002813Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides.Jacob A MayfieldSahadevan RamanAlexandrea K RamnarineVivek K MishraAnnie D HuangSandrine DudoitJeffrey ButerTan-Yun ChengDavid C YoungYashodhan M NairIsobel G OuelletBraden T GriebelShuyi MaDavid R ShermanLudovic MalletKyu Y RheeAdriaan J MinnaardD Branch MoodyMycobacterium tuberculosis (Mtb) releases the unusual terpene nucleoside 1-tuberculosinyladenosine (1-TbAd) to block lysosomal function and promote survival in human macrophages. Using conventional approaches, we found that genes Rv3377c and Rv3378c, but not Rv3376, were necessary for 1-TbAd biosynthesis. Here, we introduce linear models for mass spectrometry (limms) software as a next-generation lipidomics tool to study the essential functions of lipid biosynthetic enzymes on a whole-cell basis. Using limms, whole-cell lipid profiles deepened the phenotypic landscape of comparative mass spectrometry experiments and identified a large family of approximately 100 terpene nucleoside metabolites downstream of Rv3378c. We validated the identity of previously unknown adenine-, adenosine-, and lipid-modified tuberculosinol-containing molecules using synthetic chemistry and collisional mass spectrometry, including comprehensive profiling of bacterial lipids that fragment to adenine. We tracked terpene nucleoside genotypes and lipid phenotypes among Mycobacterium tuberculosis complex (MTC) species that did or did not evolve to productively infect either human or nonhuman mammals. Although 1-TbAd biosynthesis genes were thought to be restricted to the MTC, we identified the locus in unexpected species outside the MTC. Sequence analysis of the locus showed nucleotide usage characteristic of plasmids from plant-associated bacteria, clarifying the origin and timing of horizontal gene transfer to a pre-MTC progenitor. The data demonstrated correlation between high level terpene nucleoside biosynthesis and mycobacterial competence for human infection, and 2 mechanisms of 1-TbAd biosynthesis loss. Overall, the selective gain and evolutionary retention of tuberculosinyl metabolites in modern species that cause human TB suggest a role in human TB disease, and the newly discovered molecules represent candidate disease-specific biomarkers.https://doi.org/10.1371/journal.pbio.3002813 |
| spellingShingle | Jacob A Mayfield Sahadevan Raman Alexandrea K Ramnarine Vivek K Mishra Annie D Huang Sandrine Dudoit Jeffrey Buter Tan-Yun Cheng David C Young Yashodhan M Nair Isobel G Ouellet Braden T Griebel Shuyi Ma David R Sherman Ludovic Mallet Kyu Y Rhee Adriaan J Minnaard D Branch Moody Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides. PLoS Biology |
| title | Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides. |
| title_full | Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides. |
| title_fullStr | Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides. |
| title_full_unstemmed | Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides. |
| title_short | Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides. |
| title_sort | mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides |
| url | https://doi.org/10.1371/journal.pbio.3002813 |
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