ArticleProceedings of the National Academy of Sciences of the United States of America2014
Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 92 citations in OpenAlex.
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- Untargeted and Targeted Liquid Chromatography-Mass Spectrometry-Based Lipidomic Profiling Revealed a Potential Biomarker Panel to Distinguish Clinical Isolates of M. tuberculosis From Nontuberculous M. kansasii.Pulmonary medicine · 2026Article
- Mapping unsolved lipidomes accelerates lipid discovery in major bacterial pathogens.bioRxiv : the preprint server for biology · 2025Article
- Stable Isotopic Labeling of Dimethylallyl Pyrophosphate (DMAPP) Reveals Compartmentalization of Isoprenoid Biosynthesis during Sporulation inJournal of the American Chemical Society · 2025Article
- Unraveling Mycobacterium tuberculosis acid resistance and pH homeostasis mechanisms.FEBS letters · 2025Review
- Mycobacterium tuberculosis curli pili (MTP) and heparin-binding hemagglutinin adhesin (HBHA) facilitate regulation of central carbon metabolism, enhancement of ATP synthesis and cell wall biosynthesis.Archives of microbiology · 2025Article
- Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides.PLoS biology · 2024Article
- Actinomycetes as Producers of Biologically Active Terpenoids: Current Trends and Patents.Pharmaceuticals (Basel, Switzerland) · 2023Review
- A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.The Journal of clinical investigation · 2023Article
- The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages into storing lipids.The Journal of clinical investigation · 2023Article
- Impaired macrophage and memory T-cell responses to Bacillus Calmette-Guerin nonpolar lipid extract.Frontiers in immunology · 2023Article
- A Mycobacterium tuberculosis fingerprint in human breath allows tuberculosis detection.Nature communications · 2022Article
- Structure-guided product determination of the bacterial type II diterpene synthase Tpn2.Communications chemistry · 2022Article
- Investigation of Acid-Base Catalysis in Halimadienyl Diphosphate Synthase Involved inACS bio & med chem Au · 2022Article
- Inhibition of the Niemann-Pick C1 protein is a conserved feature of multiple strains of pathogenic mycobacteria.Nature communications · 2022Article
- A reversed phase ultra-high-performance liquid chromatography-data independent mass spectrometry method for the rapid identification of mycobacterial lipids.Journal of chromatography. A · 2022Article
- Chemical Synthesis of Cell Wall Constituents ofChemical reviews · 2021Review
- Bacterial terpenome.Natural product reports · 2021Review
- Bacterial diterpene synthases prenylate small molecules.ACS catalysis · 2021Article
- T Cells Specific for a Mycobacterial Glycolipid Expand after Intravenous Bacillus Calmette-Guérin Vaccination.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
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-Guérin. 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-tuberculosinyladenosine (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.
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