4cmw

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Crystal structure of Rv3378c

Structural highlights

4cmw is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.209Å
Ligands:CIT, EDO, PEG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TUBAT_MYCTU Tuberculosinyl transferase that catalyzes the condensation of adenosine and tuberculosinyl diphosphate (TbPP) to generate 1-tuberculosinyladenosine (1-TbAd), which acts as an antiacid that directly protects M.tuberculosis from acid pH and physically remodels M.tuberculosis phagolysosomes (PubMed:24516143, PubMed:31427817). In addition, acts as a phosphatase that catalyzes the diphosphate-removal from TbPP to produce both tuberculosinol (TOH) and isotuberculosinol (iso-TOH) (PubMed:21228491, PubMed:24475925). Has broad substrate specificity, and can also use the 3 labdadienyl diphosphates, copalyl diphosphate (CDP), ent-CDP and syn-CDP in vitro (PubMed:21290071).[1] [2] [3] [4] [5]

Publication Abstract from PubMed

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-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.

Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c.,Layre E, Lee HJ, Young DC, Jezek Martinot A, Buter J, Minnaard AJ, Annand JW, Fortune SM, Snider BB, Matsunaga I, Rubin EJ, Alber T, Moody DB Proc Natl Acad Sci U S A. 2014 Feb 10. PMID:24516143[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Nakano C, Ootsuka T, Takayama K, Mitsui T, Sato T, Hoshino T. Characterization of the Rv3378c gene product, a new diterpene synthase for producing tuberculosinol and (13R, S)-isotuberculosinol (nosyberkol), from the Mycobacterium tuberculosis H37Rv genome. Biosci Biotechnol Biochem. 2011;75(1):75-81. doi: 10.1271/bbb.100570. Epub 2011, Jan 7. PMID:21228491 doi:http://dx.doi.org/10.1271/bbb.100570
  2. ↑ Hoshino T, Nakano C, Ootsuka T, Shinohara Y, Hara T. Substrate specificity of Rv3378c, an enzyme from Mycobacterium tuberculosis, and the inhibitory activity of the bicyclic diterpenoids against macrophage phagocytosis. Org Biomol Chem. 2011 Apr 7;9(7):2156-65. doi: 10.1039/c0ob00884b. Epub 2011 Feb , 3. PMID:21290071 doi:http://dx.doi.org/10.1039/c0ob00884b
  3. ↑ Chan HC, Feng X, Ko TP, Huang CH, Hu Y, Zheng Y, Bogue S, Nakano C, Hoshino T, Zhang L, Lv P, Liu W, Crick DC, Liang PH, Wang AH, Oldfield E, Guo RT. Structure and Inhibition of Tuberculosinol Synthase and Decaprenyl Diphosphate Synthase from Mycobacterium tuberculosis. J Am Chem Soc. 2014 Feb 5. PMID:24475925 doi:http://dx.doi.org/10.1021/ja413127v
  4. ↑ Layre E, Lee HJ, Young DC, Jezek Martinot A, Buter J, Minnaard AJ, Annand JW, Fortune SM, Snider BB, Matsunaga I, Rubin EJ, Alber T, Moody DB. Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c. Proc Natl Acad Sci U S A. 2014 Feb 10. PMID:24516143 doi:http://dx.doi.org/10.1073/pnas.1315883111
  5. ↑ Buter J, Cheng TY, Ghanem M, Grootemaat AE, Raman S, Feng X, Plantijn AR, Ennis T, Wang J, Cotton RN, Layre E, Ramnarine AK, Mayfield JA, Young DC, Jezek Martinot A, Siddiqi N, Wakabayashi S, Botella H, Calderon R, Murray M, Ehrt S, Snider BB, Reed MB, Oldfield E, Tan S, Rubin EJ, Behr MA, van der Wel NN, Minnaard AJ, Moody DB. Mycobacterium tuberculosis releases an antacid that remodels phagosomes. Nat Chem Biol. 2019 Sep;15(9):889-899. doi: 10.1038/s41589-019-0336-0. Epub 2019 , Aug 19. PMID:31427817 doi:http://dx.doi.org/10.1038/s41589-019-0336-0
  6. ↑ Layre E, Lee HJ, Young DC, Jezek Martinot A, Buter J, Minnaard AJ, Annand JW, Fortune SM, Snider BB, Matsunaga I, Rubin EJ, Alber T, Moody DB. Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c. Proc Natl Acad Sci U S A. 2014 Feb 10. PMID:24516143 doi:http://dx.doi.org/10.1073/pnas.1315883111

Contents


PDB ID 4cmw

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