| Structural highlights
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
We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis , a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here.
Structure and Inhibition of Tuberculosinol Synthase and Decaprenyl Diphosphate Synthase from Mycobacterium tuberculosis.,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 J Am Chem Soc. 2014 Feb 5. PMID:24475925[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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:https://dx.doi.org/10.1271/bbb.100570
- ↑ 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:https://dx.doi.org/10.1039/c0ob00884b
- ↑ 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:https://dx.doi.org/10.1021/ja413127v
- ↑ 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:https://dx.doi.org/10.1073/pnas.1315883111
- ↑ 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:https://dx.doi.org/10.1038/s41589-019-0336-0
- ↑ 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:https://dx.doi.org/10.1021/ja413127v
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