| Structural highlights
Function
DPRE2_MYCTU Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans (PubMed:16291675, PubMed:19299584). DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX) (PubMed:22733761). The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex (PubMed:25789990). DprE2 then catalyzes the second step of epimerization, the NAD(+)-dependent reduction of DPX that leads to the formation of DPA (PubMed:22733761, PubMed:25789990). Appears to be essential for the growth and survival of M.tuberculosis (PubMed:12657046, PubMed:24517327).[1] [2] [3] [4] [5] [6]
References
- ↑ Sassetti CM, Boyd DH, Rubin EJ. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 2003 Apr;48(1):77-84. doi: 10.1046/j.1365-2958.2003.03425.x. PMID:12657046 doi:https://dx.doi.org/10.1046/j.1365-2958.2003.03425.x
- ↑ Mikusova K, Huang H, Yagi T, Holsters M, Vereecke D, D'Haeze W, Scherman MS, Brennan PJ, McNeil MR, Crick DC. Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl residues of mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J Bacteriol. 2005 Dec;187(23):8020-5. PMID:16291675 doi:https://dx.doi.org/10.1128/JB.187.23.8020-8025.2005
- ↑ Makarov V, Manina G, Mikusova K, Mollmann U, Ryabova O, Saint-Joanis B, Dhar N, Pasca MR, Buroni S, Lucarelli AP, Milano A, De Rossi E, Belanova M, Bobovska A, Dianiskova P, Kordulakova J, Sala C, Fullam E, Schneider P, McKinney JD, Brodin P, Christophe T, Waddell S, Butcher P, Albrethsen J, Rosenkrands I, Brosch R, Nandi V, Bharath S, Gaonkar S, Shandil RK, Balasubramanian V, Balganesh T, Tyagi S, Grosset J, Riccardi G, Cole ST. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science. 2009 May 8;324(5928):801-4. doi: 10.1126/science.1171583. Epub 2009 Mar , 19. PMID:19299584 doi:https://dx.doi.org/10.1126/science.1171583
- ↑ Batt SM, Jabeen T, Bhowruth V, Quill L, Lund PA, Eggeling L, Alderwick LJ, Futterer K, Besra GS. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11354-9. Epub 2012 Jun 25. PMID:22733761 doi:https://dx.doi.org/10.1073/pnas.1205735109
- ↑ Kolly GS, Boldrin F, Sala C, Dhar N, Hartkoorn RC, Ventura M, Serafini A, McKinney JD, Manganelli R, Cole ST. Assessing the essentiality of the decaprenyl-phospho-d-arabinofuranose pathway in Mycobacterium tuberculosis using conditional mutants. Mol Microbiol. 2014 Apr;92(1):194-211. doi: 10.1111/mmi.12546. Epub 2014 Mar 7. PMID:24517327 doi:https://dx.doi.org/10.1111/mmi.12546
- ↑ Bhutani I, Loharch S, Gupta P, Madathil R, Parkesh R. Structure, dynamics, and interaction of Mycobacterium tuberculosis (Mtb) DprE1 and DprE2 examined by molecular modeling, simulation, and electrostatic studies. PLoS One. 2015 Mar 19;10(3):e0119771. doi: 10.1371/journal.pone.0119771. , eCollection 2015. PMID:25789990 doi:https://dx.doi.org/10.1371/journal.pone.0119771
|
