DPRE1_MYCTU
ID DPRE1_MYCTU Reviewed; 461 AA.
AC P9WJF1; L0TDT1; P72056; Q7D4V3;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 60.
DE RecName: Full=Decaprenylphosphoryl-beta-D-ribose oxidase {ECO:0000303|PubMed:19299584, ECO:0000303|PubMed:25427196, ECO:0000303|PubMed:25789990};
DE EC=1.1.98.3 {ECO:0000269|PubMed:22733761};
DE AltName: Full=Decaprenylphospho-beta-D-ribofuranose 2-dehydrogenase {ECO:0000303|PubMed:20828197};
DE AltName: Full=Decaprenylphosphoryl-beta-D-ribofuranose 2'-epimerase subunit DprE1 {ECO:0000305|PubMed:25789990};
DE Short=Decaprenyl-phosphoribose 2'-epimerase subunit 1 {ECO:0000305|PubMed:25789990};
DE AltName: Full=Decaprenylphosphoryl-beta-D-ribofuranose 2'-oxidase {ECO:0000305};
DE AltName: Full=Decaprenylphosphoryl-beta-D-ribose 2-epimerase flavoprotein subunit {ECO:0000303|PubMed:24500695};
DE AltName: Full=FAD-dependent decaprenylphosphoryl-beta-D-ribofuranose 2-oxidase {ECO:0000303|PubMed:20828197};
GN Name=dprE1 {ECO:0000303|PubMed:19299584, ECO:0000303|PubMed:20828197};
GN OrderedLocusNames=Rv3790;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=12657046; DOI=10.1046/j.1365-2958.2003.03425.x;
RA Sassetti C.M., Boyd D.H., Rubin E.J.;
RT "Genes required for mycobacterial growth defined by high density
RT mutagenesis.";
RL Mol. Microbiol. 48:77-84(2003).
RN [3]
RP FUNCTION IN DPR EPIMERIZATION, AND PATHWAY.
RC STRAIN=H37Rv;
RX PubMed=16291675; DOI=10.1128/jb.187.23.8020-8025.2005;
RA Mikusova K., Huang H., Yagi T., Holsters M., Vereecke D., D'Haeze W.,
RA Scherman M.S., Brennan P.J., McNeil M.R., Crick D.C.;
RT "Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl
RT residues of mycobacterial arabinan, is formed via a two-step epimerization
RT of decaprenylphosphoryl ribose.";
RL J. Bacteriol. 187:8020-8025(2005).
RN [4]
RP IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [5]
RP ACTIVITY REGULATION, AND INHIBITOR SCREENING.
RC STRAIN=H37Rv;
RX PubMed=19876393; DOI=10.1371/journal.ppat.1000645;
RA Christophe T., Jackson M., Jeon H.K., Fenistein D., Contreras-Dominguez M.,
RA Kim J., Genovesio A., Carralot J.P., Ewann F., Kim E.H., Lee S.Y., Kang S.,
RA Seo M.J., Park E.J., Skovierova H., Pham H., Riccardi G., Nam J.Y.,
RA Marsollier L., Kempf M., Joly-Guillou M.L., Oh T., Shin W.K., No Z.,
RA Nehrbass U., Brosch R., Cole S.T., Brodin P.;
RT "High content screening identifies decaprenyl-phosphoribose 2' epimerase as
RT a target for intracellular antimycobacterial inhibitors.";
RL PLoS Pathog. 5:E1000645-E1000645(2009).
RN [6]
RP FUNCTION IN DPR EPIMERIZATION, ACTIVITY REGULATION, DRUG TARGET, AND
RP BTZ043-RESISTANT VARIANTS NTB1 AND NTB9.
RC STRAIN=H37Rv;
RX PubMed=19299584; DOI=10.1126/science.1171583;
RA Makarov V., Manina G., Mikusova K., Mollmann U., Ryabova O.,
RA Saint-Joanis B., Dhar N., Pasca M.R., Buroni S., Lucarelli A.P., Milano A.,
RA De Rossi E., Belanova M., Bobovska A., Dianiskova P., Kordulakova J.,
RA Sala C., Fullam E., Schneider P., McKinney J.D., Brodin P., Christophe T.,
RA Waddell S., Butcher P., Albrethsen J., Rosenkrands I., Brosch R., Nandi V.,
RA Bharath S., Gaonkar S., Shandil R.K., Balasubramanian V., Balganesh T.,
RA Tyagi S., Grosset J., Riccardi G., Cole S.T.;
RT "Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan
RT synthesis.";
RL Science 324:801-804(2009).
RN [7]
RP REVIEW, AND DRUG TARGET.
RX PubMed=20629622; DOI=10.2174/092986710791959693;
RA Manina G., Pasca M.R., Buroni S., De Rossi E., Riccardi G.;
RT "Decaprenylphosphoryl-beta-D-ribose 2'-epimerase from Mycobacterium
RT tuberculosis is a magic drug target.";
RL Curr. Med. Chem. 17:3099-3108(2010).
RN [8]
RP ACTIVITY REGULATION, MECHANISM OF ACTION OF BENZOTHIAZINONES, MUTAGENESIS
RP OF CYS-387, AND 3D-STRUCTURE MODELING.
RX PubMed=20828197; DOI=10.1021/ja106357w;
RA Trefzer C., Rengifo-Gonzalez M., Hinner M.J., Schneider P., Makarov V.,
RA Cole S.T., Johnsson K.;
RT "Benzothiazinones: prodrugs that covalently modify the
RT decaprenylphosphoryl-beta-D-ribose 2'-epimerase DprE1 of Mycobacterium
RT tuberculosis.";
RL J. Am. Chem. Soc. 132:13663-13665(2010).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [10]
RP REVIEW, AND DRUG TARGET.
RX PubMed=24037308; DOI=10.1007/s00253-013-5218-x;
RA Riccardi G., Pasca M.R., Chiarelli L.R., Manina G., Mattevi A., Binda C.;
RT "The DprE1 enzyme, one of the most vulnerable targets of Mycobacterium
RT tuberculosis.";
RL Appl. Microbiol. Biotechnol. 97:8841-8848(2013).
RN [11]
RP ACTIVITY REGULATION.
RX PubMed=24215368; DOI=10.1021/jm401382v;
RA Shirude P.S., Shandil R., Sadler C., Naik M., Hosagrahara V., Hameed S.,
RA Shinde V., Bathula C., Humnabadkar V., Kumar N., Reddy J., Panduga V.,
RA Sharma S., Ambady A., Hegde N., Whiteaker J., McLaughlin R.E., Gardner H.,
RA Madhavapeddi P., Ramachandran V., Kaur P., Narayan A., Guptha S.,
RA Awasthy D., Narayan C., Mahadevaswamy J., Vishwas K.G., Ahuja V.,
RA Srivastava A., Prabhakar K.R., Bharath S., Kale R., Ramaiah M.,
RA Choudhury N.R., Sambandamurthy V.K., Solapure S., Iyer P.S., Narayanan S.,
RA Chatterji M.;
RT "Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts,
RT kill Mycobacterium tuberculosis and are efficacious in vivo.";
RL J. Med. Chem. 56:9701-9708(2013).
RN [12]
RP REVIEW, AND DRUG TARGET.
RX PubMed=24245764; DOI=10.2174/138161282027140630122724;
RA Mikusova K., Makarov V., Neres J.;
RT "DprE1--from the discovery to the promising tuberculosis drug target.";
RL Curr. Pharm. Des. 20:4379-4403(2014).
RN [13]
RP ACTIVITY REGULATION.
RX PubMed=24818517; DOI=10.1021/jm5002937;
RA Panda M., Ramachandran S., Ramachandran V., Shirude P.S., Humnabadkar V.,
RA Nagalapur K., Sharma S., Kaur P., Guptha S., Narayan A., Mahadevaswamy J.,
RA Ambady A., Hegde N., Rudrapatna S.S., Hosagrahara V.P.,
RA Sambandamurthy V.K., Raichurkar A.;
RT "Discovery of pyrazolopyridones as a novel class of noncovalent DprE1
RT inhibitor with potent anti-mycobacterial activity.";
RL J. Med. Chem. 57:4761-4771(2014).
RN [14]
RP DISRUPTION PHENOTYPE, AND PATHWAY.
RC STRAIN=H37Rv;
RX PubMed=24517327; DOI=10.1111/mmi.12546;
RA Kolly G.S., Boldrin F., Sala C., Dhar N., Hartkoorn R.C., Ventura M.,
RA Serafini A., McKinney J.D., Manganelli R., Cole S.T.;
RT "Assessing the essentiality of the decaprenyl-phospho-D-arabinofuranose
RT pathway in Mycobacterium tuberculosis using conditional mutants.";
RL Mol. Microbiol. 92:194-211(2014).
RN [15]
RP SUBCELLULAR LOCATION.
RC STRAIN=H37Rv;
RX PubMed=25906160; DOI=10.1021/acschembio.5b00237;
RA Brecik M., Centarova I., Mukherjee R., Kolly G.S., Huszar S., Bobovska A.,
RA Kilacskova E., Mokosova V., Svetlikova Z., Sarkan M., Neres J.,
RA Kordulakova J., Cole S.T., Mikusova K.;
RT "DprE1 is a vulnerable tuberculosis drug target due to its cell wall
RT localization.";
RL ACS Chem. Biol. 10:1631-1636(2015).
RN [16]
RP ACTIVITY REGULATION.
RC STRAIN=H37Rv;
RX PubMed=25987616; DOI=10.1128/aac.00778-15;
RA Makarov V., Neres J., Hartkoorn R.C., Ryabova O.B., Kazakova E., Sarkan M.,
RA Huszar S., Piton J., Kolly G.S., Vocat A., Conroy T.M., Mikusova K.,
RA Cole S.T.;
RT "The 8-pyrrole-benzothiazinones are noncovalent inhibitors of DprE1 from
RT Mycobacterium tuberculosis.";
RL Antimicrob. Agents Chemother. 59:4446-4452(2015).
RN [17]
RP INTERACTION WITH DPRE2.
RX PubMed=25789990; DOI=10.1371/journal.pone.0119771;
RA Bhutani I., Loharch S., Gupta P., Madathil R., Parkesh R.;
RT "Structure, dynamics, and interaction of Mycobacterium tuberculosis (Mtb)
RT DprE1 and DprE2 examined by molecular modeling, simulation, and
RT electrostatic studies.";
RL PLoS ONE 10:E0119771-E0119771(2015).
RN [18]
RP MUTAGENESIS OF CYS-387.
RC STRAIN=H37Rv;
RX PubMed=27527085; DOI=10.1128/aac.01523-16;
RA Foo C.S., Lechartier B., Kolly G.S., Boy-Roettger S., Neres J.,
RA Rybniker J., Lupien A., Sala C., Piton J., Cole S.T.;
RT "Characterization of DprE1-mediated benzothiazinone resistance in
RT Mycobacterium tuberculosis.";
RL Antimicrob. Agents Chemother. 60:6451-6459(2016).
RN [19]
RP REVIEW, AND ACTIVITY REGULATION.
RX PubMed=27666194; DOI=10.1016/j.drudis.2016.09.014;
RA Piton J., Foo C.S., Cole S.T.;
RT "Structural studies of Mycobacterium tuberculosis DprE1 interacting with
RT its inhibitors.";
RL Drug Discov. Today 22:526-533(2017).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.04 ANGSTROMS) IN COMPLEXES WITH FAD AND
RP BENZOTHIAZINONE INHIBITORS, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY
RP REGULATION, AND SUBUNIT.
RX PubMed=22733761; DOI=10.1073/pnas.1205735109;
RA Batt S.M., Jabeen T., Bhowruth V., Quill L., Lund P.A., Eggeling L.,
RA Alderwick L.J., Futterer K., Besra G.S.;
RT "Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by
RT benzothiazinone inhibitors.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:11354-11359(2012).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.61 ANGSTROMS) IN COMPLEX WITH TCA1 INHIBITOR AND
RP FAD, INHIBITOR SCREENING, ACTIVITY REGULATION, AND TCA1-RESISTANT VARIANT
RP CYS-314.
RX PubMed=23776209; DOI=10.1073/pnas.1309171110;
RA Wang F., Sambandan D., Halder R., Wang J., Batt S.M., Weinrick B.,
RA Ahmad I., Yang P., Zhang Y., Kim J., Hassani M., Huszar S., Trefzer C.,
RA Ma Z., Kaneko T., Mdluli K.E., Franzblau S., Chatterjee A.K., Johnsson K.,
RA Johnson K., Mikusova K., Besra G.S., Futterer K., Robbins S.H.,
RA Barnes S.W., Walker J.R., Jacobs W.R. Jr., Schultz P.G.;
RT "Identification of a small molecule with activity against drug-resistant
RT and persistent tuberculosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:E2510-E2517(2013).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.88 ANGSTROMS) IN COMPLEX WITH FAD AND THE
RP BENZOTHIAZINONE PBTZ169 INHIBITOR, AND ACTIVITY REGULATION.
RX PubMed=24500695; DOI=10.1002/emmm.201303575;
RA Makarov V., Lechartier B., Zhang M., Neres J., van der Sar A.M.,
RA Raadsen S.A., Hartkoorn R.C., Ryabova O.B., Vocat A., Decosterd L.A.,
RA Widmer N., Buclin T., Bitter W., Andries K., Pojer F., Dyson P.J.,
RA Cole S.T.;
RT "Towards a new combination therapy for tuberculosis with next generation
RT benzothiazinones.";
RL EMBO Mol. Med. 6:372-383(2014).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.79 ANGSTROMS) IN COMPLEXES WITH FAD AND DIFFERENT
RP QUINOXALINE INHIBITORS, ACTIVITY REGULATION, INHIBITOR SCREENING,
RP TY38C-RESISTANT VARIANTS TRC11 AND TRC12, FUNCTION, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND MUTAGENESIS OF GLY-17 AND LEU-368.
RX PubMed=25427196; DOI=10.1021/cb5007163;
RA Neres J., Hartkoorn R.C., Chiarelli L.R., Gadupudi R., Pasca M.R., Mori G.,
RA Venturelli A., Savina S., Makarov V., Kolly G.S., Molteni E., Binda C.,
RA Dhar N., Ferrari S., Brodin P., Delorme V., Landry V.,
RA de Jesus Lopes Ribeiro A.L., Farina D., Saxena P., Pojer F., Carta A.,
RA Luciani R., Porta A., Zanoni G., De Rossi E., Costi M.P., Riccardi G.,
RA Cole S.T.;
RT "2-Carboxyquinoxalines kill Mycobacterium tuberculosis through noncovalent
RT inhibition of DprE1.";
RL ACS Chem. Biol. 10:705-714(2015).
CC -!- FUNCTION: Component of the DprE1-DprE2 complex that catalyzes the 2-
CC step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-
CC phospho-arabinose (DPA), a key precursor that serves as the arabinose
CC donor required for the synthesis of cell-wall arabinans
CC (PubMed:16291675, PubMed:19299584). DprE1 catalyzes the first step of
CC epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of
CC DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-
CC arabinose (DPX) (PubMed:22733761). The intermediate DPX is then
CC transferred to DprE2 subunit of the epimerase complex, most probably
CC through a 'substrate channel' at the interface of DprE1-DprE2 complex
CC (PubMed:25789990). Can also use farnesyl-phosphoryl-beta-D-ribofuranose
CC (FPR) as substrate in vitro (PubMed:25427196). Appears to be essential
CC for the growth and survival of M.tuberculosis (PubMed:12657046,
CC PubMed:24517327). {ECO:0000269|PubMed:12657046,
CC ECO:0000269|PubMed:16291675, ECO:0000269|PubMed:19299584,
CC ECO:0000269|PubMed:22733761, ECO:0000269|PubMed:24517327,
CC ECO:0000269|PubMed:25427196, ECO:0000305|PubMed:25789990}.
CC -!- FUNCTION: DprE1 is a highly vulnerable and fully validated tuberculosis
CC drug target. {ECO:0000303|PubMed:20629622, ECO:0000303|PubMed:24037308,
CC ECO:0000303|PubMed:24245764}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=FAD + H(+) + trans,octa-cis-decaprenylphospho-beta-D-
CC ribofuranose = FADH2 + trans,octa-cis-decaprenylphospho-beta-D-
CC erythro-pentofuranosid-2-ulose; Xref=Rhea:RHEA:33899,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57692, ChEBI:CHEBI:58307,
CC ChEBI:CHEBI:65067, ChEBI:CHEBI:66881; EC=1.1.98.3;
CC Evidence={ECO:0000269|PubMed:22733761};
CC -!- ACTIVITY REGULATION: Is inhibited by 8-nitro-benzothiazinones (BTZs)
CC such as BTZ043 and PBTZ169; BTZs are a new class of antimycobacterial
CC agents that kill M.tuberculosis in vitro, ex vivo, and in mouse models
CC of tuberculosis (PubMed:20828197, PubMed:19299584, PubMed:22733761,
CC PubMed:24500695). Is also inhibited by dinitrobenzamide derivatives
CC (DNBs), which thus block formation of both cell-wall lipoarabinomannan
CC and arabinogalactan via inhibition of decaprenyl-phospho-arabinose
CC (DPA) synthesis; DNBs show high activity against intracellular growth
CC of M.tuberculosis inside macrophages, including extensively drug
CC resistant (XDR) strains (PubMed:19876393). BTZs and DNBs are suicide
CC inhibitors that act via covalent modification of DprE1; the essential
CC nitro group of these compounds is reduced by DprE1 to a nitroso group,
CC which then specifically reacts with Cys-387 of DprE1 to form an
CC irreversible semimercaptal adduct (PubMed:20828197, PubMed:22733761,
CC PubMed:24500695). Many other compounds with diverse scaffolds were
CC found to act as either covalent (e.g. nitroquinoxalines,
CC nitroimidazoles) or non-covalent (e.g. the benzothiazole derivative
CC TCA1, the 2-carboxyquinoxaline Ty38C, 8-pyrrole-benzothiazinones, 1,4-
CC azaindoles, pyrazolopyridones, 4-aminoquinolone piperidine amides)
CC DprE1 inhibitors (PubMed:23776209, PubMed:25427196, PubMed:25987616,
CC PubMed:24215368, PubMed:24818517, PubMed:27666194).
CC {ECO:0000269|PubMed:19299584, ECO:0000269|PubMed:19876393,
CC ECO:0000269|PubMed:20828197, ECO:0000269|PubMed:22733761,
CC ECO:0000269|PubMed:23776209, ECO:0000269|PubMed:24215368,
CC ECO:0000269|PubMed:24500695, ECO:0000269|PubMed:24818517,
CC ECO:0000269|PubMed:25427196, ECO:0000269|PubMed:25987616,
CC ECO:0000303|PubMed:27666194}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Note=kcat is 4.1 min(-1) with farnesyl-phosphoryl-beta-D-ribofuranose
CC as substrate (at pH 8 and 30 degrees Celsius).
CC {ECO:0000269|PubMed:25427196};
CC -!- PATHWAY: Cell wall biogenesis; cell wall polysaccharide biosynthesis.
CC {ECO:0000305|PubMed:16291675, ECO:0000305|PubMed:24517327}.
CC -!- SUBUNIT: Monomer. Although forming apparent dimer in crystals, DprE1
CC does not dimerize appreciably in solution (PubMed:22733761). Interacts
CC with DprE2 to form an epimerase complex (PubMed:25789990).
CC {ECO:0000269|PubMed:22733761, ECO:0000269|PubMed:25789990}.
CC -!- SUBCELLULAR LOCATION: Periplasm {ECO:0000269|PubMed:25906160}.
CC -!- DISRUPTION PHENOTYPE: Traditional knockout mutant with dprE1 disruption
CC could not be achieved, suggesting this gene is essential
CC (PubMed:24517327). Conditional knock-down mutant of dprE1 show that
CC down-regulation of DprE1 results in rapid in vitro growth arrest,
CC swelling of the bacteria, cell wall damage, stop of cell division or
CC lysis, decreased survival in macrophages and virulence attenuation
CC (PubMed:24517327). Cells lacking this gene display impaired growth
CC (PubMed:12657046). {ECO:0000269|PubMed:12657046,
CC ECO:0000269|PubMed:24517327}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC {ECO:0000269|PubMed:19099550}.
CC -!- SIMILARITY: Belongs to the DprE1 family. {ECO:0000305}.
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DR EMBL; AL123456; CCP46619.1; -; Genomic_DNA.
DR PIR; B70697; B70697.
DR RefSeq; NP_218307.1; NC_000962.3.
DR RefSeq; WP_003420630.1; NZ_NVQJ01000009.1.
DR PDB; 4FDN; X-ray; 2.40 A; A=1-461.
DR PDB; 4FDO; X-ray; 2.40 A; A=1-461.
DR PDB; 4FDP; X-ray; 2.23 A; A/B=1-461.
DR PDB; 4FEH; X-ray; 2.04 A; A=1-461.
DR PDB; 4FF6; X-ray; 2.60 A; A/B=1-461.
DR PDB; 4KW5; X-ray; 2.61 A; A/B=1-461.
DR PDB; 4NCR; X-ray; 1.88 A; A/B=1-461.
DR PDB; 4P8C; X-ray; 1.95 A; A/B=1-461.
DR PDB; 4P8H; X-ray; 3.00 A; A/B=1-461.
DR PDB; 4P8K; X-ray; 2.49 A; A/B=1-461.
DR PDB; 4P8L; X-ray; 2.02 A; A/B=1-461.
DR PDB; 4P8M; X-ray; 2.09 A; A/B=1-461.
DR PDB; 4P8N; X-ray; 1.79 A; A/B=1-461.
DR PDB; 4P8P; X-ray; 2.20 A; A/B=1-461.
DR PDB; 4P8T; X-ray; 2.55 A; A/B=1-461.
DR PDB; 4P8Y; X-ray; 2.01 A; A/B=1-461.
DR PDB; 4PFA; X-ray; 2.56 A; A/B=1-461.
DR PDB; 4PFD; X-ray; 2.30 A; A/B=1-461.
DR PDB; 5OEP; X-ray; 2.35 A; A/B=1-461.
DR PDB; 5OEQ; X-ray; 2.25 A; A/B=1-461.
DR PDB; 6HEZ; X-ray; 2.30 A; A/B=1-461.
DR PDB; 6HF0; X-ray; 2.38 A; A/B=1-461.
DR PDB; 6HF3; X-ray; 2.20 A; A/B=1-461.
DR PDB; 6HFV; X-ray; 2.05 A; A/B=1-461.
DR PDB; 6HFW; X-ray; 2.47 A; A/B=1-461.
DR PDBsum; 4FDN; -.
DR PDBsum; 4FDO; -.
DR PDBsum; 4FDP; -.
DR PDBsum; 4FEH; -.
DR PDBsum; 4FF6; -.
DR PDBsum; 4KW5; -.
DR PDBsum; 4NCR; -.
DR PDBsum; 4P8C; -.
DR PDBsum; 4P8H; -.
DR PDBsum; 4P8K; -.
DR PDBsum; 4P8L; -.
DR PDBsum; 4P8M; -.
DR PDBsum; 4P8N; -.
DR PDBsum; 4P8P; -.
DR PDBsum; 4P8T; -.
DR PDBsum; 4P8Y; -.
DR PDBsum; 4PFA; -.
DR PDBsum; 4PFD; -.
DR PDBsum; 5OEP; -.
DR PDBsum; 5OEQ; -.
DR PDBsum; 6HEZ; -.
DR PDBsum; 6HF0; -.
DR PDBsum; 6HF3; -.
DR PDBsum; 6HFV; -.
DR PDBsum; 6HFW; -.
DR AlphaFoldDB; P9WJF1; -.
DR SMR; P9WJF1; -.
DR STRING; 83332.Rv3790; -.
DR BindingDB; P9WJF1; -.
DR ChEMBL; CHEMBL3804751; -.
DR PaxDb; P9WJF1; -.
DR DNASU; 886125; -.
DR GeneID; 886125; -.
DR KEGG; mtu:Rv3790; -.
DR TubercuList; Rv3790; -.
DR eggNOG; COG0277; Bacteria.
DR OMA; YTVAWID; -.
DR PhylomeDB; P9WJF1; -.
DR BioCyc; MetaCyc:G185E-8086-MON; -.
DR BRENDA; 1.1.98.3; 3445.
DR UniPathway; UPA00963; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0042597; C:periplasmic space; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0003885; F:D-arabinono-1,4-lactone oxidase activity; IEA:InterPro.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0035884; P:arabinan biosynthetic process; IDA:MTBBASE.
DR GO; GO:0045227; P:capsule polysaccharide biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0071555; P:cell wall organization; IEA:UniProtKB-KW.
DR GO; GO:0070592; P:cell wall polysaccharide biosynthetic process; IDA:MTBBASE.
DR GO; GO:0046677; P:response to antibiotic; IEA:UniProtKB-KW.
DR Gene3D; 3.30.465.10; -; 1.
DR InterPro; IPR007173; ALO_C.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR Pfam; PF04030; ALO; 1.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antibiotic resistance; Cell wall biogenesis/degradation; FAD;
KW Flavoprotein; Oxidoreductase; Periplasm; Reference proteome.
FT CHAIN 1..461
FT /note="Decaprenylphosphoryl-beta-D-ribose oxidase"
FT /id="PRO_0000390891"
FT DOMAIN 19..194
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT BINDING 53..63
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:22733761,
FT ECO:0000269|PubMed:23776209, ECO:0000269|PubMed:24500695,
FT ECO:0000269|PubMed:25427196, ECO:0007744|PDB:4FDP,
FT ECO:0007744|PDB:4NCR"
FT BINDING 117
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:22733761,
FT ECO:0000269|PubMed:23776209, ECO:0000269|PubMed:24500695,
FT ECO:0000269|PubMed:25427196, ECO:0007744|PDB:4FDP,
FT ECO:0007744|PDB:4KW5, ECO:0007744|PDB:4NCR"
FT BINDING 122..125
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:22733761,
FT ECO:0000269|PubMed:23776209, ECO:0000269|PubMed:24500695,
FT ECO:0000269|PubMed:25427196, ECO:0007744|PDB:4FDP,
FT ECO:0007744|PDB:4KW5, ECO:0007744|PDB:4NCR"
FT BINDING 129..132
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:22733761,
FT ECO:0000269|PubMed:23776209, ECO:0000269|PubMed:24500695,
FT ECO:0000269|PubMed:25427196, ECO:0007744|PDB:4FDP,
FT ECO:0007744|PDB:4KW5, ECO:0007744|PDB:4NCR"
FT BINDING 184
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:22733761,
FT ECO:0000269|PubMed:23776209, ECO:0000269|PubMed:24500695,
FT ECO:0000269|PubMed:25427196, ECO:0007744|PDB:4FDP,
FT ECO:0007744|PDB:4KW5, ECO:0007744|PDB:4NCR"
FT BINDING 415
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:22733761,
FT ECO:0000269|PubMed:23776209, ECO:0000269|PubMed:24500695,
FT ECO:0000269|PubMed:25427196, ECO:0007744|PDB:4FDP,
FT ECO:0007744|PDB:4KW5, ECO:0007744|PDB:4NCR"
FT VARIANT 17
FT /note="G -> C (in strain: TRC11; Ty38c-resistant mutant
FT strain lacking Rv3406, but sensitive to moxifloxacin)"
FT /evidence="ECO:0000269|PubMed:25427196"
FT VARIANT 314
FT /note="Y -> C (in a spontaneous TCA1-resistant mutant
FT strain, but sensitive to BTZ)"
FT /evidence="ECO:0000269|PubMed:23776209"
FT VARIANT 368
FT /note="L -> P (in strain: TRC12; Ty38c-resistant mutant
FT strain lacking Rv3406, but sensitive to moxifloxacin)"
FT /evidence="ECO:0000269|PubMed:25427196"
FT VARIANT 387
FT /note="C -> G (in strain: NTB9; BTZ043-resistant)"
FT /evidence="ECO:0000269|PubMed:19299584"
FT VARIANT 387
FT /note="C -> S (in strain: NTB1; BTZ043-resistant)"
FT /evidence="ECO:0000269|PubMed:19299584"
FT MUTAGEN 17
FT /note="G->C: Significantly less susceptible to Ty38c
FT inhibition. 34-fold reduction in catalytic activity."
FT /evidence="ECO:0000269|PubMed:25427196"
FT MUTAGEN 368
FT /note="L->P: Significantly less susceptible to Ty38c
FT inhibition. 7-fold reduction in catalytic activity."
FT /evidence="ECO:0000269|PubMed:25427196"
FT MUTAGEN 387
FT /note="C->A,S,T: Confers resistance to BTZ043 and PBTZ169.
FT Decreases M.tuberculosis cytotoxicity in macrophages. Does
FT not affect binding affinity of the substrate to the enzyme,
FT and only slightly affects catalytic efficiency. Is only
FT partially inhibited by PBTZ169 at high concentrations,
FT while totally inhibited by the non-covalent inhibitor
FT Ty38c."
FT /evidence="ECO:0000269|PubMed:27527085"
FT MUTAGEN 387
FT /note="C->G: Confers resistance to BTZ043 and PBTZ169. Loss
FT of covalent modification with BTZ043. Decreases
FT M.tuberculosis cytotoxicity in macrophages. Does not affect
FT binding affinity of the substrate to the enzyme, but
FT reduces catalytic efficiency by 4-fold. Is only partially
FT inhibited by PBTZ169 at high concentrations, while nearly
FT totally inhibited by the non-covalent inhibitor Ty38c."
FT /evidence="ECO:0000269|PubMed:20828197,
FT ECO:0000269|PubMed:27527085"
FT MUTAGEN 387
FT /note="C->N: Confers resistance to BTZ043 and PBTZ169.
FT Decreases M.tuberculosis cytotoxicity in macrophages. Does
FT not affect binding affinity of the substrate to the enzyme,
FT but reduces catalytic efficiency by 4-fold. Is only
FT partially inhibited by PBTZ169 at high concentrations,
FT while totally inhibited by the non-covalent inhibitor
FT Ty38c."
FT /evidence="ECO:0000269|PubMed:27527085"
FT STRAND 7..13
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 22..28
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 32..44
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 47..49
FT /evidence="ECO:0007829|PDB:4PFA"
FT STRAND 51..54
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 59..62
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 69..73
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 80..84
FT /evidence="ECO:0007829|PDB:4NCR"
FT TURN 85..87
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 89..93
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 98..105
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 106..108
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 117..119
FT /evidence="ECO:0007829|PDB:6HFW"
FT HELIX 123..129
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 136..139
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 142..145
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 146..152
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 158..161
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 163..165
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 168..174
FT /evidence="ECO:0007829|PDB:4NCR"
FT TURN 178..181
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 183..190
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 197..205
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 209..217
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 220..223
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 225..231
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:5OEQ"
FT TURN 237..241
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 243..250
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 253..255
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 258..260
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 261..263
FT /evidence="ECO:0007829|PDB:6HEZ"
FT HELIX 275..278
FT /evidence="ECO:0007829|PDB:4P8T"
FT HELIX 285..288
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 291..300
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 303..310
FT /evidence="ECO:0007829|PDB:4NCR"
FT TURN 311..313
FT /evidence="ECO:0007829|PDB:4NCR"
FT TURN 315..322
FT /evidence="ECO:0007829|PDB:4FDO"
FT HELIX 324..327
FT /evidence="ECO:0007829|PDB:4FEH"
FT TURN 328..330
FT /evidence="ECO:0007829|PDB:4FEH"
FT STRAND 332..340
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 341..343
FT /evidence="ECO:0007829|PDB:4FDN"
FT HELIX 344..356
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 365..369
FT /evidence="ECO:0007829|PDB:4NCR"
FT STRAND 382..391
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 396..409
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 416..418
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 424..430
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 434..444
FT /evidence="ECO:0007829|PDB:4NCR"
FT HELIX 453..457
FT /evidence="ECO:0007829|PDB:4NCR"
SQ SEQUENCE 461 AA; 50163 MW; B9B770002E5FE81C CRC64;
MLSVGATTTA TRLTGWGRTA PSVANVLRTP DAEMIVKAVA RVAESGGGRG AIARGLGRSY
GDNAQNGGGL VIDMTPLNTI HSIDADTKLV DIDAGVNLDQ LMKAALPFGL WVPVLPGTRQ
VTVGGAIACD IHGKNHHSAG SFGNHVRSMD LLTADGEIRH LTPTGEDAEL FWATVGGNGL
TGIIMRATIE MTPTSTAYFI ADGDVTASLD ETIALHSDGS EARYTYSSAW FDAISAPPKL
GRAAVSRGRL ATVEQLPAKL RSEPLKFDAP QLLTLPDVFP NGLANKYTFG PIGELWYRKS
GTYRGKVQNL TQFYHPLDMF GEWNRAYGPA GFLQYQFVIP TEAVDEFKKI IGVIQASGHY
SFLNVFKLFG PRNQAPLSFP IPGWNICVDF PIKDGLGKFV SELDRRVLEF GGRLYTAKDS
RTTAETFHAM YPRVDEWISV RRKVDPLRVF ASDMARRLEL L
