DPRE2_MYCTU
ID DPRE2_MYCTU Reviewed; 254 AA.
AC P9WGS9; L0TGS1; P66783; P72057;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 41.
DE RecName: Full=Decaprenylphosphoryl-2-keto-beta-D-erythro-pentose reductase {ECO:0000305};
DE EC=1.1.1.333 {ECO:0000250|UniProtKB:A0R610, ECO:0000305|PubMed:22733761};
DE AltName: Full=Decaprenyl-phospho-2'-keto-D-arabinose reductase {ECO:0000305};
DE AltName: Full=Decaprenylphospho-beta-D-erythro-pentofuranosid-2-ulose 2-reductase {ECO:0000305};
DE AltName: Full=Decaprenylphosphoryl-beta-D-ribofuranose 2'-epimerase subunit DprE2 {ECO:0000305|PubMed:25789990};
DE Short=Decaprenyl-phosphoribose 2'-epimerase subunit 2 {ECO:0000305|PubMed:25789990};
DE AltName: Full=NAD-dependent decaprenylphosphoryl-D-2-keto-erythropentose reductase {ECO:0000305};
GN Name=dprE2 {ECO:0000303|PubMed:19299584}; OrderedLocusNames=Rv3791;
GN ORFNames=MTCY13D12.25;
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 FUNCTION IN DPR EPIMERIZATION.
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 [6]
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 [7]
RP FUNCTION, AND CATALYTIC ACTIVITY.
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 [8]
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 [9]
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 [10]
RP INTERACTION WITH DPRE1, AND 3D-STRUCTURE MODELING.
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).
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). DprE2 then catalyzes the second step of
CC epimerization, the NAD(+)-dependent reduction of DPX that leads to the
CC formation of DPA (PubMed:22733761, PubMed:25789990). Appears to be
CC essential for the growth and survival of M.tuberculosis
CC (PubMed:12657046, 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:0000305|PubMed:25789990}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NAD(+) + trans,octa-cis-decaprenylphospho-beta-D-
CC arabinofuranose = H(+) + NADH + trans,octa-cis-decaprenylphospho-
CC beta-D-erythro-pentofuranosid-2-ulose; Xref=Rhea:RHEA:33895,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC ChEBI:CHEBI:65066, ChEBI:CHEBI:65067; EC=1.1.1.333;
CC Evidence={ECO:0000250|UniProtKB:A0R610, ECO:0000305|PubMed:22733761};
CC -!- PATHWAY: Cell wall biogenesis; cell wall polysaccharide biosynthesis.
CC {ECO:0000305|PubMed:16291675, ECO:0000305|PubMed:24517327}.
CC -!- SUBUNIT: Interacts with DprE1 to form an epimerase complex.
CC {ECO:0000269|PubMed:25789990}.
CC -!- SUBCELLULAR LOCATION: Periplasm {ECO:0000305|PubMed:25906160}.
CC -!- DISRUPTION PHENOTYPE: Traditional knockout mutant with dprE2 disruption
CC could not be achieved, suggesting this gene is essential
CC (PubMed:24517327). Conditional knock-down mutant of dprE2 show that
CC down-regulation of DprE2 results in growth arrest in vitro
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 short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; AL123456; CCP46620.1; -; Genomic_DNA.
DR PIR; C70697; C70697.
DR RefSeq; NP_218308.1; NC_000962.3.
DR RefSeq; WP_003420632.1; NZ_NVQJ01000009.1.
DR AlphaFoldDB; P9WGS9; -.
DR SMR; P9WGS9; -.
DR STRING; 83332.Rv3791; -.
DR PaxDb; P9WGS9; -.
DR DNASU; 886124; -.
DR GeneID; 886124; -.
DR KEGG; mtu:Rv3791; -.
DR TubercuList; Rv3791; -.
DR eggNOG; COG1028; Bacteria.
DR OMA; INAVGNP; -.
DR PhylomeDB; P9WGS9; -.
DR BioCyc; MetaCyc:G185E-8087-MON; -.
DR BRENDA; 1.1.1.333; 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:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
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 InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR Pfam; PF00106; adh_short; 1.
DR PRINTS; PR00081; GDHRDH.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 1: Evidence at protein level;
KW Cell wall biogenesis/degradation; NAD; Oxidoreductase; Periplasm;
KW Reference proteome.
FT CHAIN 1..254
FT /note="Decaprenylphosphoryl-2-keto-beta-D-erythro-pentose
FT reductase"
FT /id="PRO_0000054860"
FT ACT_SITE 160
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT BINDING 67
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P00334"
FT BINDING 164
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P00334"
SQ SEQUENCE 254 AA; 27469 MW; 09CE854881C37138 CRC64;
MVLDAVGNPQ TVLLLGGTSE IGLAICERYL HNSAARIVLA CLPDDPRRED AAAAMKQAGA
RSVELIDFDA LDTDSHPKMI EAAFSGGDVD VAIVAFGLLG DAEELWQNQR KAVQIAEINY
TAAVSVGVLL AEKMRAQGFG QIIAMSSAAG ERVRRANFVY GSTKAGLDGF YLGLSEALRE
YGVRVLVIRP GQVRTRMSAH LKEAPLTVDK EYVANLAVTA SAKGKELVWA PAAFRYVMMV
LRHIPRSIFR KLPI
