LPDA_MYCTU
ID LPDA_MYCTU Reviewed; 493 AA.
AC P9WHH7; L0TC51; O53355; Q8VJ36;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 49.
DE RecName: Full=NAD(P)H dehydrogenase (quinone);
DE EC=1.6.5.2;
DE AltName: Full=NAD(P)H quinone reductase;
DE AltName: Full=NAD(P)H: menadione oxidoreductase;
DE AltName: Full=NADH-menadione reductase;
GN Name=lpdA; Synonyms=lpdA-2; OrderedLocusNames=Rv3303c;
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 FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=17097323; DOI=10.1016/j.micinf.2006.09.004;
RA Akhtar P., Srivastava S., Srivastava A., Srivastava M., Srivastava B.S.,
RA Srivastava R.;
RT "Rv3303c of Mycobacterium tuberculosis protects tubercle bacilli against
RT oxidative stress in vivo and contributes to virulence in mice.";
RL Microbes Infect. 8:2855-2862(2006).
RN [3]
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 [4]
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 [5]
RP X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) IN COMPLEX WITH FAD, MASS
RP SPECTROMETRY, FUNCTION, SUBUNIT, SUBSTRATE SPECIFICITY, REACTION MECHANISM,
RP AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=15456792; DOI=10.1074/jbc.m410704200;
RA Argyrou A., Vetting M.W., Blanchard J.S.;
RT "Characterization of a new member of the flavoprotein disulfide reductase
RT family of enzymes from Mycobacterium tuberculosis.";
RL J. Biol. Chem. 279:52694-52702(2004).
CC -!- FUNCTION: May contribute to virulence by increasing resistance to
CC reactive oxygen intermediates. It can reduce 2,6-dimethyl-1,4-
CC benzoquinone (DMBQ), 5-hydroxy-1,4-naphthaquinone (5-HNQ) and
CC menadione. NADPH is the physiological reductant rather than NADH.
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a quinone + H(+) + NADH = a quinol + NAD(+);
CC Xref=Rhea:RHEA:46160, ChEBI:CHEBI:15378, ChEBI:CHEBI:24646,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:132124; EC=1.6.5.2;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a quinone + H(+) + NADPH = a quinol + NADP(+);
CC Xref=Rhea:RHEA:46164, ChEBI:CHEBI:15378, ChEBI:CHEBI:24646,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:132124; EC=1.6.5.2;
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Note=Binds 1 FAD per subunit.;
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.39 uM for 5-HNQ (with NADPH at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=0.44 uM for NADPH (with 5-HNQ at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=0.53 uM for NADPH (with DMBQ at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=1.6 uM for DMBQ (with NADPH at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=5.4 uM for oxidized thionicotinamide adenine dinucleotide
CC (thio_NAD)(with NADH at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=5.5 uM for 5-HNQ (with NADH at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=11 uM for DMBQ (with NADH at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=18 uM for oxidized thionicotinamide adenine dinucleotide
CC (thio_NAD)(with NADPH at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=28 uM for NADH (with 5-HNQ at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC KM=35.7 uM for menadione (at pH 7.5) {ECO:0000269|PubMed:15456792,
CC ECO:0000269|PubMed:17097323};
CC KM=36 uM for NADH (with DMBQ at pH 7.5 and at 25 degrees Celsius)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC Vmax=20 umol/min/mg enzyme with menadione (at pH 7.5)
CC {ECO:0000269|PubMed:15456792, ECO:0000269|PubMed:17097323};
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:15456792}.
CC -!- MASS SPECTROMETRY: Mass=52543; Mass_error=3; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:15456792};
CC -!- MISCELLANEOUS: Catalysis proceeds by a classical ping-pong bi-bi
CC reaction mechanism.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC -!- SIMILARITY: Belongs to the class-I pyridine nucleotide-disulfide
CC oxidoreductase family. {ECO:0000305}.
CC -!- CAUTION: Despite significant sequence similarity to lipoamide
CC dehydrogenases this protein cannot catalyze the reduction of lipoyl
CC substrates. It lacks one of two cysteine residues involved in dithiol-
CC disulfide interchange with lipoyl substrates and a His-Glu pair
CC involved in general acid catalysis. {ECO:0000305}.
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DR EMBL; AL123456; CCP46122.1; -; Genomic_DNA.
DR PIR; F70841; F70841.
DR RefSeq; NP_217820.1; NC_000962.3.
DR RefSeq; WP_009936266.1; NZ_NVQJ01000003.1.
DR PDB; 1XDI; X-ray; 2.81 A; A/B=1-493.
DR PDBsum; 1XDI; -.
DR AlphaFoldDB; P9WHH7; -.
DR SMR; P9WHH7; -.
DR STRING; 83332.Rv3303c; -.
DR DrugBank; DB03147; Flavin adenine dinucleotide.
DR PaxDb; P9WHH7; -.
DR DNASU; 887659; -.
DR GeneID; 887659; -.
DR KEGG; mtu:Rv3303c; -.
DR TubercuList; Rv3303c; -.
DR eggNOG; COG1249; Bacteria.
DR OMA; CLMAVGA; -.
DR PhylomeDB; P9WHH7; -.
DR SABIO-RK; P9WHH7; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IDA:MTBBASE.
DR GO; GO:0003955; F:NAD(P)H dehydrogenase (quinone) activity; IDA:MTBBASE.
DR GO; GO:0050136; F:NADH dehydrogenase (quinone) activity; IEA:RHEA.
DR GO; GO:0070401; F:NADP+ binding; IDA:MTBBASE.
DR GO; GO:0008753; F:NADPH dehydrogenase (quinone) activity; IEA:RHEA.
DR GO; GO:0016655; F:oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; IDA:MTBBASE.
DR GO; GO:0045454; P:cell redox homeostasis; IEA:InterPro.
DR GO; GO:1990748; P:cellular detoxification; IMP:MTBBASE.
DR Gene3D; 3.30.390.30; -; 1.
DR Gene3D; 3.50.50.60; -; 2.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR023753; FAD/NAD-binding_dom.
DR InterPro; IPR016156; FAD/NAD-linked_Rdtase_dimer_sf.
DR InterPro; IPR001100; Pyr_nuc-diS_OxRdtase.
DR InterPro; IPR004099; Pyr_nucl-diS_OxRdtase_dimer.
DR Pfam; PF07992; Pyr_redox_2; 1.
DR Pfam; PF02852; Pyr_redox_dim; 1.
DR PIRSF; PIRSF000350; Mercury_reductase_MerA; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
DR SUPFAM; SSF55424; SSF55424; 1.
PE 1: Evidence at protein level;
KW 3D-structure; FAD; Flavoprotein; NAD; Oxidoreductase; Reference proteome.
FT CHAIN 1..493
FT /note="NAD(P)H dehydrogenase (quinone)"
FT /id="PRO_0000391461"
FT BINDING 12..13
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15456792"
FT BINDING 35..37
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15456792"
FT BINDING 42..43
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15456792"
FT BINDING 52
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15456792"
FT BINDING 117
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15456792"
FT BINDING 317
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15456792"
FT BINDING 324..325
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15456792"
FT BINDING 450
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15456792"
FT STRAND 3..8
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 12..24
FT /evidence="ECO:0007829|PDB:1XDI"
FT TURN 26..28
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 29..37
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 41..45
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 48..64
FT /evidence="ECO:0007829|PDB:1XDI"
FT TURN 65..71
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 83..107
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 111..119
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 122..124
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 127..134
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 140..150
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 154..156
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 160..162
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 166..171
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 172..177
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 183..189
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 192..203
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 208..211
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 213..218
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 223..235
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 239..241
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 246..251
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 253..260
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 265..273
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 277..279
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 282..284
FT /evidence="ECO:0007829|PDB:1XDI"
FT TURN 286..290
FT /evidence="ECO:0007829|PDB:1XDI"
FT TURN 295..297
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 303..306
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 312..314
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 317..319
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 325..339
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 349..351
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 353..356
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 358..367
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 369..373
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 379..386
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 390..394
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 401..407
FT /evidence="ECO:0007829|PDB:1XDI"
FT TURN 408..410
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 412..420
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 423..436
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 440..444
FT /evidence="ECO:0007829|PDB:1XDI"
FT STRAND 450..452
FT /evidence="ECO:0007829|PDB:1XDI"
FT HELIX 454..464
FT /evidence="ECO:0007829|PDB:1XDI"
SQ SEQUENCE 493 AA; 51489 MW; 71C3F1483665278C CRC64;
MVTRIVILGG GPAGYEAALV AATSHPETTQ VTVIDCDGIG GAAVLDDCVP SKTFIASTGL
RTELRRAPHL GFHIDFDDAK ISLPQIHARV KTLAAAQSAD ITAQLLSMGV QVIAGRGELI
DSTPGLARHR IKATAADGST SEHEADVVLV ATGASPRILP SAQPDGERIL TWRQLYDLDA
LPDHLIVVGS GVTGAEFVDA YTELGVPVTV VASQDHVLPY EDADAALVLE ESFAERGVRL
FKNARAASVT RTGAGVLVTM TDGRTVEGSH ALMTIGSVPN TSGLGLERVG IQLGRGNYLT
VDRVSRTLAT GIYAAGDCTG LLPLASVAAM QGRIAMYHAL GEGVSPIRLR TVAATVFTRP
EIAAVGVPQS VIDAGSVAAR TIMLPLRTNA RAKMSEMRHG FVKIFCRRST GVVIGGVVVA
PIASELILPI AVAVQNRITV NELAQTLAVY PSLSGSITEA ARRLMAHDDL DCTAAQDAAE
QLALVPHHLP TSN
