NADK_MYCTU
ID NADK_MYCTU Reviewed; 307 AA.
AC P9WHV7; L0T903; O33196; P0A5S6;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 42.
DE RecName: Full=NAD kinase {ECO:0000255|HAMAP-Rule:MF_00361};
DE EC=2.7.1.23 {ECO:0000255|HAMAP-Rule:MF_00361};
DE AltName: Full=ATP-dependent NAD kinase {ECO:0000255|HAMAP-Rule:MF_00361};
DE AltName: Full=Poly(P)-dependent NAD kinase;
DE Short=PPNK;
GN Name=ppnK; OrderedLocusNames=Rv1695; ORFNames=MTCI125.17;
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 [GENOMIC DNA], PROTEIN SEQUENCE OF 2-11, FUNCTION,
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBSTRATE SPECIFICITY,
RP ACTIVITY REGULATION, COFACTOR, SUBUNIT, AND NOMENCLATURE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=11006082; DOI=10.1006/bbrc.2000.3433;
RA Kawai S., Mori S., Mukai T., Suzuki S., Yamada T., Hashimoto W., Murata K.;
RT "Inorganic polyphosphate / ATP-NAD kinase of Micrococcus flavus and
RT Mycobacterium tuberculosis H37Rv.";
RL Biochem. Biophys. Res. Commun. 276:57-63(2000).
RN [2]
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 [3]
RP CRYSTALLIZATION.
RX PubMed=11526331; DOI=10.1107/s0907444901011362;
RA Mori S., Kawai S., Mikami B., Murata K.;
RT "Crystallization and preliminary X-ray analysis of NAD kinase from
RT Mycobacterium tuberculosis H37Rv.";
RL Acta Crystallogr. D 57:1319-1320(2001).
RN [4]
RP SUBUNIT.
RX PubMed=16233726; DOI=10.1016/s1389-1723(04)00302-0;
RA Mori S., Yamasaki M., Maruyama Y., Momma K., Kawai S., Hashimoto W.,
RA Mikami B., Murata K.;
RT "Crystallographic studies of Mycobacterium tuberculosis polyphosphate/ATP-
RT NAD kinase complexed with NAD.";
RL J. Biosci. Bioeng. 98:391-393(2004).
RN [5]
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 [6]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF GLY-190; LEU-192; THR-195;
RP PRO-196; THR-197; GLY-198; SER-199; THR-200; TYR-202; GLY-207 AND GLY-208,
RP SUBSTRATE SPECIFICITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION,
RP COOPERATIVITY, AND SUBUNIT.
RX PubMed=15182203; DOI=10.1021/bi049650w;
RA Raffaelli N., Finaurini L., Mazzola F., Pucci L., Sorci L., Amici A.,
RA Magni G.;
RT "Characterization of Mycobacterium tuberculosis NAD kinase: functional
RT analysis of the full-length enzyme by site-directed mutagenesis.";
RL Biochemistry 43:7610-7617(2004).
RN [7]
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 [8]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS), AND SUBUNIT.
RX PubMed=15269221; DOI=10.1074/jbc.m406586200;
RA Garavaglia S., Raffaelli N., Finaurini L., Magni G., Rizzi M.;
RT "A novel fold revealed by Mycobacterium tuberculosis NAD kinase, a key
RT allosteric enzyme in NADP biosynthesis.";
RL J. Biol. Chem. 279:40980-40986(2004).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH NAD, MUTAGENESIS OF
RP ASP-85; ASN-159 AND GLU-160, AND SUBUNIT.
RX PubMed=15629142; DOI=10.1016/j.bbrc.2004.11.163;
RA Mori S., Yamasaki M., Maruyama Y., Momma K., Kawai S., Hashimoto W.,
RA Mikami B., Murata K.;
RT "NAD-binding mode and the significance of intersubunit contact revealed by
RT the crystal structure of Mycobacterium tuberculosis NAD kinase-NAD
RT complex.";
RL Biochem. Biophys. Res. Commun. 327:500-508(2005).
CC -!- FUNCTION: Involved in the regulation of the intracellular balance of
CC NAD and NADP, and is a key enzyme in the biosynthesis of NADP.
CC Catalyzes specifically the phosphorylation on 2'-hydroxyl of the
CC adenosine moiety of NAD to yield NADP. It can use ATP and other
CC nucleoside triphosphates as well as inorganic polyphosphate (poly(P))
CC as a source of phosphorus. {ECO:0000255|HAMAP-Rule:MF_00361,
CC ECO:0000269|PubMed:11006082, ECO:0000269|PubMed:15182203}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + NAD(+) = ADP + H(+) + NADP(+); Xref=Rhea:RHEA:18629,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:456216; EC=2.7.1.23;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_00361,
CC ECO:0000269|PubMed:11006082, ECO:0000269|PubMed:15182203};
CC -!- COFACTOR:
CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_00361,
CC ECO:0000269|PubMed:11006082};
CC -!- ACTIVITY REGULATION: Allosterically inhibited by NADP, NADPH, and NADH,
CC at concentrations lower than 0.5 mM. Completely inhibited by p-
CC chloromercuribenzoate. {ECO:0000269|PubMed:11006082,
CC ECO:0000269|PubMed:15182203}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.9 mM for NAD (with 5 mM ATP as phosphoryl donor at pH 7 and 37
CC degrees Celsius) {ECO:0000269|PubMed:11006082,
CC ECO:0000269|PubMed:15182203};
CC KM=1.6 mM for poly(P) (at pH 7 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:11006082, ECO:0000269|PubMed:15182203};
CC KM=1.8 mM for ATP (at pH 7 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:11006082, ECO:0000269|PubMed:15182203};
CC KM=2.9 mM for NAD (with 5 mM poly(P) as phosphoryl donor at pH 7 and
CC 37 degrees Celsius) {ECO:0000269|PubMed:11006082,
CC ECO:0000269|PubMed:15182203};
CC KM=3.8 mM for dATP (at pH 7 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:11006082, ECO:0000269|PubMed:15182203};
CC Vmax=1.2 umol/min/mg enzyme toward NAD (with ATP as phosphoryl donor
CC at pH 8 and 37 degrees Celsius) {ECO:0000269|PubMed:11006082,
CC ECO:0000269|PubMed:15182203};
CC Vmax=1.2 umol/min/mg enzyme toward NAD (with ATP as phosphoryl donor
CC at pH 7 and 37 degrees Celsius) {ECO:0000269|PubMed:11006082,
CC ECO:0000269|PubMed:15182203};
CC Vmax=1.8 umol/min/mg enzyme toward NAD (with poly(P) as phosphoryl
CC donor at pH 7 and 37 degrees Celsius) {ECO:0000269|PubMed:11006082,
CC ECO:0000269|PubMed:15182203};
CC Vmax=3.8 umol/min/mg enzyme toward NAD (with poly(P) as phosphoryl
CC donor at pH 8 and 37 degrees Celsius) {ECO:0000269|PubMed:11006082,
CC ECO:0000269|PubMed:15182203};
CC pH dependence:
CC Optimum pH is 6.5 in sodium-acetate at 50 degrees Celsius for
CC poly(P)-dependent kinase activity and optimum pH is 8 in Tris-HCl at
CC 50 degrees Celsius for ATP-dependent kinase activity.
CC {ECO:0000269|PubMed:11006082, ECO:0000269|PubMed:15182203};
CC Temperature dependence:
CC Optimum temperature is 50 degrees Celsius.
CC {ECO:0000269|PubMed:11006082, ECO:0000269|PubMed:15182203};
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:11006082,
CC ECO:0000269|PubMed:15182203, ECO:0000269|PubMed:15269221,
CC ECO:0000269|PubMed:15629142, ECO:0000269|PubMed:16233726}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_00361}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC -!- SIMILARITY: Belongs to the NAD kinase family. {ECO:0000255|HAMAP-
CC Rule:MF_00361}.
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DR EMBL; AB044336; BAB21478.1; -; Genomic_DNA.
DR EMBL; AL123456; CCP44460.1; -; Genomic_DNA.
DR PIR; F70502; F70502.
DR RefSeq; NP_216211.1; NC_000962.3.
DR RefSeq; WP_003408383.1; NZ_NVQJ01000010.1.
DR PDB; 1U0R; X-ray; 2.80 A; A/B/C/D=1-307.
DR PDB; 1U0T; X-ray; 2.30 A; A/B=1-307.
DR PDB; 1Y3H; X-ray; 2.80 A; A/B=1-307.
DR PDB; 1Y3I; X-ray; 2.60 A; A/B=1-307.
DR PDBsum; 1U0R; -.
DR PDBsum; 1U0T; -.
DR PDBsum; 1Y3H; -.
DR PDBsum; 1Y3I; -.
DR AlphaFoldDB; P9WHV7; -.
DR SMR; P9WHV7; -.
DR STRING; 83332.Rv1695; -.
DR BindingDB; P9WHV7; -.
DR ChEMBL; CHEMBL6176; -.
DR PaxDb; P9WHV7; -.
DR DNASU; 885660; -.
DR GeneID; 45425664; -.
DR GeneID; 885660; -.
DR KEGG; mtu:Rv1695; -.
DR TubercuList; Rv1695; -.
DR eggNOG; COG0061; Bacteria.
DR OMA; VNLGHVG; -.
DR PhylomeDB; P9WHV7; -.
DR BRENDA; 2.7.1.23; 3445.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-UniRule.
DR GO; GO:0051287; F:NAD binding; IDA:UniProtKB.
DR GO; GO:0003951; F:NAD+ kinase activity; IDA:UniProtKB.
DR GO; GO:0019674; P:NAD metabolic process; IEA:InterPro.
DR GO; GO:0006741; P:NADP biosynthetic process; IDA:MTBBASE.
DR GO; GO:0016310; P:phosphorylation; IDA:MTBBASE.
DR GO; GO:0006797; P:polyphosphate metabolic process; IDA:MTBBASE.
DR Gene3D; 2.60.200.30; -; 1.
DR Gene3D; 3.40.50.10330; -; 1.
DR HAMAP; MF_00361; NAD_kinase; 1.
DR InterPro; IPR017438; ATP-NAD_kinase_N.
DR InterPro; IPR017437; ATP-NAD_kinase_PpnK-typ_C.
DR InterPro; IPR016064; NAD/diacylglycerol_kinase_sf.
DR InterPro; IPR002504; NADK.
DR Pfam; PF01513; NAD_kinase; 1.
DR SUPFAM; SSF111331; SSF111331; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cytoplasm; Direct protein sequencing; Kinase;
KW NAD; NADP; Nucleotide-binding; Reference proteome; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:11006082"
FT CHAIN 2..307
FT /note="NAD kinase"
FT /id="PRO_0000120635"
FT ACT_SITE 85
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00361"
FT BINDING 85..86
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00361"
FT BINDING 90
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00361"
FT BINDING 159..160
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00361,
FT ECO:0000269|PubMed:15629142"
FT BINDING 189
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 197
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00361,
FT ECO:0000269|PubMed:15629142"
FT BINDING 200..205
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00361,
FT ECO:0000269|PubMed:15629142"
FT BINDING 259
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00361"
FT MUTAGEN 85
FT /note="D->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15629142"
FT MUTAGEN 159
FT /note="N->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15629142"
FT MUTAGEN 160
FT /note="E->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15629142"
FT MUTAGEN 190
FT /note="G->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 192
FT /note="L->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 195
FT /note="T->A: It promotes stronger allosteric interactions."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 196
FT /note="P->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 197
FT /note="T->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 198
FT /note="G->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 199
FT /note="S->A: Lower catalytic efficiency. A perturbation of
FT the allosteric interactions is observed when NAD is used as
FT substrate."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 200
FT /note="T->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 202
FT /note="Y->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 207
FT /note="G->A: Abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:15182203"
FT MUTAGEN 208
FT /note="G->A: Possesses 30% of the activity compared to the
FT wild-type enzyme. While mutant affects the catalytic
FT efficiency, it does not alter the binding affinity for ATP
FT and poly(P). It causes a decrease in the affinity for NAD
FT and alters the allosteric interactions mediated by the
FT dinucleotide, both in the presence of poly(P) and ATP."
FT /evidence="ECO:0000269|PubMed:15182203"
FT STRAND 6..14
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 15..18
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 20..30
FT /evidence="ECO:0007829|PDB:1U0T"
FT TURN 31..33
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 35..39
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 53..56
FT /evidence="ECO:0007829|PDB:1U0R"
FT TURN 57..60
FT /evidence="ECO:0007829|PDB:1U0R"
FT STRAND 63..65
FT /evidence="ECO:0007829|PDB:1U0R"
FT TURN 70..75
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 79..83
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 85..98
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 102..106
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 115..117
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 118..120
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 121..130
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 134..138
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 141..147
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 150..164
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 166..170
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 172..194
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 197..200
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 202..205
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 218..224
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 226..228
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 241..245
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 247..249
FT /evidence="ECO:0007829|PDB:1Y3I"
FT STRAND 252..256
FT /evidence="ECO:0007829|PDB:1U0T"
FT TURN 257..259
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 260..264
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 269..274
FT /evidence="ECO:0007829|PDB:1U0T"
FT STRAND 279..283
FT /evidence="ECO:0007829|PDB:1U0T"
FT HELIX 289..297
FT /evidence="ECO:0007829|PDB:1U0T"
SQ SEQUENCE 307 AA; 32904 MW; 68817BE570B6645B CRC64;
MTAHRSVLLV VHTGRDEATE TARRVEKVLG DNKIALRVLS AEAVDRGSLH LAPDDMRAMG
VEIEVVDADQ HAADGCELVL VLGGDGTFLR AAELARNASI PVLGVNLGRI GFLAEAEAEA
IDAVLEHVVA QDYRVEDRLT LDVVVRQGGR IVNRGWALNE VSLEKGPRLG VLGVVVEIDG
RPVSAFGCDG VLVSTPTGST AYAFSAGGPV LWPDLEAILV VPNNAHALFG RPMVTSPEAT
IAIEIEADGH DALVFCDGRR EMLIPAGSRL EVTRCVTSVK WARLDSAPFT DRLVRKFRLP
VTGWRGK
