NAKD2_HUMAN
ID NAKD2_HUMAN Reviewed; 442 AA.
AC Q4G0N4; B5MC93; Q6UTX5; Q96NM0;
DT 24-JUL-2007, integrated into UniProtKB/Swiss-Prot.
DT 24-JUL-2007, sequence version 2.
DT 03-AUG-2022, entry version 128.
DE RecName: Full=NAD kinase 2, mitochondrial;
DE EC=2.7.1.23;
DE AltName: Full=Mitochondrial NAD kinase;
DE AltName: Full=NAD kinase domain-containing protein 1, mitochondrial;
DE Flags: Precursor;
GN Name=NADK2; Synonyms=C5orf33, MNADK, NADKD1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 39-442 (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 164-442 (ISOFORM 2).
RA Li H., Yu R., Zhou G., Shen C., Xiao W., Li M., Ke R., Zhong G., Lin L.,
RA Yang S.;
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, BIOPHYSICOCHEMICAL PROPERTIES,
RP SUBCELLULAR LOCATION, ACTIVITY REGULATION, AND TISSUE SPECIFICITY.
RX PubMed=23212377; DOI=10.1038/ncomms2262;
RA Ohashi K., Kawai S., Murata K.;
RT "Identification and characterization of a human mitochondrial NAD kinase.";
RL Nat. Commun. 3:1248-1248(2012).
RN [7]
RP INVOLVEMENT IN DECRD.
RX PubMed=24847004; DOI=10.1093/hmg/ddu218;
RA Houten S.M., Denis S., Te Brinke H., Jongejan A., van Kampen A.H.,
RA Bradley E.J., Baas F., Hennekam R.C., Millington D.S., Young S.P.,
RA Frazier D.M., Gucsavas-Calikoglu M., Wanders R.J.;
RT "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes
RT dienoyl-CoA reductase deficiency with hyperlysinemia.";
RL Hum. Mol. Genet. 23:5009-5016(2014).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188 AND SER-367, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
CC -!- FUNCTION: Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to
CC yield NADP(+). Can use both ATP or inorganic polyphosphate as the
CC phosphoryl donor. Also has weak NADH kinase activity in vitro; however
CC NADH kinase activity is much weaker than the NAD(+) kinase activity and
CC may not be relevant in vivo. {ECO:0000269|PubMed:23212377}.
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:0000269|PubMed:23212377};
CC -!- ACTIVITY REGULATION: Inhibited by NADH, NADPH and NADP(+).
CC {ECO:0000269|PubMed:23212377}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.022 mM for NAD(+) {ECO:0000269|PubMed:23212377};
CC KM=1.7 mM for ATP {ECO:0000269|PubMed:23212377};
CC KM=1.2 mM for tetrapolyphosphate {ECO:0000269|PubMed:23212377};
CC Vmax=0.091 umol/min/mg enzyme {ECO:0000269|PubMed:23212377};
CC -!- SUBUNIT: Homodimer. {ECO:0000305|PubMed:23212377}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:23212377}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q4G0N4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q4G0N4-2; Sequence=VSP_027193;
CC Name=3;
CC IsoId=Q4G0N4-3; Sequence=VSP_027192;
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:23212377}.
CC -!- DISEASE: 2,4-dienoyl-CoA reductase deficiency (DECRD) [MIM:616034]: A
CC rare, autosomal recessive, inborn error of polyunsaturated fatty acids
CC and lysine metabolism, resulting in mitochondrial dysfunction. Affected
CC individuals have a severe encephalopathy with neurologic and metabolic
CC abnormalities beginning in early infancy. Laboratory studies show
CC increased C10:2 carnitine levels and hyperlysinemia.
CC {ECO:0000269|PubMed:24847004}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the NAD kinase family. {ECO:0000305}.
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DR EMBL; AK055158; BAB70864.1; -; mRNA.
DR EMBL; AC008807; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC008942; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC045565; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC062567; AAH62567.1; -; mRNA.
DR EMBL; AY360463; AAQ62967.1; -; mRNA.
DR CCDS; CCDS3917.1; -. [Q4G0N4-3]
DR CCDS; CCDS47197.1; -. [Q4G0N4-1]
DR RefSeq; NP_001078880.1; NM_001085411.2. [Q4G0N4-1]
DR RefSeq; NP_001274269.1; NM_001287340.1. [Q4G0N4-3]
DR RefSeq; NP_001274270.1; NM_001287341.1.
DR RefSeq; NP_694558.1; NM_153013.4. [Q4G0N4-3]
DR AlphaFoldDB; Q4G0N4; -.
DR BioGRID; 126369; 40.
DR IntAct; Q4G0N4; 5.
DR MINT; Q4G0N4; -.
DR STRING; 9606.ENSP00000371362; -.
DR iPTMnet; Q4G0N4; -.
DR PhosphoSitePlus; Q4G0N4; -.
DR BioMuta; NADK2; -.
DR DMDM; 156630863; -.
DR EPD; Q4G0N4; -.
DR jPOST; Q4G0N4; -.
DR MassIVE; Q4G0N4; -.
DR MaxQB; Q4G0N4; -.
DR PaxDb; Q4G0N4; -.
DR PeptideAtlas; Q4G0N4; -.
DR PRIDE; Q4G0N4; -.
DR ProteomicsDB; 62113; -. [Q4G0N4-1]
DR ProteomicsDB; 62114; -. [Q4G0N4-2]
DR ProteomicsDB; 62115; -. [Q4G0N4-3]
DR Antibodypedia; 50834; 158 antibodies from 20 providers.
DR DNASU; 133686; -.
DR Ensembl; ENST00000282512.7; ENSP00000282512.3; ENSG00000152620.13. [Q4G0N4-3]
DR Ensembl; ENST00000381937.9; ENSP00000371362.4; ENSG00000152620.13. [Q4G0N4-1]
DR Ensembl; ENST00000397338.5; ENSP00000380499.1; ENSG00000152620.13. [Q4G0N4-3]
DR Ensembl; ENST00000514504.5; ENSP00000421029.1; ENSG00000152620.13. [Q4G0N4-2]
DR GeneID; 133686; -.
DR KEGG; hsa:133686; -.
DR MANE-Select; ENST00000381937.9; ENSP00000371362.4; NM_001085411.3; NP_001078880.1.
DR UCSC; uc003jkf.6; human. [Q4G0N4-1]
DR CTD; 133686; -.
DR DisGeNET; 133686; -.
DR GeneCards; NADK2; -.
DR HGNC; HGNC:26404; NADK2.
DR HPA; ENSG00000152620; Tissue enriched (liver).
DR MalaCards; NADK2; -.
DR MIM; 615787; gene.
DR MIM; 616034; phenotype.
DR neXtProt; NX_Q4G0N4; -.
DR OpenTargets; ENSG00000152620; -.
DR Orphanet; 431361; Progressive encephalopathy with leukodystrophy due to DECR deficiency.
DR PharmGKB; PA162380039; -.
DR VEuPathDB; HostDB:ENSG00000152620; -.
DR eggNOG; KOG4180; Eukaryota.
DR GeneTree; ENSGT00390000006320; -.
DR HOGENOM; CLU_039559_0_0_1; -.
DR InParanoid; Q4G0N4; -.
DR OMA; QGSEGYM; -.
DR OrthoDB; 1416565at2759; -.
DR PhylomeDB; Q4G0N4; -.
DR TreeFam; TF314077; -.
DR BRENDA; 2.7.1.23; 2681.
DR PathwayCommons; Q4G0N4; -.
DR Reactome; R-HSA-196807; Nicotinate metabolism.
DR SABIO-RK; Q4G0N4; -.
DR SignaLink; Q4G0N4; -.
DR BioGRID-ORCS; 133686; 26 hits in 1039 CRISPR screens.
DR ChiTaRS; NADK2; human.
DR GenomeRNAi; 133686; -.
DR Pharos; Q4G0N4; Tbio.
DR PRO; PR:Q4G0N4; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q4G0N4; protein.
DR Bgee; ENSG00000152620; Expressed in liver and 196 other tissues.
DR ExpressionAtlas; Q4G0N4; baseline and differential.
DR Genevisible; Q4G0N4; HS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003951; F:NAD+ kinase activity; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0019674; P:NAD metabolic process; IDA:UniProtKB.
DR GO; GO:0006741; P:NADP biosynthetic process; IEA:InterPro.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR Gene3D; 2.60.200.30; -; 1.
DR Gene3D; 3.40.50.10330; -; 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 InterPro; IPR012355; NADK2_mit.
DR Pfam; PF01513; NAD_kinase; 1.
DR PIRSF; PIRSF017565; Kin_ATP-NAD_euk; 1.
DR SUPFAM; SSF111331; SSF111331; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; ATP-binding; Kinase; Mitochondrion; NAD;
KW NADP; Nucleotide-binding; Phosphoprotein; Reference proteome; Transferase;
KW Transit peptide.
FT TRANSIT 1..62
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 63..442
FT /note="NAD kinase 2, mitochondrial"
FT /id="PRO_0000296292"
FT REGION 24..60
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 76
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8C5H8"
FT MOD_RES 76
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8C5H8"
FT MOD_RES 188
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 302
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8C5H8"
FT MOD_RES 317
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8C5H8"
FT MOD_RES 317
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8C5H8"
FT MOD_RES 367
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 397
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8C5H8"
FT VAR_SEQ 1..163
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_027192"
FT VAR_SEQ 288..319
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_027193"
SQ SEQUENCE 442 AA; 49433 MW; 289EA16979AF14D8 CRC64;
MTCYRGFLLG SCCRVAGGRA AALRGPGAGG PAARPRLGGD GGGRRHLGQG QPRELAGCGS
RADGGFRPSR VVVVAKTTRY EFEQQRYRYA ELSEEDLKQL LALKGSSYSG LLERHHIHTK
NVEHIIDSLR NEGIEVRLVK RREYDEETVR WADAVIAAGG DGTMLLAASK VLDRLKPVIG
VNTDPERSEG HLCLPVRYTH SFPEALQKFY RGEFRWLWRQ RIRLYLEGTG INPVPVDLHE
QQLSLNQHNR ALNIERAHDE RSEASGPQLL PVRALNEVFI GESLSSRASY YEISVDDGPW
EKQKSSGLNL CTGTGSKAWS FNINRVATQA VEDVLNIAKR QGNLSLPLNR ELVEKVTNEY
NESLLYSPEE PKILFSIREP IANRVFSSSR QRCFSSKVCV RSRCWDACMV VDGGTSFEFN
DGAIASMMIN KEDELRTVLL EQ
