Full text data of ADK
ADK
[Confidence: low (only semi-automatic identification from reviews)]
Adenosine kinase; AK; 2.7.1.20 (Adenosine 5'-phosphotransferase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Adenosine kinase; AK; 2.7.1.20 (Adenosine 5'-phosphotransferase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P55263
ID ADK_HUMAN Reviewed; 362 AA.
AC P55263; B7Z783; B7Z800; O00741; O00742; Q16710; Q5JQ10; Q5JQ11;
read moreAC Q9BTN2;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2000, sequence version 2.
DT 22-JAN-2014, entry version 151.
DE RecName: Full=Adenosine kinase;
DE Short=AK;
DE EC=2.7.1.20;
DE AltName: Full=Adenosine 5'-phosphotransferase;
GN Name=ADK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND PROTEIN SEQUENCE OF
RP 94-133; 175-200 AND 272-289.
RC TISSUE=Liver;
RX PubMed=8577746; DOI=10.1073/pnas.93.3.1232;
RA Spychala J., Datta N.S., Takabayashi K., Datta M., Fox I.H.,
RA Gribbin T., Mitchell B.S.;
RT "Cloning of human adenosine kinase cDNA: sequence similarity to
RT microbial ribokinases and fructokinases.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:1232-1237(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION.
RX PubMed=8917457; DOI=10.1111/j.1432-1033.1996.00564.x;
RA Singh B., Hao W., Wu Z.-C., Eigl B., Gupta R.S.;
RT "Cloning and characterization of cDNA for adenosine kinase from
RT mammalian (Chinese hamster, mouse, human and rat) species. High
RT frequency mutants of Chinese hamster ovary cells involve structural
RT alterations in the gene.";
RL Eur. J. Biochem. 241:564-571(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND ALTERNATIVE
RP SPLICING.
RX PubMed=9070863; DOI=10.1006/bbrc.1997.6157;
RA McNally T., Helfrich R.J., Cowart M., Dorwin S.A., Meuth J.L.,
RA Idler K.B., Klute K.A., Simmer R.L., Kowaluk E.A., Halbert D.N.;
RT "Cloning and expression of the adenosine kinase gene from rat and
RT human tissues.";
RL Biochem. Biophys. Res. Commun. 231:645-650(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 4).
RC TISSUE=Mammary gland, and Testis;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [9]
RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, AND MUTAGENESIS OF
RP 11-LYS-LYS-12.
RX PubMed=19635462; DOI=10.1016/j.bbrc.2009.07.106;
RA Cui X.A., Singh B., Park J., Gupta R.S.;
RT "Subcellular localization of adenosine kinase in mammalian cells: The
RT long isoform of AdK is localized in the nucleus.";
RL Biochem. Biophys. Res. Commun. 388:46-50(2009).
RN [10]
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.,
RA Buerckstuemmer T., 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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF ISOFORM 2.
RX PubMed=9843365; DOI=10.1021/bi9815445;
RA Mathews I.I., Erion M.D., Ealick S.E.;
RT "Structure of human adenosine kinase at 1.5-A resolution.";
RL Biochemistry 37:15607-15620(1998).
RN [13]
RP PHOSPHORYLATION AT TYR-77.
RX PubMed=12112843;
RX DOI=10.1002/1615-9861(200206)2:6<642::AID-PROT642>3.0.CO;2-I;
RA Maguire P.B., Wynne K.J., Harney D.F., O'Donoghue N.M., Stephens G.,
RA Fitzgerald D.J.;
RT "Identification of the phosphotyrosine proteome from thrombin
RT activated platelets.";
RL Proteomics 2:642-648(2002).
RN [14]
RP VARIANTS HMAKD GLU-30; ALA-235 AND GLU-318, AND CHARACTERIZATION OF
RP VARIANTS HMAKD GLU-30; ALA-235 AND GLU-318.
RX PubMed=21963049; DOI=10.1016/j.ajhg.2011.09.004;
RA Bjursell M.K., Blom H.J., Cayuela J.A., Engvall M.L., Lesko N.,
RA Balasubramaniam S., Brandberg G., Halldin M., Falkenberg M.,
RA Jakobs C., Smith D., Struys E., von Dobeln U., Gustafsson C.M.,
RA Lundeberg J., Wedell A.;
RT "Adenosine kinase deficiency disrupts the methionine cycle and causes
RT hypermethioninemia, encephalopathy, and abnormal liver function.";
RL Am. J. Hum. Genet. 89:507-515(2011).
CC -!- FUNCTION: ATP dependent phosphorylation of adenosine and other
CC related nucleoside analogs to monophosphate derivatives. Serves as
CC a potential regulator of concentrations of extracellular adenosine
CC and intracellular adenine nucleotides.
CC -!- CATALYTIC ACTIVITY: ATP + adenosine = ADP + AMP.
CC -!- COFACTOR: Binds 3 magnesium ions per subunit.
CC -!- PATHWAY: Purine metabolism; AMP biosynthesis via salvage pathway;
CC AMP from adenosine: step 1/1.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Nucleus.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Long;
CC IsoId=P55263-1; Sequence=Displayed;
CC Name=2; Synonyms=Short;
CC IsoId=P55263-2; Sequence=VSP_046713;
CC Name=3;
CC IsoId=P55263-3; Sequence=VSP_043526;
CC Name=4;
CC IsoId=P55263-4; Sequence=VSP_004668;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Highest level in placenta,
CC liver, muscle and kidney.
CC -!- DISEASE: Hypermethioninemia due to adenosine kinase deficiency
CC (HMAKD) [MIM:614300]: A metabolic disorder characterized by global
CC developmental delay, early-onset seizures, mild dysmorphic
CC features, and characteristic biochemical anomalies, including
CC persistent hypermethioninemia with increased levels of S-
CC adenosylmethionine and S-adenosylhomocysteine. Homocysteine levels
CC are typically normal. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the carbohydrate kinase PfkB family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB01689.1; Type=Frameshift; Positions=17;
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DR EMBL; U50196; AAA97893.1; -; mRNA.
DR EMBL; U33936; AAB01689.1; ALT_FRAME; mRNA.
DR EMBL; U90338; AAB50234.1; -; mRNA.
DR EMBL; U90339; AAB50235.1; -; mRNA.
DR EMBL; AK290633; BAF83322.1; -; mRNA.
DR EMBL; AK301590; BAH13519.1; -; mRNA.
DR EMBL; AK302706; BAH13786.1; -; mRNA.
DR EMBL; AC012046; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022026; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022540; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC091699; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL357037; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL731576; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471083; EAW54555.1; -; Genomic_DNA.
DR EMBL; CH471083; EAW54556.1; -; Genomic_DNA.
DR EMBL; BC003568; AAH03568.1; -; mRNA.
DR PIR; JC5363; JC5363.
DR PIR; JC5364; JC5364.
DR RefSeq; NP_001114.2; NM_001123.3.
DR RefSeq; NP_001189378.1; NM_001202449.1.
DR RefSeq; NP_001189379.1; NM_001202450.1.
DR RefSeq; NP_006712.2; NM_006721.3.
DR UniGene; Hs.656586; -.
DR PDB; 1BX4; X-ray; 1.50 A; A=22-362.
DR PDB; 2I6A; X-ray; 2.20 A; A/B/C/D=22-362.
DR PDB; 2I6B; X-ray; 2.30 A; A/B=22-362.
DR PDBsum; 1BX4; -.
DR PDBsum; 2I6A; -.
DR PDBsum; 2I6B; -.
DR ProteinModelPortal; P55263; -.
DR SMR; P55263; 20-362.
DR IntAct; P55263; 3.
DR MINT; MINT-5001097; -.
DR STRING; 9606.ENSP00000286621; -.
DR BindingDB; P55263; -.
DR ChEMBL; CHEMBL3589; -.
DR DrugBank; DB00640; Adenosine.
DR DrugBank; DB00131; Adenosine monophosphate.
DR DrugBank; DB00171; Adenosine triphosphate.
DR DrugBank; DB00061; Pegademase bovine.
DR DrugBank; DB00811; Ribavirin.
DR GuidetoPHARMACOLOGY; 1231; -.
DR PhosphoSite; P55263; -.
DR DMDM; 6840802; -.
DR REPRODUCTION-2DPAGE; IPI00234368; -.
DR PaxDb; P55263; -.
DR PRIDE; P55263; -.
DR DNASU; 132; -.
DR Ensembl; ENST00000286621; ENSP00000286621; ENSG00000156110.
DR Ensembl; ENST00000372734; ENSP00000361819; ENSG00000156110.
DR Ensembl; ENST00000539909; ENSP00000443965; ENSG00000156110.
DR Ensembl; ENST00000541550; ENSP00000438321; ENSG00000156110.
DR GeneID; 132; -.
DR KEGG; hsa:132; -.
DR UCSC; uc010qlc.2; human.
DR CTD; 132; -.
DR GeneCards; GC10P075910; -.
DR HGNC; HGNC:257; ADK.
DR HPA; HPA038409; -.
DR MIM; 102750; gene.
DR MIM; 614300; phenotype.
DR neXtProt; NX_P55263; -.
DR Orphanet; 289290; Hypermethioninemia encephalopathy due to adenosine kinase deficiency.
DR PharmGKB; PA24579; -.
DR eggNOG; COG0524; -.
DR HOGENOM; HOG000172419; -.
DR HOVERGEN; HBG002367; -.
DR InParanoid; P55263; -.
DR KO; K00856; -.
DR OMA; CITGGNR; -.
DR OrthoDB; EOG7VMP5W; -.
DR PhylomeDB; P55263; -.
DR BioCyc; MetaCyc:HS08097-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P55263; -.
DR UniPathway; UPA00588; UER00659.
DR ChiTaRS; ADK; human.
DR EvolutionaryTrace; P55263; -.
DR GeneWiki; ADK_(gene); -.
DR GenomeRNAi; 132; -.
DR NextBio; 527; -.
DR PRO; PR:P55263; -.
DR ArrayExpress; P55263; -.
DR Bgee; P55263; -.
DR CleanEx; HS_ADK; -.
DR Genevestigator; P55263; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004001; F:adenosine kinase activity; EXP:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016773; F:phosphotransferase activity, alcohol group as acceptor; IEA:InterPro.
DR GO; GO:0046085; P:adenosine metabolic process; IEA:Ensembl.
DR GO; GO:0044209; P:AMP salvage; IEA:UniProtKB-UniPathway.
DR GO; GO:0032922; P:circadian regulation of gene expression; IEA:Ensembl.
DR GO; GO:0006175; P:dATP biosynthetic process; IEA:Ensembl.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0006166; P:purine ribonucleoside salvage; IEA:UniProtKB-KW.
DR GO; GO:0043101; P:purine-containing compound salvage; TAS:Reactome.
DR GO; GO:0044342; P:type B pancreatic cell proliferation; IEA:Ensembl.
DR InterPro; IPR001805; Adenokinase.
DR InterPro; IPR002173; Carboh/pur_kinase_PfkB_CS.
DR InterPro; IPR011611; PfkB_dom.
DR PANTHER; PTHR10584:SF24; PTHR10584:SF24; 1.
DR Pfam; PF00294; PfkB; 1.
DR PRINTS; PR00989; ADENOKINASE.
DR PROSITE; PS00583; PFKB_KINASES_1; FALSE_NEG.
DR PROSITE; PS00584; PFKB_KINASES_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disease mutation; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Purine salvage;
KW Reference proteome; Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 362 Adenosine kinase.
FT /FTId=PRO_0000080053.
FT MOTIF 8 16 Nuclear localization signal.
FT ACT_SITE 317 317
FT METAL 49 49 Magnesium 1.
FT METAL 147 147 Magnesium 2.
FT METAL 148 148 Magnesium 2.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 77 77 Phosphotyrosine.
FT VAR_SEQ 1 65 MAAAEEEPKPKKLKVEAPQALRENILFGMGNPLLDISAVVD
FT KDFLDKYSLKPNDQILAEDKHKEL -> MTSVRENILFGMG
FT NPLLDISAVVDKDFLDK (in isoform 4).
FT /FTId=VSP_004668.
FT VAR_SEQ 1 21 MAAAEEEPKPKKLKVEAPQAL -> MTSV (in isoform
FT 2).
FT /FTId=VSP_046713.
FT VAR_SEQ 186 242 Missing (in isoform 3).
FT /FTId=VSP_043526.
FT VARIANT 30 30 G -> E (in HMAKD; the mutant shows some
FT residual activity).
FT /FTId=VAR_066640.
FT VARIANT 235 235 D -> A (in HMAKD; the mutant shows some
FT residual activity).
FT /FTId=VAR_066641.
FT VARIANT 318 318 A -> E (in HMAKD; complete loss of
FT activity).
FT /FTId=VAR_066642.
FT MUTAGEN 11 12 KK->AA,AD: Abolishes nuclear
FT localization.
FT CONFLICT 98 98 H -> A (in Ref. 1; AA sequence).
FT CONFLICT 133 133 N -> D (in Ref. 2; AAB01689).
FT CONFLICT 171 171 K -> R (in Ref. 2; AAB01689).
FT CONFLICT 190 190 T -> H (in Ref. 1; AAA97893).
FT CONFLICT 219 219 I -> F (in Ref. 7; AAH03568).
FT CONFLICT 273 273 S -> V (in Ref. 1; AA sequence).
FT CONFLICT 289 289 I -> N (in Ref. 1; AA sequence).
FT CONFLICT 307 307 K -> R (in Ref. 2; AAB01689).
FT STRAND 26 29
FT STRAND 33 39
FT HELIX 42 47
FT STRAND 52 57
FT HELIX 60 62
FT HELIX 63 72
FT STRAND 76 80
FT HELIX 82 94
FT STRAND 96 99
FT STRAND 101 110
FT HELIX 111 122
FT STRAND 126 135
FT STRAND 139 145
FT STRAND 148 154
FT HELIX 156 160
FT HELIX 163 165
FT TURN 166 168
FT HELIX 170 178
FT STRAND 180 185
FT HELIX 186 190
FT HELIX 193 205
FT STRAND 209 213
FT HELIX 217 222
FT HELIX 224 230
FT HELIX 231 233
FT STRAND 235 240
FT HELIX 241 250
FT HELIX 258 266
FT STRAND 278 283
FT STRAND 286 291
FT STRAND 296 299
FT HELIX 312 327
FT TURN 328 330
FT HELIX 333 347
FT STRAND 350 353
SQ SEQUENCE 362 AA; 40545 MW; 48AA4925865BFE70 CRC64;
MAAAEEEPKP KKLKVEAPQA LRENILFGMG NPLLDISAVV DKDFLDKYSL KPNDQILAED
KHKELFDELV KKFKVEYHAG GSTQNSIKVA QWMIQQPHKA ATFFGCIGID KFGEILKRKA
AEAHVDAHYY EQNEQPTGTC AACITGDNRS LIANLAAANC YKKEKHLDLE KNWMLVEKAR
VCYIAGFFLT VSPESVLKVA HHASENNRIF TLNLSAPFIS QFYKESLMKV MPYVDILFGN
ETEAATFARE QGFETKDIKE IAKKTQALPK MNSKRQRIVI FTQGRDDTIM ATESEVTAFA
VLDQDQKEII DTNGAGDAFV GGFLSQLVSD KPLTECIRAG HYAASIIIRR TGCTFPEKPD
FH
//
ID ADK_HUMAN Reviewed; 362 AA.
AC P55263; B7Z783; B7Z800; O00741; O00742; Q16710; Q5JQ10; Q5JQ11;
read moreAC Q9BTN2;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2000, sequence version 2.
DT 22-JAN-2014, entry version 151.
DE RecName: Full=Adenosine kinase;
DE Short=AK;
DE EC=2.7.1.20;
DE AltName: Full=Adenosine 5'-phosphotransferase;
GN Name=ADK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND PROTEIN SEQUENCE OF
RP 94-133; 175-200 AND 272-289.
RC TISSUE=Liver;
RX PubMed=8577746; DOI=10.1073/pnas.93.3.1232;
RA Spychala J., Datta N.S., Takabayashi K., Datta M., Fox I.H.,
RA Gribbin T., Mitchell B.S.;
RT "Cloning of human adenosine kinase cDNA: sequence similarity to
RT microbial ribokinases and fructokinases.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:1232-1237(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION.
RX PubMed=8917457; DOI=10.1111/j.1432-1033.1996.00564.x;
RA Singh B., Hao W., Wu Z.-C., Eigl B., Gupta R.S.;
RT "Cloning and characterization of cDNA for adenosine kinase from
RT mammalian (Chinese hamster, mouse, human and rat) species. High
RT frequency mutants of Chinese hamster ovary cells involve structural
RT alterations in the gene.";
RL Eur. J. Biochem. 241:564-571(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND ALTERNATIVE
RP SPLICING.
RX PubMed=9070863; DOI=10.1006/bbrc.1997.6157;
RA McNally T., Helfrich R.J., Cowart M., Dorwin S.A., Meuth J.L.,
RA Idler K.B., Klute K.A., Simmer R.L., Kowaluk E.A., Halbert D.N.;
RT "Cloning and expression of the adenosine kinase gene from rat and
RT human tissues.";
RL Biochem. Biophys. Res. Commun. 231:645-650(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 4).
RC TISSUE=Mammary gland, and Testis;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [9]
RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, AND MUTAGENESIS OF
RP 11-LYS-LYS-12.
RX PubMed=19635462; DOI=10.1016/j.bbrc.2009.07.106;
RA Cui X.A., Singh B., Park J., Gupta R.S.;
RT "Subcellular localization of adenosine kinase in mammalian cells: The
RT long isoform of AdK is localized in the nucleus.";
RL Biochem. Biophys. Res. Commun. 388:46-50(2009).
RN [10]
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.,
RA Buerckstuemmer T., 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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF ISOFORM 2.
RX PubMed=9843365; DOI=10.1021/bi9815445;
RA Mathews I.I., Erion M.D., Ealick S.E.;
RT "Structure of human adenosine kinase at 1.5-A resolution.";
RL Biochemistry 37:15607-15620(1998).
RN [13]
RP PHOSPHORYLATION AT TYR-77.
RX PubMed=12112843;
RX DOI=10.1002/1615-9861(200206)2:6<642::AID-PROT642>3.0.CO;2-I;
RA Maguire P.B., Wynne K.J., Harney D.F., O'Donoghue N.M., Stephens G.,
RA Fitzgerald D.J.;
RT "Identification of the phosphotyrosine proteome from thrombin
RT activated platelets.";
RL Proteomics 2:642-648(2002).
RN [14]
RP VARIANTS HMAKD GLU-30; ALA-235 AND GLU-318, AND CHARACTERIZATION OF
RP VARIANTS HMAKD GLU-30; ALA-235 AND GLU-318.
RX PubMed=21963049; DOI=10.1016/j.ajhg.2011.09.004;
RA Bjursell M.K., Blom H.J., Cayuela J.A., Engvall M.L., Lesko N.,
RA Balasubramaniam S., Brandberg G., Halldin M., Falkenberg M.,
RA Jakobs C., Smith D., Struys E., von Dobeln U., Gustafsson C.M.,
RA Lundeberg J., Wedell A.;
RT "Adenosine kinase deficiency disrupts the methionine cycle and causes
RT hypermethioninemia, encephalopathy, and abnormal liver function.";
RL Am. J. Hum. Genet. 89:507-515(2011).
CC -!- FUNCTION: ATP dependent phosphorylation of adenosine and other
CC related nucleoside analogs to monophosphate derivatives. Serves as
CC a potential regulator of concentrations of extracellular adenosine
CC and intracellular adenine nucleotides.
CC -!- CATALYTIC ACTIVITY: ATP + adenosine = ADP + AMP.
CC -!- COFACTOR: Binds 3 magnesium ions per subunit.
CC -!- PATHWAY: Purine metabolism; AMP biosynthesis via salvage pathway;
CC AMP from adenosine: step 1/1.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Nucleus.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Long;
CC IsoId=P55263-1; Sequence=Displayed;
CC Name=2; Synonyms=Short;
CC IsoId=P55263-2; Sequence=VSP_046713;
CC Name=3;
CC IsoId=P55263-3; Sequence=VSP_043526;
CC Name=4;
CC IsoId=P55263-4; Sequence=VSP_004668;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Highest level in placenta,
CC liver, muscle and kidney.
CC -!- DISEASE: Hypermethioninemia due to adenosine kinase deficiency
CC (HMAKD) [MIM:614300]: A metabolic disorder characterized by global
CC developmental delay, early-onset seizures, mild dysmorphic
CC features, and characteristic biochemical anomalies, including
CC persistent hypermethioninemia with increased levels of S-
CC adenosylmethionine and S-adenosylhomocysteine. Homocysteine levels
CC are typically normal. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the carbohydrate kinase PfkB family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB01689.1; Type=Frameshift; Positions=17;
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DR EMBL; U50196; AAA97893.1; -; mRNA.
DR EMBL; U33936; AAB01689.1; ALT_FRAME; mRNA.
DR EMBL; U90338; AAB50234.1; -; mRNA.
DR EMBL; U90339; AAB50235.1; -; mRNA.
DR EMBL; AK290633; BAF83322.1; -; mRNA.
DR EMBL; AK301590; BAH13519.1; -; mRNA.
DR EMBL; AK302706; BAH13786.1; -; mRNA.
DR EMBL; AC012046; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022026; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022540; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC091699; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL357037; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL731576; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471083; EAW54555.1; -; Genomic_DNA.
DR EMBL; CH471083; EAW54556.1; -; Genomic_DNA.
DR EMBL; BC003568; AAH03568.1; -; mRNA.
DR PIR; JC5363; JC5363.
DR PIR; JC5364; JC5364.
DR RefSeq; NP_001114.2; NM_001123.3.
DR RefSeq; NP_001189378.1; NM_001202449.1.
DR RefSeq; NP_001189379.1; NM_001202450.1.
DR RefSeq; NP_006712.2; NM_006721.3.
DR UniGene; Hs.656586; -.
DR PDB; 1BX4; X-ray; 1.50 A; A=22-362.
DR PDB; 2I6A; X-ray; 2.20 A; A/B/C/D=22-362.
DR PDB; 2I6B; X-ray; 2.30 A; A/B=22-362.
DR PDBsum; 1BX4; -.
DR PDBsum; 2I6A; -.
DR PDBsum; 2I6B; -.
DR ProteinModelPortal; P55263; -.
DR SMR; P55263; 20-362.
DR IntAct; P55263; 3.
DR MINT; MINT-5001097; -.
DR STRING; 9606.ENSP00000286621; -.
DR BindingDB; P55263; -.
DR ChEMBL; CHEMBL3589; -.
DR DrugBank; DB00640; Adenosine.
DR DrugBank; DB00131; Adenosine monophosphate.
DR DrugBank; DB00171; Adenosine triphosphate.
DR DrugBank; DB00061; Pegademase bovine.
DR DrugBank; DB00811; Ribavirin.
DR GuidetoPHARMACOLOGY; 1231; -.
DR PhosphoSite; P55263; -.
DR DMDM; 6840802; -.
DR REPRODUCTION-2DPAGE; IPI00234368; -.
DR PaxDb; P55263; -.
DR PRIDE; P55263; -.
DR DNASU; 132; -.
DR Ensembl; ENST00000286621; ENSP00000286621; ENSG00000156110.
DR Ensembl; ENST00000372734; ENSP00000361819; ENSG00000156110.
DR Ensembl; ENST00000539909; ENSP00000443965; ENSG00000156110.
DR Ensembl; ENST00000541550; ENSP00000438321; ENSG00000156110.
DR GeneID; 132; -.
DR KEGG; hsa:132; -.
DR UCSC; uc010qlc.2; human.
DR CTD; 132; -.
DR GeneCards; GC10P075910; -.
DR HGNC; HGNC:257; ADK.
DR HPA; HPA038409; -.
DR MIM; 102750; gene.
DR MIM; 614300; phenotype.
DR neXtProt; NX_P55263; -.
DR Orphanet; 289290; Hypermethioninemia encephalopathy due to adenosine kinase deficiency.
DR PharmGKB; PA24579; -.
DR eggNOG; COG0524; -.
DR HOGENOM; HOG000172419; -.
DR HOVERGEN; HBG002367; -.
DR InParanoid; P55263; -.
DR KO; K00856; -.
DR OMA; CITGGNR; -.
DR OrthoDB; EOG7VMP5W; -.
DR PhylomeDB; P55263; -.
DR BioCyc; MetaCyc:HS08097-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P55263; -.
DR UniPathway; UPA00588; UER00659.
DR ChiTaRS; ADK; human.
DR EvolutionaryTrace; P55263; -.
DR GeneWiki; ADK_(gene); -.
DR GenomeRNAi; 132; -.
DR NextBio; 527; -.
DR PRO; PR:P55263; -.
DR ArrayExpress; P55263; -.
DR Bgee; P55263; -.
DR CleanEx; HS_ADK; -.
DR Genevestigator; P55263; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004001; F:adenosine kinase activity; EXP:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016773; F:phosphotransferase activity, alcohol group as acceptor; IEA:InterPro.
DR GO; GO:0046085; P:adenosine metabolic process; IEA:Ensembl.
DR GO; GO:0044209; P:AMP salvage; IEA:UniProtKB-UniPathway.
DR GO; GO:0032922; P:circadian regulation of gene expression; IEA:Ensembl.
DR GO; GO:0006175; P:dATP biosynthetic process; IEA:Ensembl.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0006166; P:purine ribonucleoside salvage; IEA:UniProtKB-KW.
DR GO; GO:0043101; P:purine-containing compound salvage; TAS:Reactome.
DR GO; GO:0044342; P:type B pancreatic cell proliferation; IEA:Ensembl.
DR InterPro; IPR001805; Adenokinase.
DR InterPro; IPR002173; Carboh/pur_kinase_PfkB_CS.
DR InterPro; IPR011611; PfkB_dom.
DR PANTHER; PTHR10584:SF24; PTHR10584:SF24; 1.
DR Pfam; PF00294; PfkB; 1.
DR PRINTS; PR00989; ADENOKINASE.
DR PROSITE; PS00583; PFKB_KINASES_1; FALSE_NEG.
DR PROSITE; PS00584; PFKB_KINASES_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disease mutation; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Purine salvage;
KW Reference proteome; Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 362 Adenosine kinase.
FT /FTId=PRO_0000080053.
FT MOTIF 8 16 Nuclear localization signal.
FT ACT_SITE 317 317
FT METAL 49 49 Magnesium 1.
FT METAL 147 147 Magnesium 2.
FT METAL 148 148 Magnesium 2.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 77 77 Phosphotyrosine.
FT VAR_SEQ 1 65 MAAAEEEPKPKKLKVEAPQALRENILFGMGNPLLDISAVVD
FT KDFLDKYSLKPNDQILAEDKHKEL -> MTSVRENILFGMG
FT NPLLDISAVVDKDFLDK (in isoform 4).
FT /FTId=VSP_004668.
FT VAR_SEQ 1 21 MAAAEEEPKPKKLKVEAPQAL -> MTSV (in isoform
FT 2).
FT /FTId=VSP_046713.
FT VAR_SEQ 186 242 Missing (in isoform 3).
FT /FTId=VSP_043526.
FT VARIANT 30 30 G -> E (in HMAKD; the mutant shows some
FT residual activity).
FT /FTId=VAR_066640.
FT VARIANT 235 235 D -> A (in HMAKD; the mutant shows some
FT residual activity).
FT /FTId=VAR_066641.
FT VARIANT 318 318 A -> E (in HMAKD; complete loss of
FT activity).
FT /FTId=VAR_066642.
FT MUTAGEN 11 12 KK->AA,AD: Abolishes nuclear
FT localization.
FT CONFLICT 98 98 H -> A (in Ref. 1; AA sequence).
FT CONFLICT 133 133 N -> D (in Ref. 2; AAB01689).
FT CONFLICT 171 171 K -> R (in Ref. 2; AAB01689).
FT CONFLICT 190 190 T -> H (in Ref. 1; AAA97893).
FT CONFLICT 219 219 I -> F (in Ref. 7; AAH03568).
FT CONFLICT 273 273 S -> V (in Ref. 1; AA sequence).
FT CONFLICT 289 289 I -> N (in Ref. 1; AA sequence).
FT CONFLICT 307 307 K -> R (in Ref. 2; AAB01689).
FT STRAND 26 29
FT STRAND 33 39
FT HELIX 42 47
FT STRAND 52 57
FT HELIX 60 62
FT HELIX 63 72
FT STRAND 76 80
FT HELIX 82 94
FT STRAND 96 99
FT STRAND 101 110
FT HELIX 111 122
FT STRAND 126 135
FT STRAND 139 145
FT STRAND 148 154
FT HELIX 156 160
FT HELIX 163 165
FT TURN 166 168
FT HELIX 170 178
FT STRAND 180 185
FT HELIX 186 190
FT HELIX 193 205
FT STRAND 209 213
FT HELIX 217 222
FT HELIX 224 230
FT HELIX 231 233
FT STRAND 235 240
FT HELIX 241 250
FT HELIX 258 266
FT STRAND 278 283
FT STRAND 286 291
FT STRAND 296 299
FT HELIX 312 327
FT TURN 328 330
FT HELIX 333 347
FT STRAND 350 353
SQ SEQUENCE 362 AA; 40545 MW; 48AA4925865BFE70 CRC64;
MAAAEEEPKP KKLKVEAPQA LRENILFGMG NPLLDISAVV DKDFLDKYSL KPNDQILAED
KHKELFDELV KKFKVEYHAG GSTQNSIKVA QWMIQQPHKA ATFFGCIGID KFGEILKRKA
AEAHVDAHYY EQNEQPTGTC AACITGDNRS LIANLAAANC YKKEKHLDLE KNWMLVEKAR
VCYIAGFFLT VSPESVLKVA HHASENNRIF TLNLSAPFIS QFYKESLMKV MPYVDILFGN
ETEAATFARE QGFETKDIKE IAKKTQALPK MNSKRQRIVI FTQGRDDTIM ATESEVTAFA
VLDQDQKEII DTNGAGDAFV GGFLSQLVSD KPLTECIRAG HYAASIIIRR TGCTFPEKPD
FH
//
MIM
102750
*RECORD*
*FIELD* NO
102750
*FIELD* TI
*102750 ADENOSINE KINASE; ADK
*FIELD* TX
DESCRIPTION
The ADK gene encodes adenosine kinase (ATP:adenosine
read more5-prime-phosphotransferase; EC 2.7.1.20), an abundant enzyme in
mammalian tissues that catalyzes the transfer of the gamma-phosphate
from ATP to adenosine, thereby serving as a potentially important
regulator of concentrations of both extracellular adenosine and
intracellular adenine nucleotides. Adenosine has widespread effects on
the cardiovascular, nervous, respiratory, and immune systems, and
inhibitors of ADK could play an important pharmacologic role in
increasing intravascular adenosine concentrations and acting as
inflammatory agents (summary by Spychala et al., 1996).
CLONING
Spychala et al. (1996) obtained full-length cDNA clones encoding
catalytically active ADK from lymphocyte, placental, and liver cDNA
libraries. On Northern blots of all tissues examined, they identified
mRNA species of 1.3 and 1.8 kb, attributable to alternative
polyadenylation sites at the 3-prime end of the gene. The encoded
protein consisted of 345 amino acids with a calculated molecular size of
38.7 kD and without any sequence similarities to other
well-characterized mammalian nucleoside kinases. In contrast, 2 regions
were identified with significant sequence identity to microbial
ribokinase and fructokinases and a bacterial inosine/guanosine kinase.
Thus, ADK is a structurally distinct mammalian nucleoside kinase that
appears to be akin to sugar kinases of microbial origin.
McNally et al. (1997) also cloned human cDNAs encoding adenosine kinase.
They found cDNAs encoding both the 345-amino acid form and a 362-amino
acid form of the enzyme. These 2 alternately spliced forms differed only
at the 5-prime end. When expressed, both isoforms of the enzyme
phosphorylated adenosine with identical kinetics and both required Mg2+
for activity.
MAPPING
The structural gene for this enzyme was tentatively assigned to
chromosome 10 by somatic cell hybrid studies (Klobutcher et al., 1976).
By the principle of gene dosage, Francke and Thompson (1979) concluded
by exclusion that ADK must be in the region 10q11-10q24.
In a case of trisomy 10p, Snyder et al. (1984) found normal levels of
ADK.
MOLECULAR GENETICS
By exome sequencing, Bjursell et al. (2011) identified a homozygous
mutation in the ADK gene (102750.0001) in 2 Swedish sibs with severe
developmental delay, mild liver dysfunction, and persistent
hypermethioninemia due to adenosine kinase deficiency (614300).
Subsequent analysis of this gene in Malaysian patients with a similar
phenotype revealed 2 different homozygous mutations in the ADK gene
(102750.0002 and 102750.0003) in 2 families. The phenotype was
characterized by global developmental delay, early-onset seizures, mild
dysmorphic features, and characteristic biochemical anomalies, including
persistent hypermethioninemia with increased levels of
S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy);
homocysteine was typically normal. Bjursell et al. (2011) concluded that
the phenotype resulted from a combination of direct adenosine toxicity,
a defect in the regulation of adenosine, and disruption of a wide range
of methyltransferase reactions.
ANIMAL MODEL
Neonatal hepatic steatosis (228100) is a fatal condition characterized
by rapid microvesicular fat infiltration and enlargement of the liver,
which shows a pale and yellowish coloration. Microvesicular fat
infiltration, liver failure, coma, and death are considered to be a
consequence of severe impairment of mitochondrial function. Boison et
al. (2002) pursued the hypothesis that a deficit in adenosine-dependent
metabolism is a causative factor for the development of microvesicular
hepatic steatosis. A deficiency of adenosine kinase, the major
adenosine-removing enzyme of postnatal liver, was expected to affect
liver function on 3 levels: availability of adenine nucleotides;
disruption of the futile cycle between AMP and adenosine; and
maintenance of transmethylation reactions. Homozygous Adk -/- mice,
generated through Adk targeting of embryonic stem cells, developed
normally during embryogenesis. However, within 4 days after birth they
displayed microvesicular hepatic steatosis and died within 14 days with
fatty liver. Adenine nucleotides were decreased and
S-adenosylhomocysteine, a potent inhibitor of transmethylation
reactions, was increased in the mutant liver. Thus, a deficiency of
adenosine metabolism is identified as a powerful contributor to the
development of neonatal hepatic steatosis, providing a model for the
rapid development of postnatally lethal fatty liver.
*FIELD* AV
.0001
HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY
ADK, ALA301GLU
In 2 Swedish sibs with hypermethioninemia due to adenosine kinase
deficiency (614300), Bjursell et al. (2011) identified a homozygous
902C-A transversion in the ADK gene, resulting in an ala301-to-glu
(A301E) substitution adjacent to the catalytic site. Each unaffected
parent was heterozygous for the mutation, which was not found in 105
controls. In vitro functional expression studies in E. coli showed that
the mutant protein had almost no enzymatic activity.
.0002
HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY
ADK, ASP218ALA
In 2 Malaysian sibs with hypermethioninemia due to adenosine kinase
deficiency (614300), Bjursell et al. (2011) identified a homozygous
653A-C transversion in the ADK gene, resulting in an asp218-to-ala
(D218A) substitution in the central beta-sheet domain. Each unaffected
parent was heterozygous for the mutation. In vitro functional expression
studies in E. coli showed that the mutant protein had about 20% residual
enzymatic activity compared to wildtype.
.0003
HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY
ADK, GLY13GLU
In 2 Malaysian sibs with hypermethioninemia due to adenosine kinase
deficiency (614300), Bjursell et al. (2011) identified a homozygous
38G-A transition in the ADK gene, resulting in a gly13-to-glu (G13E)
substitution close to the binding site for adenosine. Each unaffected
parent was heterozygous for the mutation. In vitro functional expression
studies in E. coli showed that the mutant protein had about 10% residual
enzymatic activity compared to wildtype.
*FIELD* SA
Chan et al. (1978)
*FIELD* RF
1. Bjursell, M. K.; Blom, H. J.; Cayuela, J. A.; Engvall, M. L.; Lesko,
N.; Balasubramaniam, S.; Brandberg, G.; Halldin, M.; Falkenberg, M.;
Jakobs, C.; Smith, D.; Struys, E.; von Dobeln, U.; Gustafsson, C.
M.; Lundeberg, J.; Wedell, A.: Adenosine kinase deficiency disrupts
the methionine cycle and causes hypermethioninemia, encephalopathy,
and abnormal liver function. Am. J. Hum. Genet. 89: 507-515, 2011.
2. Boison, D.; Scheurer, L.; Zumsteg, V.; Rulicke, T.; Litynski, P.;
Fowler, B.; Brandner, S.; Mohler, H.: Neonatal hepatic steatosis
by disruption of the adenosine kinase gene. Proc. Nat. Acad. Sci. 99:
6985-6990, 2002.
3. Chan, T.-S.; Cregan, R. P.; Reardon, M. P.: Adenosine kinase as
a new selective marker in somatic cell genetics: isolation of adenosine
kinase-deficient mouse cell lines and human-mouse hybrid cell lines
containing adenosine kinase. Somat. Cell Genet. 4: 1-12, 1978.
4. Francke, U.; Thompson, L.: Regional mapping, by exclusion, of
adenosine kinase (ADK) on human chromosome 10 using the gene dosage
approach. (Abstract) Cytogenet. Cell Genet. 25: 156, 1979.
5. Klobutcher, L. A.; Nichols, E. A.; Kucherlapati, R. S.; Ruddle,
F. H.: Assignment of the gene for human adenosine kinase to chromosome
10 using a somatic cell hybrid clone panel. Cytogenet. Cell Genet. 16:
171-174, 1976.
6. McNally, T.; Helfrich, R. J.; Cowart, M.; Dorwin, S. A.; Meuth,
J. L.; Idler, K. B.; Klute, K. A.; Simmer, R. L.; Kowaluk, E. A.;
Halbert, D. N.: Cloning and expression of the adenosine kinase gene
from rat and human tissues. Biochem. Biophys. Res. Commun. 231:
645-650, 1997.
7. Snyder, F. F.; Lin, C. C.; Rudd, N. L.; Shearer, J. E.; Heikkila,
E. M.; Hoo, J. J.: A de novo case of trisomy 10p: gene dosage studies
of hexokinase, inorganic pyrophosphatase and adenosine kinase. Hum.
Genet. 67: 187-189, 1984.
8. Spychala, J.; Datta, N. S.; Takabayashi, K.; Datta, M.; Fox, I.;
Gribbin, T.; Mitchell, B.: Cloning of human adenosine kinase cDNA:
sequenced similarity to microbial ribokinases and fructokinases, Proc.
Nat. Acad. Sci. 93: 1232-1237, 1996.
*FIELD* CN
Cassandra L. Kniffin - updated: 10/20/2011
Victor A. McKusick - updated: 6/14/2002
Jennifer P. Macke - updated: 5/4/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 10/21/2011
carol: 10/21/2011
ckniffin: 10/20/2011
alopez: 2/25/2010
cwells: 6/28/2002
terry: 6/14/2002
alopez: 5/4/1998
mark: 2/26/1996
mark: 2/20/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986
*RECORD*
*FIELD* NO
102750
*FIELD* TI
*102750 ADENOSINE KINASE; ADK
*FIELD* TX
DESCRIPTION
The ADK gene encodes adenosine kinase (ATP:adenosine
read more5-prime-phosphotransferase; EC 2.7.1.20), an abundant enzyme in
mammalian tissues that catalyzes the transfer of the gamma-phosphate
from ATP to adenosine, thereby serving as a potentially important
regulator of concentrations of both extracellular adenosine and
intracellular adenine nucleotides. Adenosine has widespread effects on
the cardiovascular, nervous, respiratory, and immune systems, and
inhibitors of ADK could play an important pharmacologic role in
increasing intravascular adenosine concentrations and acting as
inflammatory agents (summary by Spychala et al., 1996).
CLONING
Spychala et al. (1996) obtained full-length cDNA clones encoding
catalytically active ADK from lymphocyte, placental, and liver cDNA
libraries. On Northern blots of all tissues examined, they identified
mRNA species of 1.3 and 1.8 kb, attributable to alternative
polyadenylation sites at the 3-prime end of the gene. The encoded
protein consisted of 345 amino acids with a calculated molecular size of
38.7 kD and without any sequence similarities to other
well-characterized mammalian nucleoside kinases. In contrast, 2 regions
were identified with significant sequence identity to microbial
ribokinase and fructokinases and a bacterial inosine/guanosine kinase.
Thus, ADK is a structurally distinct mammalian nucleoside kinase that
appears to be akin to sugar kinases of microbial origin.
McNally et al. (1997) also cloned human cDNAs encoding adenosine kinase.
They found cDNAs encoding both the 345-amino acid form and a 362-amino
acid form of the enzyme. These 2 alternately spliced forms differed only
at the 5-prime end. When expressed, both isoforms of the enzyme
phosphorylated adenosine with identical kinetics and both required Mg2+
for activity.
MAPPING
The structural gene for this enzyme was tentatively assigned to
chromosome 10 by somatic cell hybrid studies (Klobutcher et al., 1976).
By the principle of gene dosage, Francke and Thompson (1979) concluded
by exclusion that ADK must be in the region 10q11-10q24.
In a case of trisomy 10p, Snyder et al. (1984) found normal levels of
ADK.
MOLECULAR GENETICS
By exome sequencing, Bjursell et al. (2011) identified a homozygous
mutation in the ADK gene (102750.0001) in 2 Swedish sibs with severe
developmental delay, mild liver dysfunction, and persistent
hypermethioninemia due to adenosine kinase deficiency (614300).
Subsequent analysis of this gene in Malaysian patients with a similar
phenotype revealed 2 different homozygous mutations in the ADK gene
(102750.0002 and 102750.0003) in 2 families. The phenotype was
characterized by global developmental delay, early-onset seizures, mild
dysmorphic features, and characteristic biochemical anomalies, including
persistent hypermethioninemia with increased levels of
S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy);
homocysteine was typically normal. Bjursell et al. (2011) concluded that
the phenotype resulted from a combination of direct adenosine toxicity,
a defect in the regulation of adenosine, and disruption of a wide range
of methyltransferase reactions.
ANIMAL MODEL
Neonatal hepatic steatosis (228100) is a fatal condition characterized
by rapid microvesicular fat infiltration and enlargement of the liver,
which shows a pale and yellowish coloration. Microvesicular fat
infiltration, liver failure, coma, and death are considered to be a
consequence of severe impairment of mitochondrial function. Boison et
al. (2002) pursued the hypothesis that a deficit in adenosine-dependent
metabolism is a causative factor for the development of microvesicular
hepatic steatosis. A deficiency of adenosine kinase, the major
adenosine-removing enzyme of postnatal liver, was expected to affect
liver function on 3 levels: availability of adenine nucleotides;
disruption of the futile cycle between AMP and adenosine; and
maintenance of transmethylation reactions. Homozygous Adk -/- mice,
generated through Adk targeting of embryonic stem cells, developed
normally during embryogenesis. However, within 4 days after birth they
displayed microvesicular hepatic steatosis and died within 14 days with
fatty liver. Adenine nucleotides were decreased and
S-adenosylhomocysteine, a potent inhibitor of transmethylation
reactions, was increased in the mutant liver. Thus, a deficiency of
adenosine metabolism is identified as a powerful contributor to the
development of neonatal hepatic steatosis, providing a model for the
rapid development of postnatally lethal fatty liver.
*FIELD* AV
.0001
HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY
ADK, ALA301GLU
In 2 Swedish sibs with hypermethioninemia due to adenosine kinase
deficiency (614300), Bjursell et al. (2011) identified a homozygous
902C-A transversion in the ADK gene, resulting in an ala301-to-glu
(A301E) substitution adjacent to the catalytic site. Each unaffected
parent was heterozygous for the mutation, which was not found in 105
controls. In vitro functional expression studies in E. coli showed that
the mutant protein had almost no enzymatic activity.
.0002
HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY
ADK, ASP218ALA
In 2 Malaysian sibs with hypermethioninemia due to adenosine kinase
deficiency (614300), Bjursell et al. (2011) identified a homozygous
653A-C transversion in the ADK gene, resulting in an asp218-to-ala
(D218A) substitution in the central beta-sheet domain. Each unaffected
parent was heterozygous for the mutation. In vitro functional expression
studies in E. coli showed that the mutant protein had about 20% residual
enzymatic activity compared to wildtype.
.0003
HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY
ADK, GLY13GLU
In 2 Malaysian sibs with hypermethioninemia due to adenosine kinase
deficiency (614300), Bjursell et al. (2011) identified a homozygous
38G-A transition in the ADK gene, resulting in a gly13-to-glu (G13E)
substitution close to the binding site for adenosine. Each unaffected
parent was heterozygous for the mutation. In vitro functional expression
studies in E. coli showed that the mutant protein had about 10% residual
enzymatic activity compared to wildtype.
*FIELD* SA
Chan et al. (1978)
*FIELD* RF
1. Bjursell, M. K.; Blom, H. J.; Cayuela, J. A.; Engvall, M. L.; Lesko,
N.; Balasubramaniam, S.; Brandberg, G.; Halldin, M.; Falkenberg, M.;
Jakobs, C.; Smith, D.; Struys, E.; von Dobeln, U.; Gustafsson, C.
M.; Lundeberg, J.; Wedell, A.: Adenosine kinase deficiency disrupts
the methionine cycle and causes hypermethioninemia, encephalopathy,
and abnormal liver function. Am. J. Hum. Genet. 89: 507-515, 2011.
2. Boison, D.; Scheurer, L.; Zumsteg, V.; Rulicke, T.; Litynski, P.;
Fowler, B.; Brandner, S.; Mohler, H.: Neonatal hepatic steatosis
by disruption of the adenosine kinase gene. Proc. Nat. Acad. Sci. 99:
6985-6990, 2002.
3. Chan, T.-S.; Cregan, R. P.; Reardon, M. P.: Adenosine kinase as
a new selective marker in somatic cell genetics: isolation of adenosine
kinase-deficient mouse cell lines and human-mouse hybrid cell lines
containing adenosine kinase. Somat. Cell Genet. 4: 1-12, 1978.
4. Francke, U.; Thompson, L.: Regional mapping, by exclusion, of
adenosine kinase (ADK) on human chromosome 10 using the gene dosage
approach. (Abstract) Cytogenet. Cell Genet. 25: 156, 1979.
5. Klobutcher, L. A.; Nichols, E. A.; Kucherlapati, R. S.; Ruddle,
F. H.: Assignment of the gene for human adenosine kinase to chromosome
10 using a somatic cell hybrid clone panel. Cytogenet. Cell Genet. 16:
171-174, 1976.
6. McNally, T.; Helfrich, R. J.; Cowart, M.; Dorwin, S. A.; Meuth,
J. L.; Idler, K. B.; Klute, K. A.; Simmer, R. L.; Kowaluk, E. A.;
Halbert, D. N.: Cloning and expression of the adenosine kinase gene
from rat and human tissues. Biochem. Biophys. Res. Commun. 231:
645-650, 1997.
7. Snyder, F. F.; Lin, C. C.; Rudd, N. L.; Shearer, J. E.; Heikkila,
E. M.; Hoo, J. J.: A de novo case of trisomy 10p: gene dosage studies
of hexokinase, inorganic pyrophosphatase and adenosine kinase. Hum.
Genet. 67: 187-189, 1984.
8. Spychala, J.; Datta, N. S.; Takabayashi, K.; Datta, M.; Fox, I.;
Gribbin, T.; Mitchell, B.: Cloning of human adenosine kinase cDNA:
sequenced similarity to microbial ribokinases and fructokinases, Proc.
Nat. Acad. Sci. 93: 1232-1237, 1996.
*FIELD* CN
Cassandra L. Kniffin - updated: 10/20/2011
Victor A. McKusick - updated: 6/14/2002
Jennifer P. Macke - updated: 5/4/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 10/21/2011
carol: 10/21/2011
ckniffin: 10/20/2011
alopez: 2/25/2010
cwells: 6/28/2002
terry: 6/14/2002
alopez: 5/4/1998
mark: 2/26/1996
mark: 2/20/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986
MIM
614300
*RECORD*
*FIELD* NO
614300
*FIELD* TI
#614300 HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because hypermethioninemia due
read moreto adenosine kinase deficiency can be caused by homozygous mutation in
the ADK gene (102750) on chromosome 10q.
DESCRIPTION
Hypermethioninemia due to adenosine kinase deficiency is an autosomal
recessive inborn error of metabolism characterized by global
developmental delay, early-onset seizures, mild dysmorphic features, and
characteristic biochemical anomalies, including persistent
hypermethioninemia with increased levels of S-adenosylmethionine
(AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine is typically
normal (summary by Bjursell et al., 2011).
CLINICAL FEATURES
Bjursell et al. (2011) reported 2 Swedish sibs with severe developmental
delay, mild liver dysfunction, and hypermethioninemia. Both had failure
to thrive in the neonatal period and later showed hypotonia, profound
psychomotor delay, and liver dysfunction. Both developed seizures before
age 3 years. Dysmorphic features included macrocephaly, frontal bossing,
hypertelorism, and slender hands and feet. During childhood, both had
sparse or absent language and slowly progressive muscular weakness and
wasting. EEG showed slow background activity with diffuse multifocal
discharges in some instances and abundant spike slow-wave complexes of
high amplitude at other times. The girl died during sleep at 10 years of
age. Liver biopsy performed at age 10 months in the boy showed slight
portal fibrosis and steatosis, and brain MRI showed cerebral atrophy
with nonspecific white matter degeneration. Brain MRI was essentially
normal at 14 months in the girl. Laboratory studies showed persistent
isolated hypermethioninemia, increased levels of S-adenosylmethionine
and S-adenosylhomocysteine, and normal or mildly increased total
homocysteine. Urinary studies showed increased excretion of adenosine.
S-adenosylhomocysteine hydrolase deficiency (613752) was excluded.
Bjursell et al. (2011) also reported 4 Malaysian patients from 2
unrelated consanguineous families with a similar disorder. All had
severe developmental delay and epilepsy, and all but 1 had macrocephaly
with frontal bossing. Liver biopsy of 3 patients showed cholestasis.
Three individuals had cardiac defects: 1 had mild pulmonary stenosis and
a small secundum atrial septal defect, another had a small secundum
atrial septal defect, and a third had a mild coarctation of the aorta.
Two patients had mild to moderate sensorineural hearing loss.
MOLECULAR GENETICS
By exome sequencing, Bjursell et al. (2011) identified a homozygous
mutation in the ADK gene (102750.0001) in 2 Swedish sibs with severe
developmental delay, mild liver dysfunction, and persistent
hypermethioninemia. Subsequent analysis of this gene in Malaysian
patients with a similar phenotype revealed different homozygous
mutations in the ADK gene in 2 families (102750.0002 and 102750.0003).
Bjursell et al. (2011) concluded that the phenotype resulted from a
combination of direct adenosine toxicity, a defect in the regulation of
adenosine, and disruption of a wide range of methyltransferase
reactions.
*FIELD* RF
1. Bjursell, M. K.; Blom, H. J.; Cayuela, J. A.; Engvall, M. L.; Lesko,
N.; Balasubramaniam, S.; Brandberg, G.; Halldin, M.; Falkenberg, M.;
Jakobs, C.; Smith, D.; Struys, E.; von Dobeln, U.; Gustafsson, C.
M.; Lundeberg, J.; Wedell, A.: Adenosine kinase deficiency disrupts
the methionine cycle and causes hypermethioninemia, encephalopathy,
and abnormal liver function. Am. J. Hum. Genet. 89: 507-515, 2011.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Macrocephaly;
Frontal bossing;
[Ears];
Hearing loss, sensorineural (in some);
[Eyes];
Hypertelorism
CARDIOVASCULAR:
[Heart];
Cardiac defects (in some);
Atrial septal defect (2 patients);
Pulmonary stenosis (1 patient);
[Vascular];
Coarctation of the aorta (1 patient)
ABDOMEN:
[Liver];
Liver dysfunction, mild;
Steatosis;
Cholestasis;
Portal fibrosis, mild
SKELETAL:
[Hands];
Slender hands;
[Feet];
Slender feet
MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle wasting
NEUROLOGIC:
[Central nervous system];
Global developmental delay, severe;
Hypotonia;
Seizures;
Poor speech development;
Cerebral atrophy;
White matter degeneration
LABORATORY ABNORMALITIES:
Abnormal liver enzymes;
Hyperbilirubinemia;
Hypermethioninemia;
Increased serum S-adenosylmethionine;
Increased serum S-adenosylhomocysteine;
Normal serum homocysteine;
Increased urinary adenosine
MISCELLANEOUS:
Onset in infancy;
Progressive disorder;
Six patients have been reported (as of October 2011)
MOLECULAR BASIS:
Caused by mutation in the adenosine kinase gene (ADK, 102750.0001)
*FIELD* CD
Cassandra L. Kniffin: 10/20/2011
*FIELD* ED
joanna: 12/29/2011
ckniffin: 10/20/2011
*FIELD* CD
Cassandra L. Kniffin: 10/20/2011
*FIELD* ED
carol: 10/21/2011
ckniffin: 10/20/2011
*RECORD*
*FIELD* NO
614300
*FIELD* TI
#614300 HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because hypermethioninemia due
read moreto adenosine kinase deficiency can be caused by homozygous mutation in
the ADK gene (102750) on chromosome 10q.
DESCRIPTION
Hypermethioninemia due to adenosine kinase deficiency is an autosomal
recessive inborn error of metabolism characterized by global
developmental delay, early-onset seizures, mild dysmorphic features, and
characteristic biochemical anomalies, including persistent
hypermethioninemia with increased levels of S-adenosylmethionine
(AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine is typically
normal (summary by Bjursell et al., 2011).
CLINICAL FEATURES
Bjursell et al. (2011) reported 2 Swedish sibs with severe developmental
delay, mild liver dysfunction, and hypermethioninemia. Both had failure
to thrive in the neonatal period and later showed hypotonia, profound
psychomotor delay, and liver dysfunction. Both developed seizures before
age 3 years. Dysmorphic features included macrocephaly, frontal bossing,
hypertelorism, and slender hands and feet. During childhood, both had
sparse or absent language and slowly progressive muscular weakness and
wasting. EEG showed slow background activity with diffuse multifocal
discharges in some instances and abundant spike slow-wave complexes of
high amplitude at other times. The girl died during sleep at 10 years of
age. Liver biopsy performed at age 10 months in the boy showed slight
portal fibrosis and steatosis, and brain MRI showed cerebral atrophy
with nonspecific white matter degeneration. Brain MRI was essentially
normal at 14 months in the girl. Laboratory studies showed persistent
isolated hypermethioninemia, increased levels of S-adenosylmethionine
and S-adenosylhomocysteine, and normal or mildly increased total
homocysteine. Urinary studies showed increased excretion of adenosine.
S-adenosylhomocysteine hydrolase deficiency (613752) was excluded.
Bjursell et al. (2011) also reported 4 Malaysian patients from 2
unrelated consanguineous families with a similar disorder. All had
severe developmental delay and epilepsy, and all but 1 had macrocephaly
with frontal bossing. Liver biopsy of 3 patients showed cholestasis.
Three individuals had cardiac defects: 1 had mild pulmonary stenosis and
a small secundum atrial septal defect, another had a small secundum
atrial septal defect, and a third had a mild coarctation of the aorta.
Two patients had mild to moderate sensorineural hearing loss.
MOLECULAR GENETICS
By exome sequencing, Bjursell et al. (2011) identified a homozygous
mutation in the ADK gene (102750.0001) in 2 Swedish sibs with severe
developmental delay, mild liver dysfunction, and persistent
hypermethioninemia. Subsequent analysis of this gene in Malaysian
patients with a similar phenotype revealed different homozygous
mutations in the ADK gene in 2 families (102750.0002 and 102750.0003).
Bjursell et al. (2011) concluded that the phenotype resulted from a
combination of direct adenosine toxicity, a defect in the regulation of
adenosine, and disruption of a wide range of methyltransferase
reactions.
*FIELD* RF
1. Bjursell, M. K.; Blom, H. J.; Cayuela, J. A.; Engvall, M. L.; Lesko,
N.; Balasubramaniam, S.; Brandberg, G.; Halldin, M.; Falkenberg, M.;
Jakobs, C.; Smith, D.; Struys, E.; von Dobeln, U.; Gustafsson, C.
M.; Lundeberg, J.; Wedell, A.: Adenosine kinase deficiency disrupts
the methionine cycle and causes hypermethioninemia, encephalopathy,
and abnormal liver function. Am. J. Hum. Genet. 89: 507-515, 2011.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Macrocephaly;
Frontal bossing;
[Ears];
Hearing loss, sensorineural (in some);
[Eyes];
Hypertelorism
CARDIOVASCULAR:
[Heart];
Cardiac defects (in some);
Atrial septal defect (2 patients);
Pulmonary stenosis (1 patient);
[Vascular];
Coarctation of the aorta (1 patient)
ABDOMEN:
[Liver];
Liver dysfunction, mild;
Steatosis;
Cholestasis;
Portal fibrosis, mild
SKELETAL:
[Hands];
Slender hands;
[Feet];
Slender feet
MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle wasting
NEUROLOGIC:
[Central nervous system];
Global developmental delay, severe;
Hypotonia;
Seizures;
Poor speech development;
Cerebral atrophy;
White matter degeneration
LABORATORY ABNORMALITIES:
Abnormal liver enzymes;
Hyperbilirubinemia;
Hypermethioninemia;
Increased serum S-adenosylmethionine;
Increased serum S-adenosylhomocysteine;
Normal serum homocysteine;
Increased urinary adenosine
MISCELLANEOUS:
Onset in infancy;
Progressive disorder;
Six patients have been reported (as of October 2011)
MOLECULAR BASIS:
Caused by mutation in the adenosine kinase gene (ADK, 102750.0001)
*FIELD* CD
Cassandra L. Kniffin: 10/20/2011
*FIELD* ED
joanna: 12/29/2011
ckniffin: 10/20/2011
*FIELD* CD
Cassandra L. Kniffin: 10/20/2011
*FIELD* ED
carol: 10/21/2011
ckniffin: 10/20/2011