Full text data of ATIC
ATIC
(PURH)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Bifunctional purine biosynthesis protein PURH; Phosphoribosylaminoimidazolecarboxamide formyltransferase; 2.1.2.3 (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase; AICAR transformylase; IMP cyclohydrolase; 3.5.4.10; ATIC; IMP synthase; Inosinicase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Bifunctional purine biosynthesis protein PURH; Phosphoribosylaminoimidazolecarboxamide formyltransferase; 2.1.2.3 (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase; AICAR transformylase; IMP cyclohydrolase; 3.5.4.10; ATIC; IMP synthase; Inosinicase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00289499
IPI00289499 Similar to Bifunctional purine biosynthesis protein PURH Phosphoribosylaminoimidazolecarboxamide formyltransferase, nucloside and nucleic acid metabolism, IMP cyclohydrolase activity soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00289499 Similar to Bifunctional purine biosynthesis protein PURH Phosphoribosylaminoimidazolecarboxamide formyltransferase, nucloside and nucleic acid metabolism, IMP cyclohydrolase activity soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P31939
ID PUR9_HUMAN Reviewed; 592 AA.
AC P31939; A8K202; E9PBU3; Q13856; Q53S28;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 10-OCT-2002, sequence version 3.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Bifunctional purine biosynthesis protein PURH;
DE Includes:
DE RecName: Full=Phosphoribosylaminoimidazolecarboxamide formyltransferase;
DE EC=2.1.2.3;
DE AltName: Full=5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase;
DE AltName: Full=AICAR transformylase;
DE Includes:
DE RecName: Full=IMP cyclohydrolase;
DE EC=3.5.4.10;
DE AltName: Full=ATIC;
DE AltName: Full=IMP synthase;
DE AltName: Full=Inosinicase;
GN Name=ATIC; Synonyms=PURH; ORFNames=OK/SW-cl.86;
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).
RC TISSUE=Hepatoma;
RX PubMed=8567683; DOI=10.1074/jbc.271.4.2225;
RA Rayl E.A., Moroson B.A., Beardsley G.P.;
RT "The human purH gene product, 5-aminoimidazole-4-carboxamide
RT ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning,
RT sequencing, expression, purification, kinetic analysis, and domain
RT mapping.";
RL J. Biol. Chem. 271:2225-2233(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=8867801; DOI=10.1093/dnares/2.6.269;
RA Yamauchi M., Seki N., Mita K., Saito T., Tsuji S., Hongo E.,
RA Morimyo M., Shiomi T., Koyama H.;
RT "Isolation of human purH gene expressed in the rodent transformant
RT cells by subtractive enrichment of 3'-untranslated region of human
RT transcript.";
RL DNA Res. 2:269-275(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=9378707;
RA Sugita T., Aya H., Ueno M., Ishizuka T., Kawashima K.;
RT "Characterization of molecularly cloned human 5-aminoimidazole-4-
RT carboxamide ribonucleotide transformylase.";
RL J. Biochem. 122:309-313(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon adenocarcinoma;
RA Shichijo S., Itoh K.;
RT "Identification of immuno-peptidmics that are recognized by tumor-
RT reactive CTL generated from TIL of colon cancer patients.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP SER-116.
RC TISSUE=Substantia nigra;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT SER-116.
RA Mural R.J., Istrail S., Sutton 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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
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 [9]
RP PROTEIN SEQUENCE OF 15-39; 91-97; 178-194; 208-225; 267-285 AND
RP 417-426, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [10]
RP PROTEIN SEQUENCE OF 178-189 AND 267-281.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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 [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-199, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [13]
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [15]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH XMP, AND
RP SUBUNIT.
RX PubMed=14756553; DOI=10.1021/bi030162i;
RA Wolan D.W., Cheong C.-G., Greasley S.E., Wilson I.A.;
RT "Structural insights into the human and avian IMP cyclohydrolase
RT mechanism via crystal structures with the bound XMP inhibitor.";
RL Biochemistry 43:1171-1183(2004).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) IN COMPLEX WITH AICAR; XMP AND
RP THE INHIBITORS BW1540 AND BW2315, FUNCTION, AND SUBUNIT.
RX PubMed=14966129; DOI=10.1074/jbc.M313691200;
RA Cheong C.-G., Wolan D.W., Greasley S.E., Horton P.A., Beardsley G.P.,
RA Wilson I.A.;
RT "Crystal structures of human bifunctional enzyme aminoimidazole-4-
RT carboxamide ribonucleotide transformylase/IMP cyclohydrolase in
RT complex with potent sulfonyl-containing antifolates.";
RL J. Biol. Chem. 279:18034-18045(2004).
RN [17]
RP VARIANT AICAR ARG-426, AND CHARACTERIZATION OF VARIANT AICAR ARG-426.
RX PubMed=15114530; DOI=10.1086/421475;
RA Marie S., Heron B., Bitoun P., Timmerman T., Van Den Berghe G.,
RA Vincent M.-F.;
RT "AICA-ribosiduria: a novel, neurologically devastating inborn error of
RT purine biosynthesis caused by mutation of ATIC.";
RL Am. J. Hum. Genet. 74:1276-1281(2004).
CC -!- FUNCTION: Bifunctional enzyme that catalyzes 2 steps in purine
CC biosynthesis.
CC -!- CATALYTIC ACTIVITY: 10-formyltetrahydrofolate + 5-amino-1-(5-
CC phospho-D-ribosyl)imidazole-4-carboxamide = tetrahydrofolate + 5-
CC formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide.
CC -!- CATALYTIC ACTIVITY: IMP + H(2)O = 5-formamido-1-(5-phospho-D-
CC ribosyl)imidazole-4-carboxamide.
CC -!- PATHWAY: Purine metabolism; IMP biosynthesis via de novo pathway;
CC 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide from 5-
CC amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide (10-formyl
CC THF route): step 1/1.
CC -!- PATHWAY: Purine metabolism; IMP biosynthesis via de novo pathway;
CC IMP from 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-
CC carboxamide: step 1/1.
CC -!- SUBUNIT: Homodimer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P31939-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P31939-2; Sequence=VSP_053495;
CC -!- DOMAIN: The IMP cyclohydrolase activity resides in the N-terminal
CC region.
CC -!- DISEASE: AICAR transformylase/IMP cyclohydrolase deficiency
CC (AICAR) [MIM:608688]: A neurologically devastating inborn error of
CC purine biosynthesis. Patients excrete massive amounts of AICA-
CC riboside in the urine and accumulate AICA-ribotide and its
CC derivatives in erythrocytes and fibroblasts. AICAR causes profound
CC mental retardation, epilepsy, dysmorphic features and congenital
CC blindness. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PurH family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ATICID227.html";
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DR EMBL; U37436; AAA97405.1; -; mRNA.
DR EMBL; D82348; BAA11559.1; -; mRNA.
DR EMBL; D89976; BAA21762.1; -; mRNA.
DR EMBL; AB062403; BAB93490.1; -; mRNA.
DR EMBL; AK290067; BAF82756.1; -; mRNA.
DR EMBL; AC073284; AAY24062.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70529.1; -; Genomic_DNA.
DR EMBL; BC008879; AAH08879.1; -; mRNA.
DR PIR; JC4642; JC4642.
DR RefSeq; NP_004035.2; NM_004044.6.
DR UniGene; Hs.90280; -.
DR PDB; 1P4R; X-ray; 2.55 A; A/B=1-592.
DR PDB; 1PKX; X-ray; 1.90 A; A/B/C/D=1-592.
DR PDB; 1PL0; X-ray; 2.60 A; A/B/C/D=1-592.
DR PDBsum; 1P4R; -.
DR PDBsum; 1PKX; -.
DR PDBsum; 1PL0; -.
DR ProteinModelPortal; P31939; -.
DR SMR; P31939; 4-592.
DR IntAct; P31939; 4.
DR MINT; MINT-4999053; -.
DR STRING; 9606.ENSP00000236959; -.
DR BindingDB; P31939; -.
DR ChEMBL; CHEMBL2518; -.
DR DrugBank; DB00116; Tetrahydrofolic acid.
DR PhosphoSite; P31939; -.
DR DMDM; 23831360; -.
DR REPRODUCTION-2DPAGE; IPI00289499; -.
DR UCD-2DPAGE; P31939; -.
DR PaxDb; P31939; -.
DR PeptideAtlas; P31939; -.
DR PRIDE; P31939; -.
DR DNASU; 471; -.
DR Ensembl; ENST00000236959; ENSP00000236959; ENSG00000138363.
DR Ensembl; ENST00000435675; ENSP00000415935; ENSG00000138363.
DR GeneID; 471; -.
DR KEGG; hsa:471; -.
DR UCSC; uc002vex.4; human.
DR CTD; 471; -.
DR GeneCards; GC02P216176; -.
DR HGNC; HGNC:794; ATIC.
DR HPA; CAB013462; -.
DR HPA; HPA021012; -.
DR MIM; 601731; gene.
DR MIM; 608688; phenotype.
DR neXtProt; NX_P31939; -.
DR Orphanet; 250977; AICA-ribosiduria.
DR PharmGKB; PA25094; -.
DR eggNOG; COG0138; -.
DR HOGENOM; HOG000230372; -.
DR HOVERGEN; HBG006912; -.
DR InParanoid; P31939; -.
DR KO; K00602; -.
DR OMA; DLLFAWK; -.
DR OrthoDB; EOG74N5GD; -.
DR PhylomeDB; P31939; -.
DR BioCyc; MetaCyc:HS06490-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P31939; -.
DR UniPathway; UPA00074; UER00133.
DR UniPathway; UPA00074; UER00135.
DR ChiTaRS; ATIC; human.
DR EvolutionaryTrace; P31939; -.
DR GeneWiki; Inosine_monophosphate_synthase; -.
DR GenomeRNAi; 471; -.
DR NextBio; 1945; -.
DR PRO; PR:P31939; -.
DR ArrayExpress; P31939; -.
DR Bgee; P31939; -.
DR CleanEx; HS_ATIC; -.
DR Genevestigator; P31939; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0003937; F:IMP cyclohydrolase activity; IEA:InterPro.
DR GO; GO:0004643; F:phosphoribosylaminoimidazolecarboxamide formyltransferase activity; IEA:InterPro.
DR GO; GO:0006189; P:'de novo' IMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0003360; P:brainstem development; IEA:Ensembl.
DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0046452; P:dihydrofolate metabolic process; IEA:Ensembl.
DR GO; GO:0009116; P:nucleoside metabolic process; IEA:Ensembl.
DR GO; GO:0031100; P:organ regeneration; IEA:Ensembl.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0006164; P:purine nucleotide biosynthetic process; IEA:InterPro.
DR GO; GO:0009168; P:purine ribonucleoside monophosphate biosynthetic process; TAS:Reactome.
DR GO; GO:0010035; P:response to inorganic substance; IEA:Ensembl.
DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:Ensembl.
DR Gene3D; 1.10.287.440; -; 1.
DR Gene3D; 3.40.140.20; -; 3.
DR Gene3D; 3.40.50.1380; -; 1.
DR InterPro; IPR024051; AICAR_Tfase_dom.
DR InterPro; IPR024050; AICAR_Tfase_insert_dom.
DR InterPro; IPR002695; AICARFT_IMPCHas.
DR InterPro; IPR016193; Cytidine_deaminase-like.
DR InterPro; IPR011607; MGS-like_dom.
DR PANTHER; PTHR11692; PTHR11692; 1.
DR Pfam; PF01808; AICARFT_IMPCHas; 1.
DR Pfam; PF02142; MGS; 1.
DR PIRSF; PIRSF000414; AICARFT_IMPCHas; 1.
DR SMART; SM00798; AICARFT_IMPCHas; 1.
DR SMART; SM00851; MGS; 1.
DR SUPFAM; SSF52335; SSF52335; 1.
DR SUPFAM; SSF53927; SSF53927; 1.
DR TIGRFAMs; TIGR00355; purH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Disease mutation; Epilepsy; Hydrolase;
KW Multifunctional enzyme; Polymorphism; Purine biosynthesis;
KW Reference proteome; Transferase.
FT CHAIN 1 592 Bifunctional purine biosynthesis protein
FT PURH.
FT /FTId=PRO_0000192156.
FT NP_BIND 12 14 IMP.
FT NP_BIND 34 37 IMP.
FT NP_BIND 64 67 IMP.
FT NP_BIND 101 104 IMP.
FT NP_BIND 125 127 IMP.
FT REGION 207 208 AICAR binding.
FT ACT_SITE 137 137 Proton acceptor (Potential).
FT ACT_SITE 267 267 Proton acceptor (Probable).
FT BINDING 316 316 AICAR; via carbonyl oxygen.
FT BINDING 339 339 AICAR.
FT BINDING 431 431 AICAR; shared with dimeric partner.
FT BINDING 451 451 AICAR; shared with dimeric partner.
FT BINDING 541 541 AICAR; via carbonyl oxygen; shared with
FT dimeric partner.
FT BINDING 588 588 AICAR; shared with dimeric partner.
FT SITE 266 266 Transition state stabilizer (Potential).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 199 199 N6-acetyllysine.
FT VAR_SEQ 1 6 MAPGQL -> MSSLS (in isoform 2).
FT /FTId=VSP_053495.
FT VARIANT 116 116 T -> S (in dbSNP:rs2372536).
FT /FTId=VAR_019306.
FT VARIANT 426 426 K -> R (in AICAR; loss of transformylase
FT activity).
FT /FTId=VAR_019307.
FT CONFLICT 165 165 D -> G (in Ref. 1; AAA97405).
FT STRAND 6 10
FT HELIX 17 25
FT TURN 26 28
FT STRAND 30 33
FT HELIX 35 42
FT TURN 43 45
FT HELIX 51 55
FT TURN 61 64
FT STRAND 65 67
FT HELIX 70 77
FT HELIX 82 91
FT STRAND 96 101
FT HELIX 106 111
FT HELIX 117 122
FT HELIX 127 137
FT TURN 138 141
FT STRAND 143 145
FT HELIX 148 150
FT HELIX 151 160
FT STRAND 161 165
FT HELIX 168 197
FT TURN 200 202
FT STRAND 203 207
FT STRAND 209 211
FT STRAND 217 220
FT STRAND 222 225
FT STRAND 227 233
FT HELIX 237 257
FT STRAND 261 266
FT STRAND 269 275
FT HELIX 281 286
FT HELIX 290 295
FT HELIX 298 308
FT TURN 311 316
FT STRAND 317 323
FT HELIX 327 334
FT STRAND 338 344
FT HELIX 348 360
FT STRAND 363 367
FT STRAND 375 381
FT STRAND 384 389
FT HELIX 397 400
FT HELIX 412 426
FT STRAND 433 437
FT STRAND 440 445
FT HELIX 451 467
FT HELIX 471 474
FT HELIX 486 496
FT HELIX 503 509
FT STRAND 512 514
FT HELIX 521 528
FT STRAND 534 540
FT STRAND 543 545
FT HELIX 546 552
FT TURN 553 555
FT STRAND 556 562
FT HELIX 568 578
FT STRAND 581 586
SQ SEQUENCE 592 AA; 64616 MW; AD778892021F0888 CRC64;
MAPGQLALFS VSDKTGLVEF ARNLTALGLN LVASGGTAKA LRDAGLAVRD VSELTGFPEM
LGGRVKTLHP AVHAGILARN IPEDNADMAR LDFNLIRVVA CNLYPFVKTV ASPGVTVEEA
VEQIDIGGVT LLRAAAKNHA RVTVVCEPED YVVVSTEMQS SESKDTSLET RRQLALKAFT
HTAQYDEAIS DYFRKQYSKG VSQMPLRYGM NPHQTPAQLY TLQPKLPITV LNGAPGFINL
CDALNAWQLV KELKEALGIP AAASFKHVSP AGAAVGIPLS EDEAKVCMVY DLYKTLTPIS
AAYARARGAD RMSSFGDFVA LSDVCDVPTA KIISREVSDG IIAPGYEEEA LTILSKKKNG
NYCVLQMDQS YKPDENEVRT LFGLHLSQKR NNGVVDKSLF SNVVTKNKDL PESALRDLIV
ATIAVKYTQS NSVCYAKNGQ VIGIGAGQQS RIHCTRLAGD KANYWWLRHH PQVLSMKFKT
GVKRAEISNA IDQYVTGTIG EDEDLIKWKA LFEEVPELLT EAEKKEWVEK LTEVSISSDA
FFPFRDNVDR AKRSGVAYIA APSGSAADKV VIEACDELGI ILAHTNLRLF HH
//
ID PUR9_HUMAN Reviewed; 592 AA.
AC P31939; A8K202; E9PBU3; Q13856; Q53S28;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 10-OCT-2002, sequence version 3.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Bifunctional purine biosynthesis protein PURH;
DE Includes:
DE RecName: Full=Phosphoribosylaminoimidazolecarboxamide formyltransferase;
DE EC=2.1.2.3;
DE AltName: Full=5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase;
DE AltName: Full=AICAR transformylase;
DE Includes:
DE RecName: Full=IMP cyclohydrolase;
DE EC=3.5.4.10;
DE AltName: Full=ATIC;
DE AltName: Full=IMP synthase;
DE AltName: Full=Inosinicase;
GN Name=ATIC; Synonyms=PURH; ORFNames=OK/SW-cl.86;
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).
RC TISSUE=Hepatoma;
RX PubMed=8567683; DOI=10.1074/jbc.271.4.2225;
RA Rayl E.A., Moroson B.A., Beardsley G.P.;
RT "The human purH gene product, 5-aminoimidazole-4-carboxamide
RT ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning,
RT sequencing, expression, purification, kinetic analysis, and domain
RT mapping.";
RL J. Biol. Chem. 271:2225-2233(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=8867801; DOI=10.1093/dnares/2.6.269;
RA Yamauchi M., Seki N., Mita K., Saito T., Tsuji S., Hongo E.,
RA Morimyo M., Shiomi T., Koyama H.;
RT "Isolation of human purH gene expressed in the rodent transformant
RT cells by subtractive enrichment of 3'-untranslated region of human
RT transcript.";
RL DNA Res. 2:269-275(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=9378707;
RA Sugita T., Aya H., Ueno M., Ishizuka T., Kawashima K.;
RT "Characterization of molecularly cloned human 5-aminoimidazole-4-
RT carboxamide ribonucleotide transformylase.";
RL J. Biochem. 122:309-313(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon adenocarcinoma;
RA Shichijo S., Itoh K.;
RT "Identification of immuno-peptidmics that are recognized by tumor-
RT reactive CTL generated from TIL of colon cancer patients.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP SER-116.
RC TISSUE=Substantia nigra;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT SER-116.
RA Mural R.J., Istrail S., Sutton 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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
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 [9]
RP PROTEIN SEQUENCE OF 15-39; 91-97; 178-194; 208-225; 267-285 AND
RP 417-426, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [10]
RP PROTEIN SEQUENCE OF 178-189 AND 267-281.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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 [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-199, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [13]
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [15]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH XMP, AND
RP SUBUNIT.
RX PubMed=14756553; DOI=10.1021/bi030162i;
RA Wolan D.W., Cheong C.-G., Greasley S.E., Wilson I.A.;
RT "Structural insights into the human and avian IMP cyclohydrolase
RT mechanism via crystal structures with the bound XMP inhibitor.";
RL Biochemistry 43:1171-1183(2004).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) IN COMPLEX WITH AICAR; XMP AND
RP THE INHIBITORS BW1540 AND BW2315, FUNCTION, AND SUBUNIT.
RX PubMed=14966129; DOI=10.1074/jbc.M313691200;
RA Cheong C.-G., Wolan D.W., Greasley S.E., Horton P.A., Beardsley G.P.,
RA Wilson I.A.;
RT "Crystal structures of human bifunctional enzyme aminoimidazole-4-
RT carboxamide ribonucleotide transformylase/IMP cyclohydrolase in
RT complex with potent sulfonyl-containing antifolates.";
RL J. Biol. Chem. 279:18034-18045(2004).
RN [17]
RP VARIANT AICAR ARG-426, AND CHARACTERIZATION OF VARIANT AICAR ARG-426.
RX PubMed=15114530; DOI=10.1086/421475;
RA Marie S., Heron B., Bitoun P., Timmerman T., Van Den Berghe G.,
RA Vincent M.-F.;
RT "AICA-ribosiduria: a novel, neurologically devastating inborn error of
RT purine biosynthesis caused by mutation of ATIC.";
RL Am. J. Hum. Genet. 74:1276-1281(2004).
CC -!- FUNCTION: Bifunctional enzyme that catalyzes 2 steps in purine
CC biosynthesis.
CC -!- CATALYTIC ACTIVITY: 10-formyltetrahydrofolate + 5-amino-1-(5-
CC phospho-D-ribosyl)imidazole-4-carboxamide = tetrahydrofolate + 5-
CC formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide.
CC -!- CATALYTIC ACTIVITY: IMP + H(2)O = 5-formamido-1-(5-phospho-D-
CC ribosyl)imidazole-4-carboxamide.
CC -!- PATHWAY: Purine metabolism; IMP biosynthesis via de novo pathway;
CC 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide from 5-
CC amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide (10-formyl
CC THF route): step 1/1.
CC -!- PATHWAY: Purine metabolism; IMP biosynthesis via de novo pathway;
CC IMP from 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-
CC carboxamide: step 1/1.
CC -!- SUBUNIT: Homodimer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P31939-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P31939-2; Sequence=VSP_053495;
CC -!- DOMAIN: The IMP cyclohydrolase activity resides in the N-terminal
CC region.
CC -!- DISEASE: AICAR transformylase/IMP cyclohydrolase deficiency
CC (AICAR) [MIM:608688]: A neurologically devastating inborn error of
CC purine biosynthesis. Patients excrete massive amounts of AICA-
CC riboside in the urine and accumulate AICA-ribotide and its
CC derivatives in erythrocytes and fibroblasts. AICAR causes profound
CC mental retardation, epilepsy, dysmorphic features and congenital
CC blindness. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PurH family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ATICID227.html";
CC -----------------------------------------------------------------------
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DR EMBL; U37436; AAA97405.1; -; mRNA.
DR EMBL; D82348; BAA11559.1; -; mRNA.
DR EMBL; D89976; BAA21762.1; -; mRNA.
DR EMBL; AB062403; BAB93490.1; -; mRNA.
DR EMBL; AK290067; BAF82756.1; -; mRNA.
DR EMBL; AC073284; AAY24062.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70529.1; -; Genomic_DNA.
DR EMBL; BC008879; AAH08879.1; -; mRNA.
DR PIR; JC4642; JC4642.
DR RefSeq; NP_004035.2; NM_004044.6.
DR UniGene; Hs.90280; -.
DR PDB; 1P4R; X-ray; 2.55 A; A/B=1-592.
DR PDB; 1PKX; X-ray; 1.90 A; A/B/C/D=1-592.
DR PDB; 1PL0; X-ray; 2.60 A; A/B/C/D=1-592.
DR PDBsum; 1P4R; -.
DR PDBsum; 1PKX; -.
DR PDBsum; 1PL0; -.
DR ProteinModelPortal; P31939; -.
DR SMR; P31939; 4-592.
DR IntAct; P31939; 4.
DR MINT; MINT-4999053; -.
DR STRING; 9606.ENSP00000236959; -.
DR BindingDB; P31939; -.
DR ChEMBL; CHEMBL2518; -.
DR DrugBank; DB00116; Tetrahydrofolic acid.
DR PhosphoSite; P31939; -.
DR DMDM; 23831360; -.
DR REPRODUCTION-2DPAGE; IPI00289499; -.
DR UCD-2DPAGE; P31939; -.
DR PaxDb; P31939; -.
DR PeptideAtlas; P31939; -.
DR PRIDE; P31939; -.
DR DNASU; 471; -.
DR Ensembl; ENST00000236959; ENSP00000236959; ENSG00000138363.
DR Ensembl; ENST00000435675; ENSP00000415935; ENSG00000138363.
DR GeneID; 471; -.
DR KEGG; hsa:471; -.
DR UCSC; uc002vex.4; human.
DR CTD; 471; -.
DR GeneCards; GC02P216176; -.
DR HGNC; HGNC:794; ATIC.
DR HPA; CAB013462; -.
DR HPA; HPA021012; -.
DR MIM; 601731; gene.
DR MIM; 608688; phenotype.
DR neXtProt; NX_P31939; -.
DR Orphanet; 250977; AICA-ribosiduria.
DR PharmGKB; PA25094; -.
DR eggNOG; COG0138; -.
DR HOGENOM; HOG000230372; -.
DR HOVERGEN; HBG006912; -.
DR InParanoid; P31939; -.
DR KO; K00602; -.
DR OMA; DLLFAWK; -.
DR OrthoDB; EOG74N5GD; -.
DR PhylomeDB; P31939; -.
DR BioCyc; MetaCyc:HS06490-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P31939; -.
DR UniPathway; UPA00074; UER00133.
DR UniPathway; UPA00074; UER00135.
DR ChiTaRS; ATIC; human.
DR EvolutionaryTrace; P31939; -.
DR GeneWiki; Inosine_monophosphate_synthase; -.
DR GenomeRNAi; 471; -.
DR NextBio; 1945; -.
DR PRO; PR:P31939; -.
DR ArrayExpress; P31939; -.
DR Bgee; P31939; -.
DR CleanEx; HS_ATIC; -.
DR Genevestigator; P31939; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0003937; F:IMP cyclohydrolase activity; IEA:InterPro.
DR GO; GO:0004643; F:phosphoribosylaminoimidazolecarboxamide formyltransferase activity; IEA:InterPro.
DR GO; GO:0006189; P:'de novo' IMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0003360; P:brainstem development; IEA:Ensembl.
DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0046452; P:dihydrofolate metabolic process; IEA:Ensembl.
DR GO; GO:0009116; P:nucleoside metabolic process; IEA:Ensembl.
DR GO; GO:0031100; P:organ regeneration; IEA:Ensembl.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0006164; P:purine nucleotide biosynthetic process; IEA:InterPro.
DR GO; GO:0009168; P:purine ribonucleoside monophosphate biosynthetic process; TAS:Reactome.
DR GO; GO:0010035; P:response to inorganic substance; IEA:Ensembl.
DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:Ensembl.
DR Gene3D; 1.10.287.440; -; 1.
DR Gene3D; 3.40.140.20; -; 3.
DR Gene3D; 3.40.50.1380; -; 1.
DR InterPro; IPR024051; AICAR_Tfase_dom.
DR InterPro; IPR024050; AICAR_Tfase_insert_dom.
DR InterPro; IPR002695; AICARFT_IMPCHas.
DR InterPro; IPR016193; Cytidine_deaminase-like.
DR InterPro; IPR011607; MGS-like_dom.
DR PANTHER; PTHR11692; PTHR11692; 1.
DR Pfam; PF01808; AICARFT_IMPCHas; 1.
DR Pfam; PF02142; MGS; 1.
DR PIRSF; PIRSF000414; AICARFT_IMPCHas; 1.
DR SMART; SM00798; AICARFT_IMPCHas; 1.
DR SMART; SM00851; MGS; 1.
DR SUPFAM; SSF52335; SSF52335; 1.
DR SUPFAM; SSF53927; SSF53927; 1.
DR TIGRFAMs; TIGR00355; purH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Disease mutation; Epilepsy; Hydrolase;
KW Multifunctional enzyme; Polymorphism; Purine biosynthesis;
KW Reference proteome; Transferase.
FT CHAIN 1 592 Bifunctional purine biosynthesis protein
FT PURH.
FT /FTId=PRO_0000192156.
FT NP_BIND 12 14 IMP.
FT NP_BIND 34 37 IMP.
FT NP_BIND 64 67 IMP.
FT NP_BIND 101 104 IMP.
FT NP_BIND 125 127 IMP.
FT REGION 207 208 AICAR binding.
FT ACT_SITE 137 137 Proton acceptor (Potential).
FT ACT_SITE 267 267 Proton acceptor (Probable).
FT BINDING 316 316 AICAR; via carbonyl oxygen.
FT BINDING 339 339 AICAR.
FT BINDING 431 431 AICAR; shared with dimeric partner.
FT BINDING 451 451 AICAR; shared with dimeric partner.
FT BINDING 541 541 AICAR; via carbonyl oxygen; shared with
FT dimeric partner.
FT BINDING 588 588 AICAR; shared with dimeric partner.
FT SITE 266 266 Transition state stabilizer (Potential).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 199 199 N6-acetyllysine.
FT VAR_SEQ 1 6 MAPGQL -> MSSLS (in isoform 2).
FT /FTId=VSP_053495.
FT VARIANT 116 116 T -> S (in dbSNP:rs2372536).
FT /FTId=VAR_019306.
FT VARIANT 426 426 K -> R (in AICAR; loss of transformylase
FT activity).
FT /FTId=VAR_019307.
FT CONFLICT 165 165 D -> G (in Ref. 1; AAA97405).
FT STRAND 6 10
FT HELIX 17 25
FT TURN 26 28
FT STRAND 30 33
FT HELIX 35 42
FT TURN 43 45
FT HELIX 51 55
FT TURN 61 64
FT STRAND 65 67
FT HELIX 70 77
FT HELIX 82 91
FT STRAND 96 101
FT HELIX 106 111
FT HELIX 117 122
FT HELIX 127 137
FT TURN 138 141
FT STRAND 143 145
FT HELIX 148 150
FT HELIX 151 160
FT STRAND 161 165
FT HELIX 168 197
FT TURN 200 202
FT STRAND 203 207
FT STRAND 209 211
FT STRAND 217 220
FT STRAND 222 225
FT STRAND 227 233
FT HELIX 237 257
FT STRAND 261 266
FT STRAND 269 275
FT HELIX 281 286
FT HELIX 290 295
FT HELIX 298 308
FT TURN 311 316
FT STRAND 317 323
FT HELIX 327 334
FT STRAND 338 344
FT HELIX 348 360
FT STRAND 363 367
FT STRAND 375 381
FT STRAND 384 389
FT HELIX 397 400
FT HELIX 412 426
FT STRAND 433 437
FT STRAND 440 445
FT HELIX 451 467
FT HELIX 471 474
FT HELIX 486 496
FT HELIX 503 509
FT STRAND 512 514
FT HELIX 521 528
FT STRAND 534 540
FT STRAND 543 545
FT HELIX 546 552
FT TURN 553 555
FT STRAND 556 562
FT HELIX 568 578
FT STRAND 581 586
SQ SEQUENCE 592 AA; 64616 MW; AD778892021F0888 CRC64;
MAPGQLALFS VSDKTGLVEF ARNLTALGLN LVASGGTAKA LRDAGLAVRD VSELTGFPEM
LGGRVKTLHP AVHAGILARN IPEDNADMAR LDFNLIRVVA CNLYPFVKTV ASPGVTVEEA
VEQIDIGGVT LLRAAAKNHA RVTVVCEPED YVVVSTEMQS SESKDTSLET RRQLALKAFT
HTAQYDEAIS DYFRKQYSKG VSQMPLRYGM NPHQTPAQLY TLQPKLPITV LNGAPGFINL
CDALNAWQLV KELKEALGIP AAASFKHVSP AGAAVGIPLS EDEAKVCMVY DLYKTLTPIS
AAYARARGAD RMSSFGDFVA LSDVCDVPTA KIISREVSDG IIAPGYEEEA LTILSKKKNG
NYCVLQMDQS YKPDENEVRT LFGLHLSQKR NNGVVDKSLF SNVVTKNKDL PESALRDLIV
ATIAVKYTQS NSVCYAKNGQ VIGIGAGQQS RIHCTRLAGD KANYWWLRHH PQVLSMKFKT
GVKRAEISNA IDQYVTGTIG EDEDLIKWKA LFEEVPELLT EAEKKEWVEK LTEVSISSDA
FFPFRDNVDR AKRSGVAYIA APSGSAADKV VIEACDELGI ILAHTNLRLF HH
//
MIM
601731
*RECORD*
*FIELD* NO
601731
*FIELD* TI
*601731 5-@AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE/IMP
CYCLOHYDROLASE; ATIC
read more;;AICARFT/IMPCHASE;;
AICAR TRANSFORMYLASE/IMP CYCLOHYDROLASE;;
PURH
*FIELD* TX
DESCRIPTION
AICARFT (5-aminoimidazole-4-carboxamide ribonucleotide
formyltransferase; EC 2.1.2.3) and IMPCHase (IMP cyclohydrolase; EC
3.5.4.10) catalyze the penultimate and final steps, respectively, of the
de novo purine biosynthetic pathway (summary by Rayl et al., 1996).
CLONING
Rayl et al. (1996) cloned a cDNA for human AICARFT/IMPCHase from a
hepatoma cDNA library. Both enzymatic activities are present in the same
protein, designated ATIC, in all species of prokaryotes and eukaryotes
studied by Rayl et al. (1996). The human ATIC cDNA encodes a deduced
591-amino acid protein that is 81% identical to the chicken sequence (Ni
et al., 1991). Rayl et al. (1996) created truncation mutants of the cDNA
and measured their enzymatic properties. In this way they were able to
localize the AICARFT activity within the amino-terminal 223 amino acids
and the IMPCHase activity to the carboxyl-terminal 406 residues.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the ATIC
gene to chromosome 2 (TMAP RH11837).
MOLECULAR GENETICS
In a 4-year-old girl who presented with dysmorphic features, severe
neurologic defects, and congenital blindness and who was found to have
AICA-ribosiduria (608688), Marie et al. (2004) found compound
heterozygosity for mutations in the ATIC gene. Sequencing of ATIC showed
a K426R mutation in the transformylase region in 1 allele (601731.0001)
inherited from the father, and a frameshift mutation caused by a
duplication/deletion event in the other allele (601731.0002), inherited
from the mother. The missense mutation was located within a conserved
region implicated in the binding of a potassium ion in the avian protein
(Greasley et al., 2001). This potassium ion has been proposed to play a
key role in stabilization of the tertiary structure of the protein. In
expression studies, recombinant protein carrying mutation K426R
completely lacked AICAR-TF activity but still showed IMP-CH activity.
The presence of massive amounts of AICA-riboside in the patient's urine
and the accumulation of AICAR (also referred to as ZMP) and its
derivatives in her erythrocytes and fibroblasts were taken by Marie et
al. (2004) to be a clear indication of deficiency in the enzyme that
utilizes this intermediate de novo purine biosynthesis, the bifunctional
enzyme AICAR transformylase/IMP cyclohydrolase.
*FIELD* AV
.0001
AICA-RIBOSIDURIA DUE TO ATIC DEFICIENCY
ATIC, LYS426ARG
In a 4-year-old girl with AICA-ribosiduria caused by deficiency of
AICAR-TF/IMP-CH (608688), Marie et al. (2004) found compound
heterozygosity for 2 mutations in the ATIC gene. The allele inherited
from the father carried a 1277A-G transition in exon 13 causing a
lys426-to-arg (K426R) amino acid substitution; the other allele,
inherited from the mother, showed a frameshift in exon 2, caused by a
duplication/deletion event (125-129dup-GGGAT; 130-132delGCT).
.0002
AICA-RIBOSIDURIA DUE TO ATIC DEFICIENCY
ATIC, 125-129DUP, 130-132DEL
See Marie et al. (2004) and 601731.0001.
*FIELD* RF
1. Greasley, S. E.; Horton, P.; Ramcharan, J.; Beardsley, G. P.; Benkovic,
S. J.; Wilson, I. A.: Crystal structure of a bifunctional transformylase
and cyclohydrolase enzyme in purine biosynthesis. Nature Struct.
Biol. 8: 402-406, 2001.
2. Marie, S.; Heron, B.; Bitoun, P.; Timmerman, T.; Van den Berghe,
G.; Vincent, M.-F.: AICA-ribosiduria: a novel, neurologically devastating
inborn error of purine biosynthesis caused by mutation of ATIC. Am.
J. Hum. Genet. 74: 1276-1281, 2004.
3. Ni, L.; Guan, K.; Zalkin, H.; Dixon, J. E.: De novo purine nucleotide
biosynthesis: cloning, sequencing and expression of a chicken PurH
cDNA encoding 5-aminoimidazole-4-carboxamide-ribonucleotide transformylase-IMP
cyclohydrolase. Gene 106: 197-205, 1991.
4. Rayl, E. A.; Moroson, B. A.; Beardsley, G. P.: The human purH
gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP
cyclohydrolase: cloning, sequencing, expression, purification, kinetic
analysis, and domain mapping. J. Biol. Chem. 271: 2225-2233, 1996.
*FIELD* CN
Joanna S. Amberger - updated: 6/7/2004
Victor A. McKusick - updated: 5/21/2004
*FIELD* CD
Alan F. Scott: 4/3/1997
*FIELD* ED
alopez: 03/08/2012
alopez: 3/19/2010
joanna: 6/7/2004
alopez: 5/25/2004
terry: 5/21/2004
alopez: 5/21/1997
alopez: 5/1/1997
alopez: 4/4/1997
alopez: 4/3/1997
*RECORD*
*FIELD* NO
601731
*FIELD* TI
*601731 5-@AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE/IMP
CYCLOHYDROLASE; ATIC
read more;;AICARFT/IMPCHASE;;
AICAR TRANSFORMYLASE/IMP CYCLOHYDROLASE;;
PURH
*FIELD* TX
DESCRIPTION
AICARFT (5-aminoimidazole-4-carboxamide ribonucleotide
formyltransferase; EC 2.1.2.3) and IMPCHase (IMP cyclohydrolase; EC
3.5.4.10) catalyze the penultimate and final steps, respectively, of the
de novo purine biosynthetic pathway (summary by Rayl et al., 1996).
CLONING
Rayl et al. (1996) cloned a cDNA for human AICARFT/IMPCHase from a
hepatoma cDNA library. Both enzymatic activities are present in the same
protein, designated ATIC, in all species of prokaryotes and eukaryotes
studied by Rayl et al. (1996). The human ATIC cDNA encodes a deduced
591-amino acid protein that is 81% identical to the chicken sequence (Ni
et al., 1991). Rayl et al. (1996) created truncation mutants of the cDNA
and measured their enzymatic properties. In this way they were able to
localize the AICARFT activity within the amino-terminal 223 amino acids
and the IMPCHase activity to the carboxyl-terminal 406 residues.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the ATIC
gene to chromosome 2 (TMAP RH11837).
MOLECULAR GENETICS
In a 4-year-old girl who presented with dysmorphic features, severe
neurologic defects, and congenital blindness and who was found to have
AICA-ribosiduria (608688), Marie et al. (2004) found compound
heterozygosity for mutations in the ATIC gene. Sequencing of ATIC showed
a K426R mutation in the transformylase region in 1 allele (601731.0001)
inherited from the father, and a frameshift mutation caused by a
duplication/deletion event in the other allele (601731.0002), inherited
from the mother. The missense mutation was located within a conserved
region implicated in the binding of a potassium ion in the avian protein
(Greasley et al., 2001). This potassium ion has been proposed to play a
key role in stabilization of the tertiary structure of the protein. In
expression studies, recombinant protein carrying mutation K426R
completely lacked AICAR-TF activity but still showed IMP-CH activity.
The presence of massive amounts of AICA-riboside in the patient's urine
and the accumulation of AICAR (also referred to as ZMP) and its
derivatives in her erythrocytes and fibroblasts were taken by Marie et
al. (2004) to be a clear indication of deficiency in the enzyme that
utilizes this intermediate de novo purine biosynthesis, the bifunctional
enzyme AICAR transformylase/IMP cyclohydrolase.
*FIELD* AV
.0001
AICA-RIBOSIDURIA DUE TO ATIC DEFICIENCY
ATIC, LYS426ARG
In a 4-year-old girl with AICA-ribosiduria caused by deficiency of
AICAR-TF/IMP-CH (608688), Marie et al. (2004) found compound
heterozygosity for 2 mutations in the ATIC gene. The allele inherited
from the father carried a 1277A-G transition in exon 13 causing a
lys426-to-arg (K426R) amino acid substitution; the other allele,
inherited from the mother, showed a frameshift in exon 2, caused by a
duplication/deletion event (125-129dup-GGGAT; 130-132delGCT).
.0002
AICA-RIBOSIDURIA DUE TO ATIC DEFICIENCY
ATIC, 125-129DUP, 130-132DEL
See Marie et al. (2004) and 601731.0001.
*FIELD* RF
1. Greasley, S. E.; Horton, P.; Ramcharan, J.; Beardsley, G. P.; Benkovic,
S. J.; Wilson, I. A.: Crystal structure of a bifunctional transformylase
and cyclohydrolase enzyme in purine biosynthesis. Nature Struct.
Biol. 8: 402-406, 2001.
2. Marie, S.; Heron, B.; Bitoun, P.; Timmerman, T.; Van den Berghe,
G.; Vincent, M.-F.: AICA-ribosiduria: a novel, neurologically devastating
inborn error of purine biosynthesis caused by mutation of ATIC. Am.
J. Hum. Genet. 74: 1276-1281, 2004.
3. Ni, L.; Guan, K.; Zalkin, H.; Dixon, J. E.: De novo purine nucleotide
biosynthesis: cloning, sequencing and expression of a chicken PurH
cDNA encoding 5-aminoimidazole-4-carboxamide-ribonucleotide transformylase-IMP
cyclohydrolase. Gene 106: 197-205, 1991.
4. Rayl, E. A.; Moroson, B. A.; Beardsley, G. P.: The human purH
gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP
cyclohydrolase: cloning, sequencing, expression, purification, kinetic
analysis, and domain mapping. J. Biol. Chem. 271: 2225-2233, 1996.
*FIELD* CN
Joanna S. Amberger - updated: 6/7/2004
Victor A. McKusick - updated: 5/21/2004
*FIELD* CD
Alan F. Scott: 4/3/1997
*FIELD* ED
alopez: 03/08/2012
alopez: 3/19/2010
joanna: 6/7/2004
alopez: 5/25/2004
terry: 5/21/2004
alopez: 5/21/1997
alopez: 5/1/1997
alopez: 4/4/1997
alopez: 4/3/1997
MIM
608688
*RECORD*
*FIELD* NO
608688
*FIELD* TI
#608688 AICAR TRANSFORMYLASE/IMP CYCLOHYDROLASE DEFICIENCY
;;ATIC DEFICIENCY;;
AICA-RIBOSURIA DUE TO ATIC DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because the phenotype can be
caused by mutation in the ATIC gene (601731), encoding the bifunctional
enzyme AICAR transformylase/IMP cyclohydrolase.
CLINICAL FEATURES
Marie et al. (2004) described a 4-year-old girl who presented with a
devastating neurologic picture involving profound mental retardation,
epilepsy, dysmorphic features, and congenital blindness. Dysmorphic
features included cutaneous dimples on the extensor side of knees,
elbows, and shoulders. By age 12 months, bilateral atrophic pigmented
chorioretinal macular lesions had developed with optic atrophy, and
abnormal electroretinograms and visual evoked potentials were observed.
Chromatograms of the patient's urine revealed 3 peaks seen neither in
control individuals' urine nor in that of ADSL-deficient patients
(608222). The major peak was identified as
5-amino-4-imidazolecarboxamide riboside (AICA-riboside), on the basis of
a positive Bratton-Marshall test, spectral analysis, and spiking with
the authentic compound. AICA-riboside is the nucleoside corresponding to
AICAR (AICA-ribotide, also termed ZMP), an intermediate of the de novo
purine biosynthetic pathway. AICA-riboside is formed by
dephosphorylation of AICAR, most likely by IMP-GMP 5-prime-nucleotidase.
When Marie et al. (2004) incubated fibroblasts from their patient with
AICA-riboside, they observed accumulation of AICAR not observed in
control cells, suggesting impairment of the final steps of purine
biosynthesis, catalyzed by the bifunctional enzyme AICAR
transformylase/IMP cyclohydrolase (ATIC; 601731). AICAR transformylase
was profoundly deficient, whereas the IMP cyclohydrolase level was 40%
of normal. The presence of massive amounts of AICA-riboside in the
patient's urine and the accumulation of AICAR and its derivatives in her
erythrocytes and fibroblasts were taken by Marie et al. (2004) to be a
clear indication of deficiency in the enzyme that utilizes this
intermediate de novo purine biosynthesis, the bifunctional enzyme
encoded by the ATIC gene.
MOLECULAR GENETICS
Marie et al. (2004) performed sequence analysis of the ATIC gene in
their patient with AICA-ribosuria and found compound heterozygosity for
mutations. A missense mutation (K426R; 601731.0001) in the
transformylase region was inherited from the father, and a frameshift
mutation caused by a duplication/deletion event (601731.0002) was
inherited from the mother. The missense mutation was located within a
conserved region implicated in the binding of a potassium ion in the
avian protein (Greasley et al., 2001). This potassium ion has been
proposed to play a key role in stabilization of the tertiary structure
of the protein. In expression studies, recombinant protein carrying the
K426R mutation completely lacked AICAR-TF activity but still showed
IMP-CH activity.
*FIELD* RF
1. Greasley, S. E.; Horton, P.; Ramcharan, J.; Beardsley, G. P.; Benkovic,
S. J.; Wilson, I. A.: Crystal structure of a bifunctional transformylase
and cyclohydrolase enzyme in purine biosynthesis. Nature Struct.
Biol. 8: 402-406, 2001.
2. Marie, S.; Heron, B.; Bitoun, P.; Timmerman, T.; Van den Berghe,
G.; Vincent, M.-F.: AICA-ribosiduria: a novel, neurologically devastating
inborn error of purine biosynthesis caused by mutation of ATIC. Am.
J. Hum. Genet. 74: 1276-1281, 2004.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Brachycephaly;
[Face];
Prominent forehead;
[Ears];
Low-set ears;
[Eyes];
Congenital blindness;
Optic atrophy;
[Nose];
High nasal bridge;
Anteverted nares;
[Mouth];
Wide mouth;
Thin upper lip
CARDIOVASCULAR:
[Heart];
Atrial septal defect
GENITOURINARY:
[External genitalia, female];
Prominent clitoris;
Fused labia minora
SKIN, NAILS, HAIR:
[Skin];
Cutaneous dimples (knees, elbows, shoulders)
NEUROLOGIC:
[Central nervous system];
Mental retardation, profound;
Seizures;
Hypotonia
LABORATORY ABNORMALITIES:
Positive urinary Bratton-Marshall test;
Elevated urinary and CSF 5-amino-4-imidazolecarboxyamide (AICA-riboside);
Elevated erythrocyte AICAR (ZMP);
Deficient fibroblast AICAR-TF activity
MOLECULAR BASIS:
Caused by mutation in the AICAR formyltransferase/IMP cyclohydrolase
gene (ATIC, 601731.0001)
*FIELD* CD
Kelly A. Przylepa: 9/13/2004
*FIELD* ED
joanna: 09/13/2004
alopez: 5/25/2004
*FIELD* CD
Victor A. McKusick: 5/25/2004
*FIELD* ED
carol: 12/07/2009
alopez: 5/25/2004
*RECORD*
*FIELD* NO
608688
*FIELD* TI
#608688 AICAR TRANSFORMYLASE/IMP CYCLOHYDROLASE DEFICIENCY
;;ATIC DEFICIENCY;;
AICA-RIBOSURIA DUE TO ATIC DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because the phenotype can be
caused by mutation in the ATIC gene (601731), encoding the bifunctional
enzyme AICAR transformylase/IMP cyclohydrolase.
CLINICAL FEATURES
Marie et al. (2004) described a 4-year-old girl who presented with a
devastating neurologic picture involving profound mental retardation,
epilepsy, dysmorphic features, and congenital blindness. Dysmorphic
features included cutaneous dimples on the extensor side of knees,
elbows, and shoulders. By age 12 months, bilateral atrophic pigmented
chorioretinal macular lesions had developed with optic atrophy, and
abnormal electroretinograms and visual evoked potentials were observed.
Chromatograms of the patient's urine revealed 3 peaks seen neither in
control individuals' urine nor in that of ADSL-deficient patients
(608222). The major peak was identified as
5-amino-4-imidazolecarboxamide riboside (AICA-riboside), on the basis of
a positive Bratton-Marshall test, spectral analysis, and spiking with
the authentic compound. AICA-riboside is the nucleoside corresponding to
AICAR (AICA-ribotide, also termed ZMP), an intermediate of the de novo
purine biosynthetic pathway. AICA-riboside is formed by
dephosphorylation of AICAR, most likely by IMP-GMP 5-prime-nucleotidase.
When Marie et al. (2004) incubated fibroblasts from their patient with
AICA-riboside, they observed accumulation of AICAR not observed in
control cells, suggesting impairment of the final steps of purine
biosynthesis, catalyzed by the bifunctional enzyme AICAR
transformylase/IMP cyclohydrolase (ATIC; 601731). AICAR transformylase
was profoundly deficient, whereas the IMP cyclohydrolase level was 40%
of normal. The presence of massive amounts of AICA-riboside in the
patient's urine and the accumulation of AICAR and its derivatives in her
erythrocytes and fibroblasts were taken by Marie et al. (2004) to be a
clear indication of deficiency in the enzyme that utilizes this
intermediate de novo purine biosynthesis, the bifunctional enzyme
encoded by the ATIC gene.
MOLECULAR GENETICS
Marie et al. (2004) performed sequence analysis of the ATIC gene in
their patient with AICA-ribosuria and found compound heterozygosity for
mutations. A missense mutation (K426R; 601731.0001) in the
transformylase region was inherited from the father, and a frameshift
mutation caused by a duplication/deletion event (601731.0002) was
inherited from the mother. The missense mutation was located within a
conserved region implicated in the binding of a potassium ion in the
avian protein (Greasley et al., 2001). This potassium ion has been
proposed to play a key role in stabilization of the tertiary structure
of the protein. In expression studies, recombinant protein carrying the
K426R mutation completely lacked AICAR-TF activity but still showed
IMP-CH activity.
*FIELD* RF
1. Greasley, S. E.; Horton, P.; Ramcharan, J.; Beardsley, G. P.; Benkovic,
S. J.; Wilson, I. A.: Crystal structure of a bifunctional transformylase
and cyclohydrolase enzyme in purine biosynthesis. Nature Struct.
Biol. 8: 402-406, 2001.
2. Marie, S.; Heron, B.; Bitoun, P.; Timmerman, T.; Van den Berghe,
G.; Vincent, M.-F.: AICA-ribosiduria: a novel, neurologically devastating
inborn error of purine biosynthesis caused by mutation of ATIC. Am.
J. Hum. Genet. 74: 1276-1281, 2004.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Brachycephaly;
[Face];
Prominent forehead;
[Ears];
Low-set ears;
[Eyes];
Congenital blindness;
Optic atrophy;
[Nose];
High nasal bridge;
Anteverted nares;
[Mouth];
Wide mouth;
Thin upper lip
CARDIOVASCULAR:
[Heart];
Atrial septal defect
GENITOURINARY:
[External genitalia, female];
Prominent clitoris;
Fused labia minora
SKIN, NAILS, HAIR:
[Skin];
Cutaneous dimples (knees, elbows, shoulders)
NEUROLOGIC:
[Central nervous system];
Mental retardation, profound;
Seizures;
Hypotonia
LABORATORY ABNORMALITIES:
Positive urinary Bratton-Marshall test;
Elevated urinary and CSF 5-amino-4-imidazolecarboxyamide (AICA-riboside);
Elevated erythrocyte AICAR (ZMP);
Deficient fibroblast AICAR-TF activity
MOLECULAR BASIS:
Caused by mutation in the AICAR formyltransferase/IMP cyclohydrolase
gene (ATIC, 601731.0001)
*FIELD* CD
Kelly A. Przylepa: 9/13/2004
*FIELD* ED
joanna: 09/13/2004
alopez: 5/25/2004
*FIELD* CD
Victor A. McKusick: 5/25/2004
*FIELD* ED
carol: 12/07/2009
alopez: 5/25/2004