GATM_HUMAN
ID GATM_HUMAN Reviewed; 423 AA.
AC P50440; B4DH99; B4DPI3; Q53EQ4;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 208.
DE RecName: Full=Glycine amidinotransferase, mitochondrial;
DE EC=2.1.4.1 {ECO:0000269|PubMed:27233232, ECO:0000269|PubMed:3800397};
DE AltName: Full=L-arginine:glycine amidinotransferase;
DE AltName: Full=Transamidinase;
DE Flags: Precursor;
GN Name=GATM; Synonyms=AGAT;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RX PubMed=8313955; DOI=10.1016/0014-5793(94)80394-3;
RA Humm A., Huber R., Mann K.;
RT "The amino acid sequences of human and pig L-arginine:glycine
RT amidinotransferase.";
RL FEBS Lett. 339:101-107(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Kidney;
RA Austruy E., Belley L., Millasot P., Junien C., Jeanpierre C.;
RT "Characterization of the human cDNA with partial homology with the gamma
RT subunit of sodium potassium ATPase of rat, mouse, rabbit and sheep.";
RL Submitted (APR-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Brain, and Kidney;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT HIS-110.
RC TISSUE=Kidney;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RX PubMed=3800397; DOI=10.1016/0003-9861(86)90385-1;
RA Gross M.D., Eggen M.A., Simon A.M., Van Pilsum J.F.;
RT "The purification and characterization of human kidney L-arginine:glycine
RT amidinotransferase.";
RL Arch. Biochem. Biophys. 251:747-755(1986).
RN [8]
RP ACTIVE SITE CYS-407.
RX PubMed=9148748; DOI=10.1042/bj3220771;
RA Humm A., Fritsche E., Mann K., Goehl U., Huber R.;
RT "Recombinant expression and isolation of human L-arginine:glycine
RT amidinotransferase and identification of its active-site cysteine
RT residue.";
RL Biochem. J. 322:771-776(1997).
RN [9]
RP REVIEW.
RX PubMed=9165070;
RA Humm A., Fritsche E., Steinbacher S.;
RT "Structure and reaction mechanism of L-arginine:glycine
RT amidinotransferase.";
RL Biol. Chem. 378:193-197(1997).
RN [10]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=16820567; DOI=10.1161/circulationaha.105.000448;
RA Cullen M.E., Yuen A.H., Felkin L.E., Smolenski R.T., Hall J.L., Grindle S.,
RA Miller L.W., Birks E.J., Yacoub M.H., Barton P.J.;
RT "Myocardial expression of the arginine:glycine amidinotransferase gene is
RT elevated in heart failure and normalized after recovery: potential
RT implications for local creatine synthesis.";
RL Circulation 114:I16-I20(2006).
RN [11]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=16125225; DOI=10.1016/j.placenta.2005.07.004;
RA McMinn J., Wei M., Schupf N., Cusmai J., Johnson E.B., Smith A.C.,
RA Weksberg R., Thaker H.M., Tycko B.;
RT "Unbalanced placental expression of imprinted genes in human intrauterine
RT growth restriction.";
RL Placenta 27:540-549(2006).
RN [12]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16614068; DOI=10.1073/pnas.0511031103;
RA Monk D., Arnaud P., Apostolidou S., Hills F.A., Kelsey G., Stanier P.,
RA Feil R., Moore G.E.;
RT "Limited evolutionary conservation of imprinting in the human placenta.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:6623-6628(2006).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-385, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA 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 [14]
RP INVOLVEMENT IN CCDS3.
RX PubMed=20682460; DOI=10.1016/j.ymgme.2010.06.021;
RA Edvardson S., Korman S.H., Livne A., Shaag A., Saada A., Nalbandian R.,
RA Allouche-Arnon H., Gomori J.M., Katz-Brull R.;
RT "l-arginine:glycine amidinotransferase (AGAT) deficiency: clinical
RT presentation and response to treatment in two patients with a novel
RT mutation.";
RL Mol. Genet. Metab. 101:228-232(2010).
RN [15]
RP INVOLVEMENT IN CCDS3.
RX PubMed=22386973; DOI=10.1016/j.ymgme.2012.01.017;
RA Ndika J.D., Johnston K., Barkovich J.A., Wirt M.D., O'Neill P.,
RA Betsalel O.T., Jakobs C., Salomons G.S.;
RT "Developmental progress and creatine restoration upon long-term creatine
RT supplementation of a patient with arginine:glycine amidinotransferase
RT deficiency.";
RL Mol. Genet. Metab. 106:48-54(2012).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-46 AND SER-49, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 38-423.
RC TISSUE=Kidney;
RX PubMed=9218780; DOI=10.1093/emboj/16.12.3373;
RA Humm A., Fritsche E., Steinbacher S., Huber R.;
RT "Crystal structure and mechanism of human L-arginine:glycine
RT amidinotransferase: a mitochondrial enzyme involved in creatine
RT biosynthesis.";
RL EMBO J. 16:3373-3385(1997).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.36 ANGSTROMS) OF MUTANTS ASN-170; ASN-254 AND
RP SER-407, BIOPHYSICOCHEMICAL PROPERTIES, REACTION MECHANISM, AND MUTAGENESIS
RP OF ASP-170; GLU-233; ASP-254; HIS-303; ASP-305; ARG-322; SER-355; CYS-407
RP AND CYS-410.
RX PubMed=9266688; DOI=10.1111/j.1432-1033.1997.00483.x;
RA Fritsche E., Humm A., Huber R.;
RT "Substrate binding and catalysis by L-arginine:glycine amidinotransferase
RT -- a mutagenesis and crystallographic study.";
RL Eur. J. Biochem. 247:483-490(1997).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 38-423.
RX PubMed=9915841; DOI=10.1074/jbc.274.5.3026;
RA Fritsche E., Humm A., Huber R.;
RT "The ligand-induced structural changes of human L-arginine:glycine
RT amidinotransferase. A mutational and crystallographic study.";
RL J. Biol. Chem. 274:3026-3032(1999).
RN [21]
RP INVOLVEMENT IN CCDS3.
RX PubMed=11555793; DOI=10.1086/323765;
RA Item C.B., Stockler-Ipsiroglu S., Stromberger C., Muhl A., Alessandri M.G.,
RA Bianchi M.C., Tosetti M., Fornai F., Cioni G.;
RT "Arginine:glycine amidinotransferase deficiency: the third inborn error of
RT creatine metabolism in humans.";
RL Am. J. Hum. Genet. 69:1127-1133(2001).
RN [22]
RP VARIANTS CCDS3 GLN-413 AND TRP-413.
RX PubMed=23660394; DOI=10.1016/j.ymgme.2013.04.006;
RA Comeaux M.S., Wang J., Wang G., Kleppe S., Zhang V.W., Schmitt E.S.,
RA Craigen W.J., Renaud D., Sun Q., Wong L.J.;
RT "Biochemical, molecular, and clinical diagnoses of patients with cerebral
RT creatine deficiency syndromes.";
RL Mol. Genet. Metab. 109:260-268(2013).
RN [23]
RP VARIANT CCDS3 SER-203.
RX PubMed=23770102; DOI=10.1016/j.nmd.2013.04.011;
RA Nouioua S., Cheillan D., Zaouidi S., Salomons G.S., Amedjout N.,
RA Kessaci F., Boulahdour N., Hamadouche T., Tazir M.;
RT "Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine
RT amidinotransferase (AGAT) deficiency.";
RL Neuromuscul. Disord. 23:670-674(2013).
RN [24]
RP VARIANTS CCDS3 PRO-185; SER-203 AND TRP-413.
RX PubMed=26490222; DOI=10.1016/j.ymgme.2015.10.003;
RA Stockler-Ipsiroglu S., Apatean D., Battini R., DeBrosse S., Dessoffy K.,
RA Edvardson S., Eichler F., Johnston K., Koeller D.M., Nouioua S., Tazir M.,
RA Verma A., Dowling M.D., Wierenga K.J., Wierenga A.M., Zhang V., Wong L.J.;
RT "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features
RT and long term outcomes in 16 patients diagnosed worldwide.";
RL Mol. Genet. Metab. 116:252-259(2015).
RN [25]
RP VARIANTS CCDS3 GLN-23; VAL-93; ASN-102; LEU-105; LYS-181; PRO-185; CYS-189;
RP SER-203; THR-208; HIS-282; VAL-329; LEU-346; TRP-413; GLN-413 AND GLN-415,
RP CHARACTERIZATION OF VARIANTS CCDS3 GLN-23; VAL-93; ASN-102; LEU-105;
RP LYS-181; PRO-185; CYS-189; SER-203; THR-208; HIS-282; VAL-329; LEU-346;
RP TRP-413; GLN-413 AND GLN-415, VARIANTS CYS-231 AND GLY-234,
RP CHARACTERIZATION OF VARIANTS CYS-231 AND GLY-234, AND CATALYTIC ACTIVITY.
RX PubMed=27233232; DOI=10.1002/humu.23018;
RA DesRoches C.L., Bruun T., Wang P., Marshall C.R., Mercimek-Mahmutoglu S.;
RT "Arginine-Glycine Amidinotransferase Deficiency and Functional
RT Characterization of Missense Variants in GATM.";
RL Hum. Mutat. 37:926-932(2016).
RN [26]
RP VARIANTS FRTS1 SER-320; ALA-336; ILE-336 AND LEU-341, INVOLVEMENT IN FRTS1,
RP AND CHARACTERIZATION OF VARIANTS FRTS1 SER-320; ALA-336; ILE-336 AND
RP LEU-341.
RX PubMed=29654216; DOI=10.1681/asn.2017111179;
RA Reichold M., Klootwijk E.D., Reinders J., Otto E.A., Milani M., Broeker C.,
RA Laing C., Wiesner J., Devi S., Zhou W., Schmitt R., Tegtmeier I.,
RA Sterner C., Doellerer H., Renner K., Oefner P.J., Dettmer K.,
RA Simbuerger J.M., Witzgall R., Stanescu H.C., Dumitriu S., Iancu D.,
RA Patel V., Mozere M., Tekman M., Jaureguiberry G., Issler N., Kesselheim A.,
RA Walsh S.B., Gale D.P., Howie A.J., Martins J.R., Hall A.M., Kasgharian M.,
RA O'Brien K., Ferreira C.R., Atwal P.S., Jain M., Hammers A.,
RA Charles-Edwards G., Choe C.U., Isbrandt D., Cebrian-Serrano A., Davies B.,
RA Sandford R.N., Pugh C., Konecki D.S., Povey S., Bockenhauer D.,
RA Lichter-Konecki U., Gahl W.A., Unwin R.J., Warth R., Kleta R.;
RT "Glycine amidinotransferase (GATM), renal Fanconi syndrome, and kidney
RT failure.";
RL J. Am. Soc. Nephrol. 29:1849-1858(2018).
CC -!- FUNCTION: Catalyzes the biosynthesis of guanidinoacetate, the immediate
CC precursor of creatine. Creatine plays a vital role in energy metabolism
CC in muscle tissues. May play a role in embryonic and central nervous
CC system development. May be involved in the response to heart failure by
CC elevating local creatine synthesis. {ECO:0000269|PubMed:16125225,
CC ECO:0000269|PubMed:16614068, ECO:0000269|PubMed:16820567}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glycine + L-arginine = guanidinoacetate + L-ornithine;
CC Xref=Rhea:RHEA:13201, ChEBI:CHEBI:32682, ChEBI:CHEBI:46911,
CC ChEBI:CHEBI:57305, ChEBI:CHEBI:57742; EC=2.1.4.1;
CC Evidence={ECO:0000269|PubMed:27233232, ECO:0000269|PubMed:3800397};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.0 uM for arginine {ECO:0000269|PubMed:3800397,
CC ECO:0000269|PubMed:9266688};
CC KM=3.0 uM for glycine {ECO:0000269|PubMed:3800397,
CC ECO:0000269|PubMed:9266688};
CC Vmax=0.44 umol/min/mg enzyme {ECO:0000269|PubMed:3800397,
CC ECO:0000269|PubMed:9266688};
CC -!- PATHWAY: Amine and polyamine biosynthesis; creatine biosynthesis;
CC creatine from L-arginine and glycine: step 1/2.
CC -!- SUBUNIT: Homodimer. There is an equilibrium between the monomeric and
CC dimeric forms, shifted towards the side of the monomer.
CC {ECO:0000269|PubMed:3800397}.
CC -!- INTERACTION:
CC P50440; Q6UY14-3: ADAMTSL4; NbExp=3; IntAct=EBI-2552594, EBI-10173507;
CC P50440; Q14457: BECN1; NbExp=3; IntAct=EBI-2552594, EBI-949378;
CC P50440; Q9Y6G5: COMMD10; NbExp=3; IntAct=EBI-2552594, EBI-1550310;
CC P50440; Q9UI10: EIF2B4; NbExp=3; IntAct=EBI-2552594, EBI-2340132;
CC P50440; Q13322-4: GRB10; NbExp=3; IntAct=EBI-2552594, EBI-12353035;
CC P50440; Q13352: ITGB3BP; NbExp=3; IntAct=EBI-2552594, EBI-712105;
CC P50440; Q14693: LPIN1; NbExp=3; IntAct=EBI-2552594, EBI-5278370;
CC P50440; Q96CM3: RPUSD4; NbExp=3; IntAct=EBI-2552594, EBI-7825200;
CC P50440; P11684: SCGB1A1; NbExp=3; IntAct=EBI-2552594, EBI-7797649;
CC P50440; Q9P1W8: SIRPG; NbExp=3; IntAct=EBI-2552594, EBI-1268284;
CC P50440; Q8NFB2: TMEM185A; NbExp=3; IntAct=EBI-2552594, EBI-21757569;
CC P50440; Q13829: TNFAIP1; NbExp=3; IntAct=EBI-2552594, EBI-2505861;
CC P50440; Q6ZMY6-2: WDR88; NbExp=3; IntAct=EBI-2552594, EBI-25857007;
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Mitochondrion inner membrane;
CC Peripheral membrane protein; Intermembrane side. Note=Probably attached
CC to the outer side of the inner membrane.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Mitochondrial;
CC IsoId=P50440-1; Sequence=Displayed;
CC Name=2; Synonyms=Cytoplasmic;
CC IsoId=P50440-2; Sequence=VSP_000235;
CC Name=3;
CC IsoId=P50440-3; Sequence=VSP_039871;
CC -!- TISSUE SPECIFICITY: Expressed in brain, heart, kidney, liver, lung,
CC salivary gland and skeletal muscle tissue, with the highest expression
CC in kidney. Biallelically expressed in placenta and fetal tissues.
CC {ECO:0000269|PubMed:16125225, ECO:0000269|PubMed:16614068,
CC ECO:0000269|PubMed:16820567}.
CC -!- INDUCTION: Expression is elevated in the myocardium during heart
CC failure, and decreased in inter-uterine growth restriction (IUGR)-
CC associated placenta. {ECO:0000269|PubMed:16125225,
CC ECO:0000269|PubMed:16820567}.
CC -!- DOMAIN: One chain folds into a compact single domain composed of
CC repeating units, five beta-beta-alpha-beta modules, which surround the
CC central active site.
CC -!- DISEASE: Cerebral creatine deficiency syndrome 3 (CCDS3) [MIM:612718]:
CC An autosomal recessive disorder characterized by developmental
CC delay/regression, intellectual disability, severe disturbance of
CC expressive and cognitive speech, and severe depletion of
CC creatine/phosphocreatine in the brain. Most patients develop a myopathy
CC characterized by muscle weakness and atrophy later in life.
CC {ECO:0000269|PubMed:11555793, ECO:0000269|PubMed:20682460,
CC ECO:0000269|PubMed:22386973, ECO:0000269|PubMed:23660394,
CC ECO:0000269|PubMed:23770102, ECO:0000269|PubMed:26490222,
CC ECO:0000269|PubMed:27233232}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Fanconi renotubular syndrome 1 (FRTS1) [MIM:134600]: A form of
CC Fanconi renotubular syndrome, a disease due to a generalized
CC dysfunction of the proximal kidney tubule resulting in decreased solute
CC and water reabsorption. Patients have polydipsia and polyuria with
CC phosphaturia, glycosuria and aminoaciduria. They may develop
CC hypophosphatemic rickets or osteomalacia, acidosis and a tendency
CC toward dehydration. Some eventually develop renal insufficiency. FRTS1
CC inheritance is autosomal dominant. {ECO:0000269|PubMed:29654216}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the amidinotransferase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAG60595.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; S68805; AAB29892.1; -; mRNA.
DR EMBL; X86401; CAA60153.1; -; mRNA.
DR EMBL; AK294995; BAG58060.1; -; mRNA.
DR EMBL; AK298350; BAG60595.1; ALT_INIT; mRNA.
DR EMBL; AK223585; BAD97305.1; -; mRNA.
DR EMBL; AC025580; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC004141; AAH04141.1; -; mRNA.
DR CCDS; CCDS10122.1; -. [P50440-1]
DR PIR; S41734; S41734.
DR PIR; S54161; S54161.
DR RefSeq; NP_001473.1; NM_001482.2. [P50440-1]
DR PDB; 1JDW; X-ray; 1.90 A; A=1-423.
DR PDB; 1JDX; X-ray; 2.40 A; A=38-423.
DR PDB; 2JDW; X-ray; 2.10 A; A=1-423.
DR PDB; 2JDX; X-ray; 2.90 A; A=38-423.
DR PDB; 3JDW; X-ray; 2.40 A; A=1-423.
DR PDB; 4JDW; X-ray; 2.50 A; A=1-423.
DR PDB; 5JDW; X-ray; 2.60 A; A=38-423.
DR PDB; 6JDW; X-ray; 2.50 A; A=38-423.
DR PDB; 7JDW; X-ray; 2.37 A; A=38-423.
DR PDB; 8JDW; X-ray; 2.30 A; A=38-423.
DR PDB; 9JDW; X-ray; 2.50 A; A=38-423.
DR PDBsum; 1JDW; -.
DR PDBsum; 1JDX; -.
DR PDBsum; 2JDW; -.
DR PDBsum; 2JDX; -.
DR PDBsum; 3JDW; -.
DR PDBsum; 4JDW; -.
DR PDBsum; 5JDW; -.
DR PDBsum; 6JDW; -.
DR PDBsum; 7JDW; -.
DR PDBsum; 8JDW; -.
DR PDBsum; 9JDW; -.
DR AlphaFoldDB; P50440; -.
DR SMR; P50440; -.
DR BioGRID; 108898; 10.
DR IntAct; P50440; 23.
DR STRING; 9606.ENSP00000379895; -.
DR DrugBank; DB04454; Alpha-Aminobutyric Acid.
DR DrugBank; DB02068; Delta-Amino Valeric Acid.
DR DrugBank; DB02530; gamma-Aminobutyric acid.
DR DrugBank; DB00145; Glycine.
DR DrugBank; DB04185; Norvaline.
DR DrugBank; DB00129; Ornithine.
DR iPTMnet; P50440; -.
DR PhosphoSitePlus; P50440; -.
DR BioMuta; GATM; -.
DR DMDM; 1730201; -.
DR REPRODUCTION-2DPAGE; IPI00032103; -.
DR EPD; P50440; -.
DR jPOST; P50440; -.
DR MassIVE; P50440; -.
DR MaxQB; P50440; -.
DR PaxDb; P50440; -.
DR PeptideAtlas; P50440; -.
DR PRIDE; P50440; -.
DR ProteomicsDB; 56222; -. [P50440-1]
DR ProteomicsDB; 56223; -. [P50440-2]
DR ProteomicsDB; 56224; -. [P50440-3]
DR Antibodypedia; 11803; 337 antibodies from 28 providers.
DR DNASU; 2628; -.
DR Ensembl; ENST00000396659.8; ENSP00000379895.3; ENSG00000171766.17. [P50440-1]
DR Ensembl; ENST00000558336.5; ENSP00000454008.1; ENSG00000171766.17. [P50440-3]
DR Ensembl; ENST00000675323.1; ENSP00000502445.1; ENSG00000171766.17. [P50440-3]
DR GeneID; 2628; -.
DR KEGG; hsa:2628; -.
DR MANE-Select; ENST00000396659.8; ENSP00000379895.3; NM_001482.3; NP_001473.1.
DR UCSC; uc001zvc.4; human. [P50440-1]
DR CTD; 2628; -.
DR DisGeNET; 2628; -.
DR GeneCards; GATM; -.
DR GeneReviews; GATM; -.
DR HGNC; HGNC:4175; GATM.
DR HPA; ENSG00000171766; Group enriched (kidney, liver, pancreas).
DR MalaCards; GATM; -.
DR MIM; 134600; phenotype.
DR MIM; 602360; gene.
DR MIM; 612718; phenotype.
DR neXtProt; NX_P50440; -.
DR OpenTargets; ENSG00000171766; -.
DR Orphanet; 35704; L-Arginine:glycine amidinotransferase deficiency.
DR Orphanet; 3337; Primary Fanconi renotubular syndrome.
DR PharmGKB; PA28590; -.
DR VEuPathDB; HostDB:ENSG00000171766; -.
DR eggNOG; ENOG502QVCA; Eukaryota.
DR GeneTree; ENSGT00390000011613; -.
DR HOGENOM; CLU_047415_1_0_1; -.
DR InParanoid; P50440; -.
DR OMA; SHNEWDP; -.
DR PhylomeDB; P50440; -.
DR TreeFam; TF300256; -.
DR BioCyc; MetaCyc:HS10376-MON; -.
DR BRENDA; 2.1.4.1; 2681.
DR PathwayCommons; P50440; -.
DR Reactome; R-HSA-71288; Creatine metabolism.
DR SignaLink; P50440; -.
DR UniPathway; UPA00104; UER00579.
DR BioGRID-ORCS; 2628; 7 hits in 1070 CRISPR screens.
DR ChiTaRS; GATM; human.
DR EvolutionaryTrace; P50440; -.
DR GeneWiki; GATM_(gene); -.
DR GenomeRNAi; 2628; -.
DR Pharos; P50440; Tbio.
DR PRO; PR:P50440; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; P50440; protein.
DR Bgee; ENSG00000171766; Expressed in body of pancreas and 205 other tissues.
DR ExpressionAtlas; P50440; baseline and differential.
DR Genevisible; P50440; HS.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:MGI.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0015067; F:amidinotransferase activity; IBA:GO_Central.
DR GO; GO:0015068; F:glycine amidinotransferase activity; IDA:UniProtKB.
DR GO; GO:0006601; P:creatine biosynthetic process; IDA:MGI.
DR GO; GO:0006600; P:creatine metabolic process; IMP:CAFA.
DR GO; GO:0007611; P:learning or memory; IMP:CAFA.
DR GO; GO:0014889; P:muscle atrophy; IMP:CAFA.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR DisProt; DP00099; -.
DR InterPro; IPR033195; AmidinoTrfase.
DR PANTHER; PTHR10488; PTHR10488; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cytoplasm;
KW Disease variant; Membrane; Mitochondrion; Mitochondrion inner membrane;
KW Phosphoprotein; Reference proteome; Transferase; Transit peptide.
FT TRANSIT 1..37
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 38..423
FT /note="Glycine amidinotransferase, mitochondrial"
FT /id="PRO_0000001206"
FT ACT_SITE 254
FT ACT_SITE 303
FT ACT_SITE 407
FT /note="Amidino-cysteine intermediate"
FT /evidence="ECO:0000269|PubMed:9148748"
FT MOD_RES 46
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 49
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 385
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VAR_SEQ 1..37
FT /note="MLRVRCLRGGSRGAEAVHYIGSRLGRTLTGWVQRTFQ -> MNILK (in
FT isoform 2)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_000235"
FT VAR_SEQ 388..423
FT /note="ITTIKVNIRNANSLGGGFHCWTCDVRRRGTLQSYLD -> MYNK (in
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_039871"
FT VARIANT 23
FT /note="R -> Q (in CCDS3; unknown pathological significance;
FT reduces glycine amidinotransferase activity;
FT dbSNP:rs370155767)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076483"
FT VARIANT 93
FT /note="I -> V (in CCDS3; unknown pathological significance;
FT reduces glycine amidinotransferase activity;
FT dbSNP:rs34991226)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076484"
FT VARIANT 102
FT /note="K -> N (in CCDS3; unknown pathological significance;
FT reduces glycine amidinotransferase activity;
FT dbSNP:rs376335787)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076485"
FT VARIANT 105
FT /note="P -> L (in CCDS3; loss of glycine amidinotransferase
FT activity; dbSNP:rs147804855)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076486"
FT VARIANT 110
FT /note="Q -> H (in dbSNP:rs1288775)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_020305"
FT VARIANT 181
FT /note="E -> K (in CCDS3; loss of glycine amidinotransferase
FT activity; dbSNP:rs376982466)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076487"
FT VARIANT 185
FT /note="A -> P (in CCDS3; decreases glycine
FT amidinotransferase activity)"
FT /evidence="ECO:0000269|PubMed:26490222,
FT ECO:0000269|PubMed:27233232"
FT /id="VAR_076488"
FT VARIANT 189
FT /note="R -> C (in CCDS3; loss of glycine amidinotransferase
FT activity; dbSNP:rs377578020)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076489"
FT VARIANT 203
FT /note="Y -> S (in CCDS3; loss of glycine amidinotransferase
FT activity; dbSNP:rs397514709)"
FT /evidence="ECO:0000269|PubMed:23770102,
FT ECO:0000269|PubMed:26490222, ECO:0000269|PubMed:27233232"
FT /id="VAR_069816"
FT VARIANT 208
FT /note="A -> T (in CCDS3; loss of glycine amidinotransferase
FT activity; dbSNP:rs374059924)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076490"
FT VARIANT 231
FT /note="S -> C (decreases glycine amidinotransferase
FT activity; dbSNP:rs202225656)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076491"
FT VARIANT 234
FT /note="D -> G (decreases glycine amidinotransferase
FT activity; dbSNP:rs146057680)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076492"
FT VARIANT 282
FT /note="R -> H (in CCDS3; decreases glycine
FT amidinotransferase activity; dbSNP:rs371447931)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076493"
FT VARIANT 320
FT /note="P -> S (in FRTS1; results in GATM protein
FT aggregation; GATM deposits affect mitochondrial morphology
FT leading to abnormal and elongated mitochondria)"
FT /evidence="ECO:0000269|PubMed:29654216"
FT /id="VAR_084378"
FT VARIANT 329
FT /note="L -> V (in CCDS3; decreases glycine
FT amidinotransferase activity; dbSNP:rs373802463)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076494"
FT VARIANT 336
FT /note="T -> A (in FRTS1; results in GATM protein
FT aggregation; GATM deposits affect mitochondrial morphology
FT leading to abnormal and elongated mitochondria)"
FT /evidence="ECO:0000269|PubMed:29654216"
FT /id="VAR_084379"
FT VARIANT 336
FT /note="T -> I (in FRTS1; results in GATM protein
FT aggregation; GATM deposits affect mitochondrial morphology
FT and are associated with increased ROS production,
FT activation of the NLRP3 inflammasome and enhanced
FT expression of the profibrotic cytokine IL-18)"
FT /evidence="ECO:0000269|PubMed:29654216"
FT /id="VAR_084380"
FT VARIANT 341
FT /note="P -> L (in FRTS1; results in GATM protein
FT aggregation; GATM deposits affect mitochondrial morphology
FT leading to abnormal and elongated mitochondria)"
FT /evidence="ECO:0000269|PubMed:29654216"
FT /id="VAR_084381"
FT VARIANT 346
FT /note="P -> L (in CCDS3; decreases glycine
FT amidinotransferase activity; dbSNP:rs142814307)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076495"
FT VARIANT 413
FT /note="R -> Q (in CCDS3; loss of glycine amidinotransferase
FT activity; dbSNP:rs1461653218)"
FT /evidence="ECO:0000269|PubMed:23660394,
FT ECO:0000269|PubMed:27233232"
FT /id="VAR_071789"
FT VARIANT 413
FT /note="R -> W (in CCDS3; loss of glycine amidinotransferase
FT activity; dbSNP:rs1244824806)"
FT /evidence="ECO:0000269|PubMed:23660394,
FT ECO:0000269|PubMed:26490222, ECO:0000269|PubMed:27233232"
FT /id="VAR_071790"
FT VARIANT 415
FT /note="R -> Q (in CCDS3; unknown pathological significance;
FT reduces glycine amidinotransferase activity;
FT dbSNP:rs374592247)"
FT /evidence="ECO:0000269|PubMed:27233232"
FT /id="VAR_076496"
FT MUTAGEN 170
FT /note="D->N: Complete loss of activity."
FT /evidence="ECO:0000269|PubMed:9266688"
FT MUTAGEN 233
FT /note="E->K: Complete loss of activity; when associated
FT with S-407."
FT /evidence="ECO:0000269|PubMed:9266688"
FT MUTAGEN 254
FT /note="D->N: Significantly reduced activity."
FT /evidence="ECO:0000269|PubMed:9266688"
FT MUTAGEN 303
FT /note="H->V: Complete loss of activity."
FT /evidence="ECO:0000269|PubMed:9266688"
FT MUTAGEN 305
FT /note="D->A: Complete loss of activity."
FT /evidence="ECO:0000269|PubMed:9266688"
FT MUTAGEN 322
FT /note="R->E: Significantly reduced activity."
FT /evidence="ECO:0000269|PubMed:9266688"
FT MUTAGEN 355
FT /note="S->A: Significantly reduced activity."
FT /evidence="ECO:0000269|PubMed:9266688"
FT MUTAGEN 407
FT /note="C->S: Complete loss of activity; when associated
FT with K-233."
FT /evidence="ECO:0000269|PubMed:9266688"
FT MUTAGEN 410
FT /note="C->A: No effect on activity."
FT /evidence="ECO:0000269|PubMed:9266688"
FT CONFLICT 98
FT /note="N -> I (in Ref. 3; BAG60595)"
FT /evidence="ECO:0000305"
FT CONFLICT 246
FT /note="T -> I (in Ref. 3; BAG60595)"
FT /evidence="ECO:0000305"
FT CONFLICT 384
FT /note="E -> G (in Ref. 3; BAG58060)"
FT /evidence="ECO:0000305"
FT CONFLICT 395
FT /note="I -> V (in Ref. 3; BAG60595)"
FT /evidence="ECO:0000305"
FT STRAND 70..73
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 75..80
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 93..96
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 101..103
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 104..110
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 113..115
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 117..136
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 140..142
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 152..154
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 159..161
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 168..171
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 172..176
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 178..181
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 187..189
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 192..195
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 197..205
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 209..212
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 220..222
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 232..240
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 248..250
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 255..257
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 258..261
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 264..267
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 275..285
FT /evidence="ECO:0007829|PDB:1JDW"
FT TURN 286..288
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 290..293
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 296..298
FT /evidence="ECO:0007829|PDB:1JDW"
FT TURN 305..307
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 308..312
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 315..318
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 327..332
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 336..338
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 352..354
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 356..360
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 363..366
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 369..373
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 377..385
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 389..393
FT /evidence="ECO:0007829|PDB:1JDW"
FT HELIX 396..399
FT /evidence="ECO:0007829|PDB:1JDW"
FT TURN 400..402
FT /evidence="ECO:0007829|PDB:1JDW"
FT TURN 405..408
FT /evidence="ECO:0007829|PDB:1JDW"
FT STRAND 409..415
FT /evidence="ECO:0007829|PDB:1JDW"
SQ SEQUENCE 423 AA; 48455 MW; 5BEF7A8A039B70FB CRC64;
MLRVRCLRGG SRGAEAVHYI GSRLGRTLTG WVQRTFQSTQ AATASSRNSC AADDKATEPL
PKDCPVSSYN EWDPLEEVIV GRAENACVPP FTIEVKANTY EKYWPFYQKQ GGHYFPKDHL
KKAVAEIEEM CNILKTEGVT VRRPDPIDWS LKYKTPDFES TGLYSAMPRD ILIVVGNEII
EAPMAWRSRF FEYRAYRSII KDYFHRGAKW TTAPKPTMAD ELYNQDYPIH SVEDRHKLAA
QGKFVTTEFE PCFDAADFIR AGRDIFAQRS QVTNYLGIEW MRRHLAPDYR VHIISFKDPN
PMHIDATFNI IGPGIVLSNP DRPCHQIDLF KKAGWTIITP PTPIIPDDHP LWMSSKWLSM
NVLMLDEKRV MVDANEVPIQ KMFEKLGITT IKVNIRNANS LGGGFHCWTC DVRRRGTLQS
YLD
