ASSY_HUMAN
ID ASSY_HUMAN Reviewed; 412 AA.
AC P00966; Q6LDL2; Q86UZ0; Q96GT4;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2002, sequence version 2.
DT 03-AUG-2022, entry version 233.
DE RecName: Full=Argininosuccinate synthase {ECO:0000305};
DE EC=6.3.4.5 {ECO:0000269|PubMed:18473344, ECO:0000269|PubMed:27287393, ECO:0000269|PubMed:8792870};
DE AltName: Full=Citrulline--aspartate ligase;
GN Name=ASS1 {ECO:0000312|HGNC:HGNC:758};
GN Synonyms=ASS {ECO:0000312|HGNC:HGNC:758};
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].
RX PubMed=6194510; DOI=10.1093/nar/11.18.6505;
RA Bock H.-G.O., Su T.-S., O'Brien W.E., Beaudet A.L.;
RT "Sequence for human argininosuccinate synthetase cDNA.";
RL Nucleic Acids Res. 11:6505-6512(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6321498; DOI=10.1016/s0021-9258(17)43275-3;
RA Freytag S.O., Bock H.-G.O., Beaudet A.L., O'Brien W.E.;
RT "Molecular structures of human argininosuccinate synthetase pseudogenes.
RT Evolutionary and mechanistic implications.";
RL J. Biol. Chem. 259:3160-3166(1984).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CTLN1 LEU-108; ARG-179;
RP VAL-362 AND ARG-390.
RX PubMed=11941481; DOI=10.1007/s00439-002-0686-6;
RA Haeberle J., Pauli S., Linnebank M., Kleijer W.J., Bakker H.D.,
RA Wanders R.J.A., Harms E., Koch H.G.;
RT "Structure of the human argininosuccinate synthetase gene and an improved
RT system for molecular diagnostics in patients with classical and mild
RT citrullinemia.";
RL Hum. Genet. 110:327-333(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Small intestine;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney, and 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 [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-24.
RX PubMed=3027451; DOI=10.1007/bf01819307;
RA Jinno Y., Nomiyama H., Matuo S., Shimada K., Matsuda I., Saheki T.;
RT "Structure of the 5' end region of the human argininosuccinate synthetase
RT gene.";
RL J. Inherit. Metab. Dis. 8:157-159(1985).
RN [7]
RP PROTEIN SEQUENCE OF 148-161.
RX PubMed=2788888;
RA Isashiki Y., Noda T., Kobayashi K., Sase M., Saheki T., Titani K.;
RT "Identification of essential arginine residue(s) for Mg-ATP binding of
RT human argininosuccinate synthetase.";
RL Protein Seq. Data Anal. 2:283-287(1989).
RN [8]
RP PROTEIN SEQUENCE OF 200-209.
RC TISSUE=Colon carcinoma;
RX PubMed=9150948; DOI=10.1002/elps.1150180344;
RA Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J.;
RT "A two-dimensional gel database of human colon carcinoma proteins.";
RL Electrophoresis 18:605-613(1997).
RN [9]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=1708740; DOI=10.1016/0378-1119(91)90125-u;
RA Surh L.C., Beaudet A.L., O'Brien W.E.;
RT "Molecular characterization of the murine argininosuccinate synthetase
RT locus.";
RL Gene 99:181-189(1991).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-180 AND THR-219, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-219, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-113 AND THR-219, 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 [14]
RP ACETYLATION AT LYS-165 AND LYS-176, MUTAGENESIS OF LYS-165 AND LYS-176,
RP INTERACTION WITH CLOCK, AND SUBCELLULAR LOCATION.
RX PubMed=28985504; DOI=10.1016/j.molcel.2017.09.008;
RA Lin R., Mo Y., Zha H., Qu Z., Xie P., Zhu Z.J., Xu Y., Xiong Y., Guan K.L.;
RT "CLOCK acetylates ASS1 to drive circadian rhythm of ureagenesis.";
RL Mol. Cell 68:198-209(2017).
RN [15]
RP CHARACTERIZATION OF VARIANTS CLNT1 VAL-192; ARG-280; CYS-272 AND TRP-304,
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=8792870; DOI=10.1159/000474998;
RA Shaheen N., Kobayashi K., Terazono H., Fukushige T., Horiuchi M.,
RA Saheki T.;
RT "Characterization of human wild-type and mutant argininosuccinate
RT synthetase proteins expressed in bacterial cells.";
RL Enzyme Protein 48:251-264(1994).
RN [16]
RP INTERACTION WITH NMRAL1.
RX PubMed=17496144; DOI=10.1073/pnas.0700480104;
RA Zheng X., Dai X., Zhao Y., Chen Q., Lu F., Yao D., Yu Q., Liu X., Zhang C.,
RA Gu X., Luo M.;
RT "Restructuring of the dinucleotide-binding fold in an NADP(H) sensor
RT protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:8809-8814(2007).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH CITRULLINE AND
RP ASPARTATE, AND SUBUNIT.
RX PubMed=18323623; DOI=10.1107/s0907444907067455;
RA Karlberg T., Collins R., van den Berg S., Flores A., Hammarstrom M.,
RA Hogbom M., Holmberg Schiavone L., Uppenberg J.;
RT "Structure of human argininosuccinate synthetase.";
RL Acta Crystallogr. D 64:279-286(2008).
RN [18]
RP INVOLVEMENT IN CTLN1, AND VARIANTS CTLN1 SER-14; HIS-157; ASN-180; TRP-304;
RP SER-324; TRP-363 AND ARG-390.
RX PubMed=2358466; DOI=10.1016/s0021-9258(19)38601-6;
RA Kobayashi K., Jackson M.J., Tick D.B., O'Brien W.E., Beaudet A.L.;
RT "Heterogeneity of mutations in argininosuccinate synthetase causing human
RT citrullinemia.";
RL J. Biol. Chem. 265:11361-11367(1990).
RN [19]
RP VARIANTS CTLN1 LEU-18 AND CYS-86.
RX PubMed=1943692;
RA Kobayashi K., Rosenbloom C., Beaudet A.L., O'Brien W.E.;
RT "Additional mutations in argininosuccinate synthetase causing
RT citrullinemia.";
RL Mol. Biol. Med. 8:95-100(1991).
RN [20]
RP VARIANTS CTLN1 THR-118; VAL-192; CYS-272; ARG-280; TRP-304 AND LEU-363.
RX PubMed=7977368;
RA Kobayashi K., Shaheen N., Terazono H., Saheki T.;
RT "Mutations in argininosuccinate synthetase mRNA of Japanese patients,
RT causing classical citrullinemia.";
RL Am. J. Hum. Genet. 55:1103-1112(1994).
RN [21]
RP VARIANTS CTLN1 ALA-69; LEU-108; ASP-117; ILE-119; GLN-270 AND ARG-390.
RX PubMed=11708871; DOI=10.1006/mgme.2001.3221;
RA Vilaseca M.A., Kobayashi K., Briones P., Lambruschini N., Campistol J.,
RA Tabata A., Alomar A., Rodes M., Lluch M., Saheki T.;
RT "Phenotype and genotype heterogeneity in Mediterranean citrullinemia.";
RL Mol. Genet. Metab. 74:396-398(2001).
RN [22]
RP VARIANTS CTLN1 ARG-19; HIS-86; SER-95; SER-96; ASP-117; SER-117; CYS-157;
RP ARG-179; LYS-191; HIS-265; MET-269; CYS-272; LYS-283; TRP-304; GLN-310;
RP SER-324; VAL-362; GLN-363; TRP-363; ILE-389 AND ARG-390.
RX PubMed=12815590; DOI=10.1002/humu.10230;
RA Gao H.-Z., Kobayashi K., Tabata A., Tsuge H., Iijima M., Yasuda T.,
RA Kalkanoglu H.S., Dursun A., Tokatli A., Coskun T., Trefz F.K., Skladal D.,
RA Mandel H., Seidel J., Kodama S., Shirane S., Ichida T., Makino S.,
RA Yoshino M., Kang J.-H., Mizuguchi M., Barshop B.A., Fuchinoue S.,
RA Seneca S., Zeesman S., Knerr I., Rodes M., Wasant P., Yoshida I.,
RA De Meirleir L., Abdul-Jalil M., Begum L., Horiuchi M., Katunuma N.,
RA Nakagawa S., Saheki T.;
RT "Identification of 16 novel mutations in the argininosuccinate synthetase
RT gene and genotype-phenotype correlation in 38 classical citrullinemia
RT patients.";
RL Hum. Mutat. 22:24-34(2003).
RN [23]
RP VARIANTS CTLN1 SER-14; LEU-40; GLN-127; ARG-179; ASP-190; GLU-202; MET-263;
RP MET-269; SER-324; GLY-345 AND VAL-362.
RX PubMed=14680976; DOI=10.1016/j.ymgme.2003.08.002;
RA Haeberle J., Pauli S., Schmidt E., Schulze-Eilfing B., Berning C.,
RA Koch H.G.;
RT "Mild citrullinemia in Caucasians is an allelic variant of
RT argininosuccinate synthetase deficiency (citrullinemia type 1).";
RL Mol. Genet. Metab. 80:302-306(2003).
RN [24]
RP VARIANT CTLN1 ARG-310.
RX PubMed=15863597; DOI=10.1097/01.aog.0000157769.90230.24;
RA Enns G.M., O'Brien W.E., Kobayashi K., Shinzawa H., Pellegrino J.E.;
RT "Postpartum 'psychosis' in mild argininosuccinate synthetase deficiency.";
RL Obstet. Gynecol. 105:1244-1246(2005).
RN [25]
RP VARIANTS CTLN1 ASN-124; HIS-157; GLN-270; GLN-279; LYS-283; SER-324;
RP GLY-363 AND ARG-390.
RX PubMed=16475226; DOI=10.1002/pd.1390;
RA Kleijer W.J., Garritsen V.H., van der Sterre M.L., Berning C., Haeberle J.,
RA Huijmans J.G.M.;
RT "Prenatal diagnosis of citrullinemia and argininosuccinic aciduria:
RT evidence for a transmission ratio distortion in citrullinemia.";
RL Prenat. Diagn. 26:242-247(2006).
RN [26]
RP VARIANTS CTLN1 CYS-265 AND VAL-302, CHARACTERIZATION OF VARIANTS CTLN1
RP THR-118; ARG-179; VAL-263; CYS-265; VAL-302; SER-324; VAL-362 AND ARG-390,
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=18473344; DOI=10.1002/humu.20784;
RA Berning C., Bieger I., Pauli S., Vermeulen T., Vogl T., Rummel T.,
RA Hoehne W., Koch H.G., Rolinski B., Gempel K., Haeberle J.;
RT "Investigation of citrullinemia type I variants by in vitro expression
RT studies.";
RL Hum. Mutat. 29:1222-1227(2008).
RN [27]
RP VARIANTS CTLN1 PRO-79; HIS-96; GLN-127; TRP-127; PRO-160; GLN-191; PRO-206;
RP CYS-265; THR-277; ILE-284; SER-291; GLY-296; VAL-324; PHE-341; ARG-347 AND
RP ASP-359.
RX PubMed=19006241; DOI=10.1002/humu.20847;
RA Engel K., Hoehne W., Haeberle J.;
RT "Mutations and polymorphisms in the human argininosuccinate synthetase
RT (ASS1) gene.";
RL Hum. Mutat. 30:300-307(2009).
RN [28]
RP VARIANTS CTLN1 LYS-283 AND ARG-337.
RX PubMed=23611581; DOI=10.1016/j.braindev.2013.03.005;
RA Wu T.F., Liu Y.P., Li X.Y., Wang Q., Song J.Q., Yang Y.L.;
RT "Prenatal diagnosis of citrullinemia type 1: a Chinese family with a novel
RT mutation of the ASS1 gene.";
RL Brain Dev. 36:264-267(2014).
RN [29]
RP VARIANTS CTLN1 PRO-91; CYS-157; ILE-180; LYS-283 AND ARG-390, AND VARIANT
RP LEU-127.
RX PubMed=24889030; DOI=10.1016/j.ymgme.2014.05.004;
RA Miller M.J., Soler-Alfonso C.R., Grund J.E., Fang P., Sun Q., Elsea S.H.,
RA Sutton V.R.;
RT "Improved standards for prenatal diagnosis of citrullinemia.";
RL Mol. Genet. Metab. 112:205-209(2014).
RN [30]
RP VARIANTS CTLN1 GLY-141 AND CYS-265.
RX PubMed=25179242; DOI=10.1016/j.cca.2014.08.028;
RA Kimani J.K., Wei T., Chol K., Li Y., Yu P., Ye S., Huang X., Qi M.;
RT "Functional analysis of novel splicing and missense mutations identified in
RT the ASS1 gene in classical citrullinemia patients.";
RL Clin. Chim. Acta 438:323-329(2015).
RN [31]
RP VARIANTS CTLN1 PRO-91; LEU-96; SER-117; THR-118; ILE-119; ASN-124; CYS-157;
RP HIS-157; CYS-272; HIS-272 AND LEU-272, CHARACTERIZATION OF VARIANTS CTLN1
RP PRO-91; SER-95; HIS-96; LEU-96; SER-96; SER-117; THR-118; ILE-119; ASN-124;
RP GLN-127; TRP-127; CYS-157; HIS-157; ASN-180; ILE-180; GLN-191; GLN-270;
RP CYS-272; HIS-272 AND LEU-272, CHARACTERIZATION OF VARIANT LEU-127,
RP CATALYTIC ACTIVITY, PATHWAY, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=27287393; DOI=10.1136/jmedgenet-2016-103937;
RA Diez-Fernandez C., Wellauer O., Gemperle C., Ruefenacht V., Fingerhut R.,
RA Haeberle J.;
RT "Kinetic mutations in argininosuccinate synthetase deficiency:
RT characterisation and in vitro correction by substrate supplementation.";
RL J. Med. Genet. 53:710-719(2016).
RN [32]
RP VARIANTS CTLN1 27-GLN--LYS-412 DEL; ILE-64; PRO-79; 97-CYS--LYS-412 DEL;
RP CYS-100; HIS-100; ASP-111; CYS-117; 138-GLN--LYS-412 DEL; SER-157; PRO-160;
RP 163-TYR--LYS-412 DEL; PRO-164; LYS-184; ASP-190; PRO-206; ARG-230; ILE-237;
RP PRO-258; VAL-258; CYS-265; 275-GLY--LYS-412 DEL; THR-277; 279-ARG--LYS-412
RP DEL; ILE-284; PRO-290; SER-291; GLY-296; ASP-299; VAL-302; GLY-306;
RP CYS-307; 311-GLN--LYS-412 DEL; MET-321; SER-324; VAL-324; HIS-335; PHE-341;
RP 344-ARG--LYS-412 DEL; ARG-347; VAL-356; 357-GLN--LYS-412 DEL; ASP-359;
RP 380-GLN--LYS-412 DEL AND PRO-389.
RX PubMed=28111830; DOI=10.1002/humu.23184;
RA Diez-Fernandez C., Ruefenacht V., Haeberle J.;
RT "Mutations in the human argininosuccinate synthetase (ASS1) gene, impact on
RT patients, common changes, and structural considerations.";
RL Hum. Mutat. 38:471-484(2017).
CC -!- FUNCTION: One of the enzymes of the urea cycle, the metabolic pathway
CC transforming neurotoxic amonia produced by protein catabolism into
CC inocuous urea in the liver of ureotelic animals. Catalyzes the
CC formation of arginosuccinate from aspartate, citrulline and ATP and
CC together with ASL it is responsible for the biosynthesis of arginine in
CC most body tissues. {ECO:0000305|PubMed:18473344,
CC ECO:0000305|PubMed:27287393, ECO:0000305|PubMed:8792870}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-aspartate + L-citrulline = 2-(N(omega)-L-
CC arginino)succinate + AMP + diphosphate + H(+); Xref=Rhea:RHEA:10932,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29991, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57472, ChEBI:CHEBI:57743,
CC ChEBI:CHEBI:456215; EC=6.3.4.5;
CC Evidence={ECO:0000269|PubMed:18473344, ECO:0000269|PubMed:27287393,
CC ECO:0000269|PubMed:8792870};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=112 uM for citrulline (at pH 7.0 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:18473344};
CC KM=68 uM for aspartate (at pH 7.0 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:18473344};
CC Vmax=143 nmol/min/mg enzyme toward citrulline (at pH 7.0 and 37
CC degrees Celsius) {ECO:0000269|PubMed:18473344};
CC Vmax=116 nmol/min/mg enzyme toward aspartate (at pH 7.0 and 37
CC degrees {ECO:0000269|PubMed:18473344};
CC -!- PATHWAY: Amino-acid biosynthesis; L-arginine biosynthesis; L-arginine
CC from L-ornithine and carbamoyl phosphate: step 2/3.
CC {ECO:0000305|PubMed:18473344, ECO:0000305|PubMed:27287393,
CC ECO:0000305|PubMed:8792870}.
CC -!- PATHWAY: Nitrogen metabolism; urea cycle; (N(omega)-L-
CC arginino)succinate from L-aspartate and L-citrulline: step 1/1.
CC {ECO:0000305|PubMed:18473344, ECO:0000305|PubMed:27287393,
CC ECO:0000305|PubMed:8792870}.
CC -!- SUBUNIT: Homotetramer (PubMed:18323623). Interacts with NMRAL1
CC (PubMed:17496144). Interacts with CLOCK; in a circadian manner
CC (PubMed:28985504). Forms tissue-specific complexes with ASL, SLC7A1,
CC HSP90AA1 and nitric oxide synthase NOS1, NOS2 or NOS3; the complex
CC regulates cell-autonomous L-arginine synthesis and citrulline recycling
CC while channeling extracellular L-arginine to nitric oxide synthesis
CC pathway. {ECO:0000250|UniProtKB:P16460, ECO:0000269|PubMed:17496144,
CC ECO:0000269|PubMed:18323623, ECO:0000269|PubMed:28985504}.
CC -!- INTERACTION:
CC P00966; P10398: ARAF; NbExp=4; IntAct=EBI-536842, EBI-365961;
CC P00966; P00966: ASS1; NbExp=3; IntAct=EBI-536842, EBI-536842;
CC P00966; Q9HBL8: NMRAL1; NbExp=3; IntAct=EBI-536842, EBI-2862643;
CC P00966; Q9NVM4: PRMT7; NbExp=9; IntAct=EBI-536842, EBI-3215577;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:28985504,
CC ECO:0000305|PubMed:27287393}.
CC -!- TISSUE SPECIFICITY: Expressed in adult liver.
CC {ECO:0000269|PubMed:1708740}.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal liver and kidney.
CC {ECO:0000269|PubMed:1708740}.
CC -!- PTM: Acetylated by CLOCK in a circadian manner which negatively
CC regulates its enzyme activity. Deacetylated by histone deacetylases.
CC {ECO:0000269|PubMed:28985504}.
CC -!- DISEASE: Citrullinemia 1 (CTLN1) [MIM:215700]: The classic form of
CC citrullinemia, an autosomal recessive disease characterized primarily
CC by elevated serum and urine citrulline levels. Ammonia intoxication is
CC another manifestation. It is a disorder of the urea cycle, usually
CC manifesting in the first few days of life. Affected infants appear
CC normal at birth, but as ammonia builds up in the body they present
CC symptoms such as lethargy, poor feeding, vomiting, seizures and loss of
CC consciousness. Less commonly, a milder form can develop later in
CC childhood or adulthood. {ECO:0000269|PubMed:11708871,
CC ECO:0000269|PubMed:11941481, ECO:0000269|PubMed:12815590,
CC ECO:0000269|PubMed:14680976, ECO:0000269|PubMed:15863597,
CC ECO:0000269|PubMed:16475226, ECO:0000269|PubMed:18473344,
CC ECO:0000269|PubMed:19006241, ECO:0000269|PubMed:1943692,
CC ECO:0000269|PubMed:2358466, ECO:0000269|PubMed:23611581,
CC ECO:0000269|PubMed:24889030, ECO:0000269|PubMed:25179242,
CC ECO:0000269|PubMed:27287393, ECO:0000269|PubMed:28111830,
CC ECO:0000269|PubMed:7977368}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the argininosuccinate synthase family. Type 1
CC subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Argininosuccinate synthetase 1 (ASS1); Note=Leiden
CC Open Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/ASS1";
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DR EMBL; X01630; CAA25771.1; -; mRNA.
DR EMBL; L00084; AAA51783.1; -; Genomic_DNA.
DR EMBL; L00079; AAA51783.1; JOINED; Genomic_DNA.
DR EMBL; L00080; AAA51783.1; JOINED; Genomic_DNA.
DR EMBL; L00081; AAA51783.1; JOINED; Genomic_DNA.
DR EMBL; L00082; AAA51783.1; JOINED; Genomic_DNA.
DR EMBL; L00083; AAA51783.1; JOINED; Genomic_DNA.
DR EMBL; AY034076; AAK67487.1; -; Genomic_DNA.
DR EMBL; AK027126; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC009243; AAH09243.1; -; mRNA.
DR EMBL; BC021676; AAH21676.1; -; mRNA.
DR EMBL; M34903; AAA51782.1; -; Genomic_DNA.
DR CCDS; CCDS6933.1; -.
DR PIR; A01195; AJHURS.
DR RefSeq; NP_000041.2; NM_000050.4.
DR RefSeq; NP_446464.1; NM_054012.3.
DR RefSeq; XP_005272257.1; XM_005272200.3.
DR PDB; 2NZ2; X-ray; 2.40 A; A=1-412.
DR PDBsum; 2NZ2; -.
DR AlphaFoldDB; P00966; -.
DR SMR; P00966; -.
DR BioGRID; 106937; 139.
DR DIP; DIP-34055N; -.
DR IntAct; P00966; 33.
DR MINT; P00966; -.
DR STRING; 9606.ENSP00000361471; -.
DR DrugBank; DB00125; Arginine.
DR DrugBank; DB00128; Aspartic acid.
DR DrugBank; DB00171; ATP.
DR DrugBank; DB00155; Citrulline.
DR DrugCentral; P00966; -.
DR GlyGen; P00966; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P00966; -.
DR MetOSite; P00966; -.
DR PhosphoSitePlus; P00966; -.
DR BioMuta; ASS1; -.
DR DMDM; 20141195; -.
DR CPTAC; CPTAC-169; -.
DR CPTAC; CPTAC-170; -.
DR EPD; P00966; -.
DR jPOST; P00966; -.
DR MassIVE; P00966; -.
DR PaxDb; P00966; -.
DR PeptideAtlas; P00966; -.
DR PRIDE; P00966; -.
DR ProteomicsDB; 51293; -.
DR Antibodypedia; 4531; 515 antibodies from 38 providers.
DR DNASU; 445; -.
DR Ensembl; ENST00000352480.10; ENSP00000253004.6; ENSG00000130707.18.
DR Ensembl; ENST00000372393.7; ENSP00000361469.2; ENSG00000130707.18.
DR Ensembl; ENST00000372394.5; ENSP00000361471.1; ENSG00000130707.18.
DR GeneID; 445; -.
DR KEGG; hsa:445; -.
DR MANE-Select; ENST00000352480.10; ENSP00000253004.6; NM_054012.4; NP_446464.1.
DR CTD; 445; -.
DR DisGeNET; 445; -.
DR GeneCards; ASS1; -.
DR GeneReviews; ASS1; -.
DR HGNC; HGNC:758; ASS1.
DR HPA; ENSG00000130707; Group enriched (kidney, liver).
DR MalaCards; ASS1; -.
DR MIM; 215700; phenotype.
DR MIM; 603470; gene.
DR neXtProt; NX_P00966; -.
DR OpenTargets; ENSG00000130707; -.
DR Orphanet; 247546; Acute neonatal citrullinemia type I.
DR Orphanet; 247573; Adult-onset citrullinemia type I.
DR PharmGKB; PA162376926; -.
DR VEuPathDB; HostDB:ENSG00000130707; -.
DR eggNOG; KOG1706; Eukaryota.
DR GeneTree; ENSGT00390000004524; -.
DR HOGENOM; CLU_032784_4_2_1; -.
DR InParanoid; P00966; -.
DR OMA; GRAYFNT; -.
DR OrthoDB; 1459745at2759; -.
DR PhylomeDB; P00966; -.
DR TreeFam; TF300736; -.
DR BioCyc; MetaCyc:HS05425-MON; -.
DR BRENDA; 6.3.4.5; 2681.
DR PathwayCommons; P00966; -.
DR Reactome; R-HSA-70635; Urea cycle.
DR SABIO-RK; P00966; -.
DR SignaLink; P00966; -.
DR UniPathway; UPA00068; UER00113.
DR UniPathway; UPA00158; UER00272.
DR BioGRID-ORCS; 445; 25 hits in 1044 CRISPR screens.
DR ChiTaRS; ASS1; human.
DR EvolutionaryTrace; P00966; -.
DR GeneWiki; Argininosuccinate_synthetase_1; -.
DR GenomeRNAi; 445; -.
DR Pharos; P00966; Tbio.
DR PRO; PR:P00966; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; P00966; protein.
DR Bgee; ENSG00000130707; Expressed in right lobe of liver and 205 other tissues.
DR ExpressionAtlas; P00966; baseline and differential.
DR Genevisible; P00966; HS.
DR GO; GO:0070852; C:cell body fiber; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IEA:Ensembl.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0016597; F:amino acid binding; IMP:BHF-UCL.
DR GO; GO:0004055; F:argininosuccinate synthase activity; IMP:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR GO; GO:0015643; F:toxic substance binding; IEA:Ensembl.
DR GO; GO:0006953; P:acute-phase response; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0006526; P:arginine biosynthetic process; IMP:UniProtKB.
DR GO; GO:0000053; P:argininosuccinate metabolic process; IMP:BHF-UCL.
DR GO; GO:0006531; P:aspartate metabolic process; IMP:BHF-UCL.
DR GO; GO:0071418; P:cellular response to amine stimulus; IEA:Ensembl.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0071242; P:cellular response to ammonium ion; IEA:Ensembl.
DR GO; GO:0071320; P:cellular response to cAMP; IEA:Ensembl.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IEA:Ensembl.
DR GO; GO:0071499; P:cellular response to laminar fluid shear stress; IMP:BHF-UCL.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0071400; P:cellular response to oleic acid; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0007623; P:circadian rhythm; IDA:UniProtKB.
DR GO; GO:0000052; P:citrulline metabolic process; IMP:BHF-UCL.
DR GO; GO:0060539; P:diaphragm development; IEA:Ensembl.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0007494; P:midgut development; IEA:Ensembl.
DR GO; GO:1903038; P:negative regulation of leukocyte cell-cell adhesion; IMP:BHF-UCL.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IMP:BHF-UCL.
DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR GO; GO:0060416; P:response to growth hormone; IEA:Ensembl.
DR GO; GO:0010046; P:response to mycotoxin; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
DR GO; GO:0000050; P:urea cycle; IMP:UniProtKB.
DR CDD; cd01999; Argininosuccinate_Synthase; 1.
DR Gene3D; 3.40.50.620; -; 1.
DR Gene3D; 3.90.1260.10; -; 1.
DR HAMAP; MF_00005; Arg_succ_synth_type1; 1.
DR InterPro; IPR001518; Arginosuc_synth.
DR InterPro; IPR018223; Arginosuc_synth_CS.
DR InterPro; IPR023434; Arginosuc_synth_type_1_subfam.
DR InterPro; IPR024074; AS_cat/multimer_dom_body.
DR InterPro; IPR014729; Rossmann-like_a/b/a_fold.
DR PANTHER; PTHR11587; PTHR11587; 1.
DR Pfam; PF00764; Arginosuc_synth; 1.
DR SUPFAM; SSF69864; SSF69864; 1.
DR TIGRFAMs; TIGR00032; argG; 1.
DR PROSITE; PS00564; ARGININOSUCCIN_SYN_1; 1.
DR PROSITE; PS00565; ARGININOSUCCIN_SYN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amino-acid biosynthesis; Arginine biosynthesis;
KW ATP-binding; Cytoplasm; Direct protein sequencing; Disease variant; Ligase;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Urea cycle.
FT CHAIN 1..412
FT /note="Argininosuccinate synthase"
FT /id="PRO_0000148554"
FT BINDING 10..18
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 36
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 87
FT /ligand="L-citrulline"
FT /ligand_id="ChEBI:CHEBI:57743"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 92
FT /ligand="L-citrulline"
FT /ligand_id="ChEBI:CHEBI:57743"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 115..123
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 119
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 123
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 123
FT /ligand="L-citrulline"
FT /ligand_id="ChEBI:CHEBI:57743"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 124
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 127
FT /ligand="L-citrulline"
FT /ligand_id="ChEBI:CHEBI:57743"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 180
FT /ligand="L-citrulline"
FT /ligand_id="ChEBI:CHEBI:57743"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 189
FT /ligand="L-citrulline"
FT /ligand_id="ChEBI:CHEBI:57743"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 270
FT /ligand="L-citrulline"
FT /ligand_id="ChEBI:CHEBI:57743"
FT /evidence="ECO:0000269|PubMed:18323623"
FT BINDING 282
FT /ligand="L-citrulline"
FT /ligand_id="ChEBI:CHEBI:57743"
FT /evidence="ECO:0000269|PubMed:18323623"
FT MOD_RES 87
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P09034"
FT MOD_RES 112
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P16460"
FT MOD_RES 113
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 165
FT /note="N6-acetyllysine; by CLOCK"
FT /evidence="ECO:0000269|PubMed:28985504"
FT MOD_RES 176
FT /note="N6-acetyllysine; by CLOCK"
FT /evidence="ECO:0000269|PubMed:28985504"
FT MOD_RES 180
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT MOD_RES 219
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT VARIANT 14
FT /note="G -> S (in CTLN1; dbSNP:rs121908636)"
FT /evidence="ECO:0000269|PubMed:14680976,
FT ECO:0000269|PubMed:2358466"
FT /id="VAR_000681"
FT VARIANT 18
FT /note="S -> L (in CTLN1; dbSNP:rs121908643)"
FT /evidence="ECO:0000269|PubMed:1943692"
FT /id="VAR_000682"
FT VARIANT 19
FT /note="C -> R (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:12815590"
FT /id="VAR_015891"
FT VARIANT 27..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078387"
FT VARIANT 40
FT /note="Q -> L (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:14680976"
FT /id="VAR_058337"
FT VARIANT 64
FT /note="V -> I (in CTLN1; unknown pathological significance;
FT dbSNP:rs556297791)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078388"
FT VARIANT 69
FT /note="V -> A (in CTLN1; dbSNP:rs771594651)"
FT /evidence="ECO:0000269|PubMed:11708871"
FT /id="VAR_016013"
FT VARIANT 79
FT /note="S -> P (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058338"
FT VARIANT 86
FT /note="R -> C (in CTLN1; dbSNP:rs121908644)"
FT /evidence="ECO:0000269|PubMed:1943692"
FT /id="VAR_000683"
FT VARIANT 86
FT /note="R -> H (in CTLN1; dbSNP:rs575001023)"
FT /evidence="ECO:0000269|PubMed:12815590"
FT /id="VAR_015892"
FT VARIANT 91
FT /note="T -> P (in CTLN1; decreased affinity for aspartate;
FT decreased affinity for citrulline; decreased
FT argininosuccinate synthase activity; dbSNP:rs769018733)"
FT /evidence="ECO:0000269|PubMed:24889030,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_078389"
FT VARIANT 95
FT /note="R -> S (in CTLN1; increased thermal stability; loss
FT of argininosuccinate synthase activity)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_015893"
FT VARIANT 96
FT /note="P -> H (in CTLN1; decreased affinity for aspartate;
FT decreased affinity for citrulline; decreased
FT argininosuccinate synthase activity)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_058339"
FT VARIANT 96
FT /note="P -> L (in CTLN1; decreased thermal stability;
FT decreased affinity for aspartate; decreased affinity for
FT citrulline; loss of argininosuccinate synthase activity)"
FT /evidence="ECO:0000269|PubMed:27287393"
FT /id="VAR_078390"
FT VARIANT 96
FT /note="P -> S (in CTLN1; no effect on thermal stability;
FT decreased argininosuccinate synthase activity)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_015894"
FT VARIANT 97..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078391"
FT VARIANT 100
FT /note="R -> C (in CTLN1; dbSNP:rs370695114)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078392"
FT VARIANT 100
FT /note="R -> H (in CTLN1; dbSNP:rs138279074)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078393"
FT VARIANT 108
FT /note="R -> L (in CTLN1; dbSNP:rs35269064)"
FT /evidence="ECO:0000269|PubMed:11708871,
FT ECO:0000269|PubMed:11941481"
FT /id="VAR_016014"
FT VARIANT 111
FT /note="A -> D (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078394"
FT VARIANT 117
FT /note="G -> C (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078395"
FT VARIANT 117
FT /note="G -> D (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:11708871,
FT ECO:0000269|PubMed:12815590"
FT /id="VAR_015896"
FT VARIANT 117
FT /note="G -> S (in CTLN1; decreased thermal stability; loss
FT of argininosuccinate synthase activity; dbSNP:rs770944877)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_015895"
FT VARIANT 118
FT /note="A -> T (in CTLN1; decreased thermal stability;
FT decreased affinity for aspartate; decreased affinity for
FT citrulline; decreased argininosuccinate synthase activity;
FT dbSNP:rs775305020)"
FT /evidence="ECO:0000269|PubMed:18473344,
FT ECO:0000269|PubMed:27287393, ECO:0000269|PubMed:7977368"
FT /id="VAR_000684"
FT VARIANT 119
FT /note="T -> I (in CTLN1; decreased thermal stability; loss
FT of argininosuccinate synthase activity)"
FT /evidence="ECO:0000269|PubMed:11708871,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_016015"
FT VARIANT 124
FT /note="D -> N (in CTLN1; loss of argininosuccinate synthase
FT activity; dbSNP:rs936192871)"
FT /evidence="ECO:0000269|PubMed:16475226,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_058340"
FT VARIANT 127
FT /note="R -> L (increased thermal stability; loss of
FT argininosuccinate synthase activity; dbSNP:rs201623252)"
FT /evidence="ECO:0000269|PubMed:24889030,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_078396"
FT VARIANT 127
FT /note="R -> Q (in CTLN1; increased thermal stability; loss
FT of argininosuccinate synthase activity; dbSNP:rs201623252)"
FT /evidence="ECO:0000269|PubMed:14680976,
FT ECO:0000269|PubMed:19006241, ECO:0000269|PubMed:27287393"
FT /id="VAR_058341"
FT VARIANT 127
FT /note="R -> W (in CTLN1; severe clinical course; loss of
FT argininosuccinate synthase activity; dbSNP:rs771794639)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_058342"
FT VARIANT 138..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078397"
FT VARIANT 141
FT /note="V -> G (in CTLN1; dbSNP:rs1184442048)"
FT /evidence="ECO:0000269|PubMed:25179242"
FT /id="VAR_072792"
FT VARIANT 157
FT /note="R -> C (in CTLN1; decreased thermal stability; loss
FT of argininosuccinate synthase activity; dbSNP:rs770585183)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:24889030, ECO:0000269|PubMed:27287393"
FT /id="VAR_015897"
FT VARIANT 157
FT /note="R -> H (in CTLN1; loss of argininosuccinate synthase
FT activity; dbSNP:rs121908637)"
FT /evidence="ECO:0000269|PubMed:16475226,
FT ECO:0000269|PubMed:2358466, ECO:0000269|PubMed:27287393"
FT /id="VAR_000685"
FT VARIANT 157
FT /note="R -> S (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078398"
FT VARIANT 160
FT /note="L -> P (in CTLN1; dbSNP:rs969835605)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058343"
FT VARIANT 163..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078399"
FT VARIANT 164
FT /note="A -> P (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078400"
FT VARIANT 179
FT /note="W -> R (in CTLN1; mild; decreased affinity for
FT aspartate; decreased affinity for citrulline; decreased
FT argininosuccinate synthase activity; dbSNP:rs121908646)"
FT /evidence="ECO:0000269|PubMed:11941481,
FT ECO:0000269|PubMed:12815590, ECO:0000269|PubMed:14680976,
FT ECO:0000269|PubMed:18473344"
FT /id="VAR_015898"
FT VARIANT 180
FT /note="S -> I (in CTLN1; increased thermal stability; loss
FT of argininosuccinate synthase activity; dbSNP:rs121908638)"
FT /evidence="ECO:0000269|PubMed:24889030,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_078401"
FT VARIANT 180
FT /note="S -> N (in CTLN1; decreased thermal stability;
FT decreased affinity for aspartate; decreased affinity for
FT citrulline; decreased argininosuccinate synthase activity;
FT dbSNP:rs121908638)"
FT /evidence="ECO:0000269|PubMed:2358466,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_000686"
FT VARIANT 184
FT /note="N -> K (in CTLN1; dbSNP:rs368192467)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078402"
FT VARIANT 190
FT /note="Y -> D (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:14680976,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058344"
FT VARIANT 191
FT /note="E -> K (in CTLN1; dbSNP:rs777828000)"
FT /evidence="ECO:0000269|PubMed:12815590"
FT /id="VAR_015899"
FT VARIANT 191
FT /note="E -> Q (in CTLN1; loss of argininosuccinate synthase
FT activity)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:27287393"
FT /id="VAR_058345"
FT VARIANT 192
FT /note="A -> V (in CTLN1; decreased protein abundance)"
FT /evidence="ECO:0000269|PubMed:7977368,
FT ECO:0000269|PubMed:8792870"
FT /id="VAR_000687"
FT VARIANT 202
FT /note="A -> E (in CTLN1; dbSNP:rs376371866)"
FT /evidence="ECO:0000269|PubMed:14680976"
FT /id="VAR_058346"
FT VARIANT 206
FT /note="L -> P (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058347"
FT VARIANT 230
FT /note="G -> R (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078403"
FT VARIANT 237
FT /note="N -> I (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078404"
FT VARIANT 258
FT /note="A -> P (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078405"
FT VARIANT 258
FT /note="A -> V (in CTLN1; dbSNP:rs753078725)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078406"
FT VARIANT 263
FT /note="V -> M (in CTLN1; mild clinical course; no effect on
FT affinity for aspartate; no effect on affinity for
FT citrulline; decreased argininosuccinate synthase activity;
FT dbSNP:rs192838388)"
FT /evidence="ECO:0000269|PubMed:14680976,
FT ECO:0000269|PubMed:18473344"
FT /id="VAR_058348"
FT VARIANT 265
FT /note="R -> C (in CTLN1; severe clinical course; loss of
FT argininosuccinate synthase activity; dbSNP:rs148918985)"
FT /evidence="ECO:0000269|PubMed:18473344,
FT ECO:0000269|PubMed:19006241, ECO:0000269|PubMed:25179242,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058349"
FT VARIANT 265
FT /note="R -> H (in CTLN1; dbSNP:rs398123131)"
FT /evidence="ECO:0000269|PubMed:12815590"
FT /id="VAR_015900"
FT VARIANT 269
FT /note="V -> M (in CTLN1; dbSNP:rs370595480)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:14680976"
FT /id="VAR_015901"
FT VARIANT 270
FT /note="E -> Q (in CTLN1; loss of argininosuccinate synthase
FT activity; dbSNP:rs775163147)"
FT /evidence="ECO:0000269|PubMed:11708871,
FT ECO:0000269|PubMed:16475226, ECO:0000269|PubMed:27287393"
FT /id="VAR_016007"
FT VARIANT 272
FT /note="R -> C (in CTLN1; increased thermal stability;
FT decreased affinity for aspartate; decreased affinity for
FT citrulline; decreased argininosuccinate synthase activity;
FT dbSNP:rs762387914)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:27287393, ECO:0000269|PubMed:7977368,
FT ECO:0000269|PubMed:8792870"
FT /id="VAR_000688"
FT VARIANT 272
FT /note="R -> H (in CTLN1; increased thermal stability;
FT decreased affinity for aspartate; decreased affinity for
FT citrulline; decreased argininosuccinate synthase activity;
FT dbSNP:rs768215008)"
FT /evidence="ECO:0000269|PubMed:27287393"
FT /id="VAR_078407"
FT VARIANT 272
FT /note="R -> L (in CTLN1; increased thermal stability;
FT decreased affinity for aspartate; decreased affinity for
FT citrulline; decreased argininosuccinate synthase activity;
FT dbSNP:rs768215008)"
FT /evidence="ECO:0000269|PubMed:27287393"
FT /id="VAR_078408"
FT VARIANT 275..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078409"
FT VARIANT 277
FT /note="K -> T (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058350"
FT VARIANT 279..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078410"
FT VARIANT 279
FT /note="R -> Q (in CTLN1; dbSNP:rs371265106)"
FT /evidence="ECO:0000269|PubMed:16475226"
FT /id="VAR_016008"
FT VARIANT 280
FT /note="G -> R (in CTLN1; loss of argininosuccinate synthase
FT activity)"
FT /evidence="ECO:0000269|PubMed:7977368,
FT ECO:0000269|PubMed:8792870"
FT /id="VAR_000689"
FT VARIANT 283
FT /note="E -> K (in CTLN1; dbSNP:rs765338121)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:16475226, ECO:0000269|PubMed:23611581,
FT ECO:0000269|PubMed:24889030"
FT /id="VAR_015902"
FT VARIANT 284
FT /note="T -> I (in CTLN1; mild clinical course;
FT dbSNP:rs886039853)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058351"
FT VARIANT 290
FT /note="L -> P (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078411"
FT VARIANT 291
FT /note="Y -> S (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058352"
FT VARIANT 296
FT /note="D -> G (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058353"
FT VARIANT 299
FT /note="A -> D (in CTLN1; dbSNP:rs768394647)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078412"
FT VARIANT 302
FT /note="M -> V (in CTLN1; no effect on affinity for
FT aspartate; no effect on affinity for citrulline; decreased
FT argininosuccinate synthase activity)"
FT /evidence="ECO:0000269|PubMed:18473344,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058354"
FT VARIANT 304
FT /note="R -> W (in CTLN1; decreased protein abundance;
FT dbSNP:rs121908642)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:2358466, ECO:0000269|PubMed:7977368"
FT /id="VAR_000690"
FT VARIANT 306
FT /note="V -> G (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078413"
FT VARIANT 307
FT /note="R -> C (in CTLN1; dbSNP:rs183276875)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_058355"
FT VARIANT 310
FT /note="K -> Q (in CTLN1; dbSNP:rs121908648)"
FT /evidence="ECO:0000269|PubMed:12815590"
FT /id="VAR_016009"
FT VARIANT 310
FT /note="K -> R (in CTLN1; dbSNP:rs199751308)"
FT /evidence="ECO:0000269|PubMed:15863597"
FT /id="VAR_015903"
FT VARIANT 311..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078414"
FT VARIANT 321
FT /note="V -> M (in CTLN1; dbSNP:rs727503813)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078415"
FT VARIANT 324
FT /note="G -> S (in CTLN1; loss of argininosuccinate synthase
FT activity; dbSNP:rs121908639)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:14680976, ECO:0000269|PubMed:16475226,
FT ECO:0000269|PubMed:18473344, ECO:0000269|PubMed:2358466,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_000691"
FT VARIANT 324
FT /note="G -> V (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058356"
FT VARIANT 335
FT /note="R -> H (in CTLN1; dbSNP:rs555388438)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078416"
FT VARIANT 337
FT /note="C -> R (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:23611581"
FT /id="VAR_078417"
FT VARIANT 341
FT /note="S -> F (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058357"
FT VARIANT 344..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078418"
FT VARIANT 345
FT /note="V -> G (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:14680976"
FT /id="VAR_058358"
FT VARIANT 347
FT /note="G -> R (in CTLN1; severe clinical course)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058359"
FT VARIANT 356
FT /note="G -> V (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078419"
FT VARIANT 357..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078420"
FT VARIANT 359
FT /note="Y -> D (in CTLN1; mild clinical course)"
FT /evidence="ECO:0000269|PubMed:19006241,
FT ECO:0000269|PubMed:28111830"
FT /id="VAR_058360"
FT VARIANT 362
FT /note="G -> V (in CTLN1; mild; no effect on affinity for
FT aspartate; no effect on affinity for citrulline; decreased
FT argininosuccinate synthase activity; dbSNP:rs121908647)"
FT /evidence="ECO:0000269|PubMed:11941481,
FT ECO:0000269|PubMed:12815590, ECO:0000269|PubMed:14680976,
FT ECO:0000269|PubMed:18473344"
FT /id="VAR_015904"
FT VARIANT 363
FT /note="R -> G (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:16475226"
FT /id="VAR_016010"
FT VARIANT 363
FT /note="R -> L (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:7977368"
FT /id="VAR_000692"
FT VARIANT 363
FT /note="R -> Q (in CTLN1; dbSNP:rs771937610)"
FT /evidence="ECO:0000269|PubMed:12815590"
FT /id="VAR_016011"
FT VARIANT 363
FT /note="R -> W (in CTLN1; dbSNP:rs121908640)"
FT /evidence="ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:2358466"
FT /id="VAR_000693"
FT VARIANT 380..412
FT /note="Missing (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078421"
FT VARIANT 389
FT /note="T -> I (in CTLN1; dbSNP:rs1474017319)"
FT /evidence="ECO:0000269|PubMed:12815590"
FT /id="VAR_016012"
FT VARIANT 389
FT /note="T -> P (in CTLN1)"
FT /evidence="ECO:0000269|PubMed:28111830"
FT /id="VAR_078422"
FT VARIANT 390
FT /note="G -> R (in CTLN1; loss of argininosuccinate synthase
FT activity; dbSNP:rs121908641)"
FT /evidence="ECO:0000269|PubMed:11708871,
FT ECO:0000269|PubMed:11941481, ECO:0000269|PubMed:12815590,
FT ECO:0000269|PubMed:16475226, ECO:0000269|PubMed:18473344,
FT ECO:0000269|PubMed:2358466, ECO:0000269|PubMed:24889030"
FT /id="VAR_000694"
FT MUTAGEN 165
FT /note="K->Q,R: Significant loss of acetylation but no
FT decrease in enzyme activity; when associated with Q-176 or
FT R-176."
FT /evidence="ECO:0000269|PubMed:28985504"
FT MUTAGEN 176
FT /note="K->Q,R: Significant loss of acetylation but no
FT decrease in enzyme activity; when associated with Q-165 or
FT R-165."
FT /evidence="ECO:0000269|PubMed:28985504"
FT CONFLICT 325..327
FT /note="FWH -> LRP (in Ref. 1; CAA25771 and 2; AAA51783)"
FT /evidence="ECO:0000305"
FT STRAND 5..10
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 15..26
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 29..39
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 44..54
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 57..63
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 65..71
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 73..78
FT /evidence="ECO:0007829|PDB:2NZ2"
FT TURN 84..86
FT /evidence="ECO:0007829|PDB:2NZ2"
FT TURN 90..93
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 94..109
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 112..115
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 124..135
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 140..142
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 144..146
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 148..151
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 158..166
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 181..183
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 188..190
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 193..196
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 204..206
FT /evidence="ECO:0007829|PDB:2NZ2"
FT TURN 213..215
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 221..228
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 231..237
FT /evidence="ECO:0007829|PDB:2NZ2"
FT TURN 238..240
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 247..261
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 265..271
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 277..283
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 285..301
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 304..323
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 326..328
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 329..341
FT /evidence="ECO:0007829|PDB:2NZ2"
FT TURN 342..344
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 347..354
FT /evidence="ECO:0007829|PDB:2NZ2"
FT STRAND 357..364
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 372..375
FT /evidence="ECO:0007829|PDB:2NZ2"
FT HELIX 385..404
FT /evidence="ECO:0007829|PDB:2NZ2"
SQ SEQUENCE 412 AA; 46530 MW; 47CAD2373AE47E47 CRC64;
MSSKGSVVLA YSGGLDTSCI LVWLKEQGYD VIAYLANIGQ KEDFEEARKK ALKLGAKKVF
IEDVSREFVE EFIWPAIQSS ALYEDRYLLG TSLARPCIAR KQVEIAQREG AKYVSHGATG
KGNDQVRFEL SCYSLAPQIK VIAPWRMPEF YNRFKGRNDL MEYAKQHGIP IPVTPKNPWS
MDENLMHISY EAGILENPKN QAPPGLYTKT QDPAKAPNTP DILEIEFKKG VPVKVTNVKD
GTTHQTSLEL FMYLNEVAGK HGVGRIDIVE NRFIGMKSRG IYETPAGTIL YHAHLDIEAF
TMDREVRKIK QGLGLKFAEL VYTGFWHSPE CEFVRHCIAK SQERVEGKVQ VSVLKGQVYI
LGRESPLSLY NEELVSMNVQ GDYEPTDATG FININSLRLK EYHRLQSKVT AK
