ID NAGS_HUMAN Reviewed; 534 AA. AC Q8N159; B2RAZ9; Q8IWR4; DT 13-SEP-2005, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2002, sequence version 1. DT 07-SEP-2016, entry version 122. DE RecName: Full=N-acetylglutamate synthase, mitochondrial; DE EC=2.3.1.1; DE AltName: Full=Amino-acid acetyltransferase; DE Contains: DE RecName: Full=N-acetylglutamate synthase long form; DE Contains: DE RecName: Full=N-acetylglutamate synthase short form; DE Contains: DE RecName: Full=N-acetylglutamate synthase conserved domain form; DE Flags: Precursor; GN Name=NAGS; 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 [GENOMIC DNA / MRNA], TISSUE SPECIFICITY, AND RP VARIANTS NAGSD PRO-279; PRO-430 AND ARG-484. RX PubMed=12754705; DOI=10.1002/humu.10216; RA Haeberle J., Schmidt E., Pauli S., Kreuder J.G., Plecko B., Galler A., RA Wermuth B., Harms E., Koch H.G.; RT "Mutation analysis in patients with N-acetylglutamate synthase RT deficiency."; RL Hum. Mutat. 21:593-597(2003). RN [2] 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., 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 [3] RP NUCLEOTIDE SEQUENCE [MRNA] OF 94-534, ENZYME REGULATION, AND TISSUE RP SPECIFICITY. RC TISSUE=Liver; RX PubMed=12459178; DOI=10.1016/S0006-291X(02)02696-7; RA Caldovic L., Morizono H., Gracia Panglao M., Gallegos R., Yu X., RA Shi D., Malamy M.H., Allewell N.M., Tuchman M.; RT "Cloning and expression of the human N-acetylglutamate synthase RT gene."; RL Biochem. Biophys. Res. Commun. 299:581-586(2002). RN [4] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 377-534 IN COMPLEX WITH RP N-ACETYL-GLUTAMATE, ENZYME REGULATION, SUBSTRATE-BINDING SITES, RP SUBUNIT, AND MUTAGENESIS OF TYR-441; ASN-479 AND TYR-485. RX PubMed=23894642; DOI=10.1371/journal.pone.0070369; RA Zhao G., Jin Z., Allewell N.M., Tuchman M., Shi D.; RT "Crystal structure of the N-acetyltransferase domain of human N- RT acetyl-L-glutamate synthase in complex with N-acetyl-L-glutamate RT provides insights into its catalytic and regulatory mechanisms."; RL PLoS ONE 8:E70369-E70369(2013). RN [5] RP VARIANTS NAGSD ARG-200; PRO-410; PRO-430; ARG-484 AND THR-518, AND RP CHARACTERIZATION OF VARIANTS NAGSD ARG-200; PRO-410; PRO-430; ARG-484 RP AND THR-518. RX PubMed=15878741; DOI=10.1016/j.bbadis.2005.02.006; RA Schmidt E., Nuoffer J.-M., Haeberle J., Pauli S., Guffon N., RA Vianey-Saban C., Wermuth B., Koch H.G.; RT "Identification of novel mutations of the human N-acetylglutamate RT synthase gene and their functional investigation by expression RT studies."; RL Biochim. Biophys. Acta 1740:54-59(2005). CC -!- FUNCTION: Plays a role in the regulation of ureagenesis by CC producing the essential cofactor N-acetylglutamate (NAG), thus CC modulating carbamoylphosphate synthase I (CPSI) activity. CC -!- CATALYTIC ACTIVITY: Acetyl-CoA + L-glutamate = CoA + N-acetyl-L- CC glutamate. CC -!- ENZYME REGULATION: Increased by L-arginine. CC {ECO:0000269|PubMed:12459178, ECO:0000269|PubMed:23894642}. CC -!- PATHWAY: Amino-acid biosynthesis; L-arginine biosynthesis; N(2)- CC acetyl-L-ornithine from L-glutamate: step 1/4. CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:23894642}. CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix. CC -!- TISSUE SPECIFICITY: Highly expressed in the adult liver, kidney CC and small intestine. Weakly expressed in the fetal liver, lung, CC pancreas, placenta, heart and brain tissue. CC {ECO:0000269|PubMed:12459178, ECO:0000269|PubMed:12754705}. CC -!- DOMAIN: The Amino-acid kinase domain (AAK) mediates binding of the CC allosteric activator L-arginine. CC -!- PTM: Probably processed by mitochondrial processing peptidase CC (MPP). The long form has not yet been isolated (By similarity). CC {ECO:0000250}. CC -!- DISEASE: N-acetylglutamate synthase deficiency (NAGSD) CC [MIM:237310]: Rare autosomal recessively inherited metabolic CC disorder leading to severe neonatal or late-onset hyperammonemia CC without increased excretion of orotic acid. Clinical symptoms are CC somnolence, tachypnea, feeding difficulties, a severe neurologic CC presentation characterized by uncontrollable movements, CC developmental delay, visual impairment, failure to thrive and CC hyperammonemia precipitated by the introduction of high-protein CC diet or febrile illness. {ECO:0000269|PubMed:12754705, CC ECO:0000269|PubMed:15878741}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the acetyltransferase family. CC {ECO:0000305}. CC -!- SIMILARITY: Contains 1 N-acetyltransferase domain. CC {ECO:0000255|PROSITE-ProRule:PRU00532}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=N-acetylglutamate synthase CC entry; CC URL="https://en.wikipedia.org/wiki/N-acetylglutamate_synthase"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY116537; AAM75385.1; -; Genomic_DNA. DR EMBL; AY116538; AAM75386.1; -; mRNA. DR EMBL; AK314432; BAG37046.1; -; mRNA. DR EMBL; AY158070; AAN76451.1; -; mRNA. DR CCDS; CCDS11473.1; -. DR RefSeq; NP_694551.1; NM_153006.2. DR UniGene; Hs.8876; -. DR PDB; 4K30; X-ray; 2.10 A; A/B/X/Y=377-534. DR PDBsum; 4K30; -. DR ProteinModelPortal; Q8N159; -. DR SMR; Q8N159; 115-527. DR BioGrid; 127816; 1. DR IntAct; Q8N159; 1. DR MINT; MINT-1431825; -. DR STRING; 9606.ENSP00000293404; -. DR iPTMnet; Q8N159; -. DR PhosphoSite; Q8N159; -. DR BioMuta; NAGS; -. DR DMDM; 74714699; -. DR EPD; Q8N159; -. DR PaxDb; Q8N159; -. DR PeptideAtlas; Q8N159; -. DR PRIDE; Q8N159; -. DR Ensembl; ENST00000293404; ENSP00000293404; ENSG00000161653. DR GeneID; 162417; -. DR KEGG; hsa:162417; -. DR UCSC; uc002ies.4; human. DR CTD; 162417; -. DR GeneCards; NAGS; -. DR HGNC; HGNC:17996; NAGS. DR HPA; CAB004587; -. DR MalaCards; NAGS; -. DR MIM; 237310; phenotype. DR MIM; 608300; gene. DR neXtProt; NX_Q8N159; -. DR Orphanet; 927; Hyperammonemia due to N-acetylglutamate synthetase deficiency. DR PharmGKB; PA134968729; -. DR eggNOG; KOG2436; Eukaryota. DR eggNOG; COG0548; LUCA. DR GeneTree; ENSGT00390000005602; -. DR HOGENOM; HOG000007983; -. DR HOVERGEN; HBG080036; -. DR InParanoid; Q8N159; -. DR KO; K11067; -. DR OMA; LTMEPVL; -. DR OrthoDB; EOG091G0FPD; -. DR PhylomeDB; Q8N159; -. DR TreeFam; TF332628; -. DR BRENDA; 2.3.1.1; 2681. DR Reactome; R-HSA-70635; Urea cycle. DR UniPathway; UPA00068; UER00106. DR ChiTaRS; NAGS; human. DR GenomeRNAi; 162417; -. DR PRO; PR:Q8N159; -. DR Proteomes; UP000005640; Chromosome 17. DR Bgee; ENSG00000161653; -. DR CleanEx; HS_NAGS; -. DR ExpressionAtlas; Q8N159; baseline and differential. DR Genevisible; Q8N159; HS. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0004042; F:acetyl-CoA:L-glutamate N-acetyltransferase activity; TAS:BHF-UCL. DR GO; GO:0034618; F:arginine binding; IBA:GO_Central. DR GO; GO:0006526; P:arginine biosynthetic process; IBA:GO_Central. DR GO; GO:0006536; P:glutamate metabolic process; TAS:BHF-UCL. DR GO; GO:0000050; P:urea cycle; TAS:Reactome. DR Gene3D; 3.40.1160.10; -; 1. DR InterPro; IPR016181; Acyl_CoA_acyltransferase. DR InterPro; IPR001048; Asp/Glu/Uridylate_kinase. DR InterPro; IPR011243; GlcNAc_Synth_met. DR InterPro; IPR006855; Vertebrate-like_GNAT_dom. DR Pfam; PF04768; NAT; 1. DR PIRSF; PIRSF036442; NAGS_animal; 1. DR SUPFAM; SSF53633; SSF53633; 1. DR SUPFAM; SSF55729; SSF55729; 1. DR PROSITE; PS51731; GNAT_NAGS; 1. PE 1: Evidence at protein level; KW 3D-structure; Acyltransferase; Complete proteome; Disease mutation; KW Mitochondrion; Reference proteome; Transferase; Transit peptide; KW Urea cycle. FT TRANSIT 1 18 Mitochondrion. {ECO:0000255}. FT CHAIN 19 534 N-acetylglutamate synthase long form. FT {ECO:0000255}. FT /FTId=PRO_0000041930. FT CHAIN 51 534 N-acetylglutamate synthase short form. FT {ECO:0000250}. FT /FTId=PRO_0000041931. FT CHAIN 92 534 N-acetylglutamate synthase conserved FT domain form. {ECO:0000250}. FT /FTId=PRO_0000041932. FT DOMAIN 375 526 N-acetyltransferase. FT {ECO:0000255|PROSITE-ProRule:PRU00532}. FT REGION 19 376 Amino-acid kinase domain (AAK). FT REGION 474 479 Substrate binding. FT BINDING 401 401 Substrate. FT BINDING 444 444 Substrate. FT VARIANT 200 200 C -> R (in NAGSD; markedly decreases FT activity). {ECO:0000269|PubMed:15878741}. FT /FTId=VAR_023505. FT VARIANT 279 279 A -> P (in NAGSD). FT {ECO:0000269|PubMed:12754705}. FT /FTId=VAR_023506. FT VARIANT 410 410 S -> P (in NAGSD; markedly decreases FT activity). {ECO:0000269|PubMed:15878741}. FT /FTId=VAR_023507. FT VARIANT 430 430 L -> P (in NAGSD; markedly decreases FT activity; dbSNP:rs104894605). FT {ECO:0000269|PubMed:12754705, FT ECO:0000269|PubMed:15878741}. FT /FTId=VAR_023508. FT VARIANT 484 484 W -> R (in NAGSD; markedly decreases FT activity; dbSNP:rs104894606). FT {ECO:0000269|PubMed:12754705, FT ECO:0000269|PubMed:15878741}. FT /FTId=VAR_023509. FT VARIANT 518 518 A -> T (in NAGSD; markedly decreases FT activity; dbSNP:rs745511282). FT {ECO:0000269|PubMed:15878741}. FT /FTId=VAR_023510. FT MUTAGEN 441 441 Y->F: 15% reduction in catalytic FT activity. {ECO:0000269|PubMed:23894642}. FT MUTAGEN 479 479 N->A: 7-fold reduction in catalytic FT activity. {ECO:0000269|PubMed:23894642}. FT MUTAGEN 485 485 Y->F: 10-fold reduction in catalytic FT activity. {ECO:0000269|PubMed:23894642}. FT CONFLICT 94 94 E -> M (in Ref. 3; AAN76451). FT {ECO:0000305}. FT STRAND 378 382 {ECO:0000244|PDB:4K30}. FT HELIX 383 385 {ECO:0000244|PDB:4K30}. FT HELIX 388 399 {ECO:0000244|PDB:4K30}. FT HELIX 407 411 {ECO:0000244|PDB:4K30}. FT HELIX 412 414 {ECO:0000244|PDB:4K30}. FT STRAND 415 420 {ECO:0000244|PDB:4K30}. FT STRAND 424 435 {ECO:0000244|PDB:4K30}. FT STRAND 438 447 {ECO:0000244|PDB:4K30}. FT HELIX 451 467 {ECO:0000244|PDB:4K30}. FT STRAND 471 476 {ECO:0000244|PDB:4K30}. FT HELIX 482 487 {ECO:0000244|PDB:4K30}. FT STRAND 489 494 {ECO:0000244|PDB:4K30}. FT STRAND 496 503 {ECO:0000244|PDB:4K30}. FT HELIX 508 510 {ECO:0000244|PDB:4K30}. FT HELIX 511 519 {ECO:0000244|PDB:4K30}. SQ SEQUENCE 534 AA; 58156 MW; 1328039080EB936C CRC64; MATALMAVVL RAAAVAPRLR GRGGTGGARR LSCGARRRAA RGTSPGRRLS TAWSQPQPPP EEYAGADDVS QSPVAEEPSW VPSPRPPVPH ESPEPPSGRS LVQRDIQAFL NQCGASPGEA RHWLTQFQTC HHSADKPFAV IEVDEEVLKC QQGVSSLAFA LAFLQRMDMK PLVVLGLPAP TAPSGCLSFW EAKAQLAKSC KVLVDALRHN AAAAVPFFGG GSVLRAAEPA PHASYGGIVS VETDLLQWCL ESGSIPILCP IGETAARRSV LLDSLEVTAS LAKALRPTKI IFLNNTGGLR DSSHKVLSNV NLPADLDLVC NAEWVSTKER QQMRLIVDVL SRLPHHSSAV ITAASTLLTE LFSNKGSGTL FKNAERMLRV RSLDKLDQGR LVDLVNASFG KKLRDDYLAS LRPRLHSIYV SEGYNAAAIL TMEPVLGGTP YLDKFVVSSS RQGQGSGQML WECLRRDLQT LFWRSRVTNP INPWYFKHSD GSFSNKQWIF FWFGLADIRD SYELVNHAKG LPDSFHKPAS DPGS //