NAGS_HUMAN
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 03-AUG-2022, entry version 157.
DE RecName: Full=N-acetylglutamate synthase, mitochondrial;
DE EC=2.3.1.1 {ECO:0000269|PubMed:12459178, ECO:0000269|PubMed:23894642, ECO:0000269|PubMed:7126172};
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], TISSUE SPECIFICITY, AND VARIANTS
RP 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., 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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 94-534, FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVITY REGULATION, AND TISSUE 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., Shi D.,
RA Malamy M.H., Allewell N.M., Tuchman M.;
RT "Cloning and expression of the human N-acetylglutamate synthase gene.";
RL Biochem. Biophys. Res. Commun. 299:581-586(2002).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=7126172; DOI=10.1042/bj2050123;
RA Bachmann C., Kraehenbuehl S., Colombo J.P.;
RT "Purification and properties of acetyl-CoA:L-glutamate N-acetyltransferase
RT from human liver.";
RL Biochem. J. 205:123-127(1982).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 377-534 IN COMPLEX WITH
RP N-ACETYL-GLUTAMATE, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP SUBSTRATE-BINDING SITES, SUBUNIT, DOMAIN, AND MUTAGENESIS OF TYR-441;
RP 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-acetyl-L-
RT glutamate synthase in complex with N-acetyl-L-glutamate provides insights
RT into its catalytic and regulatory mechanisms.";
RL PLoS ONE 8:E70369-E70369(2013).
RN [6]
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 AND
RP 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 synthase
RT gene and their functional investigation by expression studies.";
RL Biochim. Biophys. Acta 1740:54-59(2005).
RN [7]
RP VARIANTS NAGSD VAL-167; LEU-260; MET-264; ASN-291; ARG-391; CYS-398;
RP ASP-457 AND CYS-512.
RX PubMed=27037498; DOI=10.1002/humu.22995;
RA Sancho-Vaello E., Marco-Marin C., Gougeard N., Fernandez-Murga L.,
RA Ruefenacht V., Mustedanagic M., Rubio V., Haeberle J.;
RT "Understanding N-acetyl-L-glutamate synthase deficiency: mutational
RT spectrum, impact of clinical mutations on enzyme functionality, and
RT structural considerations.";
RL Hum. Mutat. 37:679-694(2016).
CC -!- FUNCTION: Plays a role in the regulation of ureagenesis by producing
CC the essential cofactor N-acetylglutamate (NAG), thus modulating
CC carbamoylphosphate synthase I (CPS1) activity.
CC {ECO:0000269|PubMed:12459178, ECO:0000269|PubMed:23894642,
CC ECO:0000269|PubMed:7126172}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + L-glutamate = CoA + H(+) + N-acetyl-L-glutamate;
CC Xref=Rhea:RHEA:24292, ChEBI:CHEBI:15378, ChEBI:CHEBI:29985,
CC ChEBI:CHEBI:44337, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288; EC=2.3.1.1;
CC Evidence={ECO:0000269|PubMed:12459178, ECO:0000269|PubMed:23894642,
CC ECO:0000269|PubMed:7126172};
CC -!- ACTIVITY REGULATION: Increased by L-arginine.
CC {ECO:0000269|PubMed:12459178, ECO:0000269|PubMed:23894642}.
CC -!- PATHWAY: Amino-acid biosynthesis; L-arginine biosynthesis; N(2)-acetyl-
CC L-ornithine from L-glutamate: step 1/4.
CC -!- SUBUNIT: Homodimer. Homotetramer. {ECO:0000269|PubMed:23894642}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000305|PubMed:7126172}.
CC -!- TISSUE SPECIFICITY: Highly expressed in the adult liver, kidney and
CC small intestine. Weakly expressed in the fetal liver, lung, pancreas,
CC placenta, heart and brain tissue. {ECO:0000269|PubMed:12459178,
CC ECO:0000269|PubMed:12754705}.
CC -!- DOMAIN: The amino-acid kinase (AAK) domain mediates binding of the
CC allosteric activator L-arginine. {ECO:0000305|PubMed:23894642}.
CC -!- PTM: Probably processed by mitochondrial processing peptidase (MPP).
CC The long form has not yet been isolated (By similarity). {ECO:0000250}.
CC -!- DISEASE: N-acetylglutamate synthase deficiency (NAGSD) [MIM:237310]:
CC Rare autosomal recessively inherited metabolic disorder leading to
CC severe neonatal or late-onset hyperammonemia without increased
CC excretion of orotic acid. Clinical symptoms are somnolence, tachypnea,
CC feeding difficulties, a severe neurologic presentation characterized by
CC uncontrollable movements, developmental delay, visual impairment,
CC failure to thrive and hyperammonemia precipitated by the introduction
CC of high-protein diet or febrile illness. {ECO:0000269|PubMed:12754705,
CC ECO:0000269|PubMed:15878741, ECO:0000269|PubMed:27037498}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the acetyltransferase family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=N-acetylglutamate synthase entry;
CC URL="https://en.wikipedia.org/wiki/N-acetylglutamate_synthase";
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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 PDB; 4K30; X-ray; 2.10 A; A/B/X/Y=377-534.
DR PDBsum; 4K30; -.
DR AlphaFoldDB; Q8N159; -.
DR SMR; Q8N159; -.
DR BioGRID; 127816; 11.
DR IntAct; Q8N159; 1.
DR STRING; 9606.ENSP00000293404; -.
DR DrugBank; DB09326; Ammonia N-13.
DR DrugBank; DB00142; Glutamic acid.
DR iPTMnet; Q8N159; -.
DR PhosphoSitePlus; Q8N159; -.
DR BioMuta; NAGS; -.
DR DMDM; 74714699; -.
DR MassIVE; Q8N159; -.
DR PaxDb; Q8N159; -.
DR PeptideAtlas; Q8N159; -.
DR PRIDE; Q8N159; -.
DR ProteomicsDB; 71564; -.
DR Antibodypedia; 29652; 87 antibodies from 23 providers.
DR DNASU; 162417; -.
DR Ensembl; ENST00000293404.8; ENSP00000293404.2; ENSG00000161653.11.
DR GeneID; 162417; -.
DR KEGG; hsa:162417; -.
DR MANE-Select; ENST00000293404.8; ENSP00000293404.2; NM_153006.3; NP_694551.1.
DR UCSC; uc002ies.4; human.
DR CTD; 162417; -.
DR DisGeNET; 162417; -.
DR GeneCards; NAGS; -.
DR GeneReviews; NAGS; -.
DR HGNC; HGNC:17996; NAGS.
DR HPA; ENSG00000161653; Group enriched (intestine, liver).
DR MalaCards; NAGS; -.
DR MIM; 237310; phenotype.
DR MIM; 608300; gene.
DR neXtProt; NX_Q8N159; -.
DR OpenTargets; ENSG00000161653; -.
DR Orphanet; 927; Hyperammonemia due to N-acetylglutamate synthase deficiency.
DR PharmGKB; PA134968729; -.
DR VEuPathDB; HostDB:ENSG00000161653; -.
DR eggNOG; KOG2436; Eukaryota.
DR GeneTree; ENSGT00390000005602; -.
DR InParanoid; Q8N159; -.
DR OMA; FQTCYHS; -.
DR OrthoDB; 769117at2759; -.
DR PhylomeDB; Q8N159; -.
DR TreeFam; TF332628; -.
DR BRENDA; 2.3.1.1; 2681.
DR PathwayCommons; Q8N159; -.
DR Reactome; R-HSA-70635; Urea cycle.
DR SignaLink; Q8N159; -.
DR UniPathway; UPA00068; UER00106.
DR BioGRID-ORCS; 162417; 13 hits in 1086 CRISPR screens.
DR ChiTaRS; NAGS; human.
DR GenomeRNAi; 162417; -.
DR Pharos; Q8N159; Tbio.
DR PRO; PR:Q8N159; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q8N159; protein.
DR Bgee; ENSG00000161653; Expressed in ileal mucosa and 97 other tissues.
DR ExpressionAtlas; Q8N159; baseline and differential.
DR Genevisible; Q8N159; HS.
DR GO; GO:0005759; C:mitochondrial matrix; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0004042; F:acetyl-CoA:L-glutamate N-acetyltransferase activity; IDA:UniProtKB.
DR GO; GO:0103045; F:methione N-acyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0006526; P:arginine biosynthetic process; IBA:GO_Central.
DR GO; GO:0006536; P:glutamate metabolic process; IBA:GO_Central.
DR GO; GO:0000050; P:urea cycle; TAS:Reactome.
DR Gene3D; 3.40.1160.10; -; 1.
DR InterPro; IPR036393; AceGlu_kinase-like_sf.
DR InterPro; IPR016181; Acyl_CoA_acyltransferase.
DR InterPro; IPR011243; GlcNAc_Synth_met.
DR InterPro; IPR000182; GNAT_dom.
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; Disease variant; Mitochondrion;
KW Reference proteome; Transferase; Transit peptide; Urea cycle.
FT TRANSIT 1..18
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 19..534
FT /note="N-acetylglutamate synthase long form"
FT /evidence="ECO:0000255"
FT /id="PRO_0000041930"
FT CHAIN 51..534
FT /note="N-acetylglutamate synthase short form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000041931"
FT CHAIN 92..534
FT /note="N-acetylglutamate synthase conserved domain form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000041932"
FT DOMAIN 375..526
FT /note="N-acetyltransferase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00532"
FT REGION 19..376
FT /note="Amino-acid kinase domain (AAK)"
FT REGION 19..99
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 79..94
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 401
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23894642,
FT ECO:0007744|PDB:4K30"
FT BINDING 444
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23894642,
FT ECO:0007744|PDB:4K30"
FT BINDING 474..479
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23894642,
FT ECO:0007744|PDB:4K30"
FT VARIANT 167
FT /note="M -> V (in NAGSD; unknown pathological significance;
FT dbSNP:rs760267963)"
FT /evidence="ECO:0000269|PubMed:27037498"
FT /id="VAR_077329"
FT VARIANT 200
FT /note="C -> R (in NAGSD; markedly decreases activity;
FT dbSNP:rs1188223411)"
FT /evidence="ECO:0000269|PubMed:15878741"
FT /id="VAR_023505"
FT VARIANT 260
FT /note="P -> L (in NAGSD; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:27037498"
FT /id="VAR_077330"
FT VARIANT 264
FT /note="T -> M (in NAGSD; unknown pathological significance;
FT dbSNP:rs1251891037)"
FT /evidence="ECO:0000269|PubMed:27037498"
FT /id="VAR_077331"
FT VARIANT 279
FT /note="A -> P (in NAGSD)"
FT /evidence="ECO:0000269|PubMed:12754705"
FT /id="VAR_023506"
FT VARIANT 291
FT /note="I -> N (in NAGSD; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:27037498"
FT /id="VAR_077332"
FT VARIANT 391
FT /note="L -> R (in NAGSD; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:27037498"
FT /id="VAR_077333"
FT VARIANT 398
FT /note="S -> C (in NAGSD; unknown pathological significance;
FT dbSNP:rs1312599995)"
FT /evidence="ECO:0000269|PubMed:27037498"
FT /id="VAR_077334"
FT VARIANT 410
FT /note="S -> P (in NAGSD; markedly decreases activity)"
FT /evidence="ECO:0000269|PubMed:15878741"
FT /id="VAR_023507"
FT VARIANT 430
FT /note="L -> P (in NAGSD; markedly decreases activity;
FT dbSNP:rs104894605)"
FT /evidence="ECO:0000269|PubMed:12754705,
FT ECO:0000269|PubMed:15878741"
FT /id="VAR_023508"
FT VARIANT 457
FT /note="G -> D (in NAGSD; unknown pathological significance;
FT dbSNP:rs1204011876)"
FT /evidence="ECO:0000269|PubMed:27037498"
FT /id="VAR_077335"
FT VARIANT 484
FT /note="W -> R (in NAGSD; markedly decreases activity;
FT dbSNP:rs104894606)"
FT /evidence="ECO:0000269|PubMed:12754705,
FT ECO:0000269|PubMed:15878741"
FT /id="VAR_023509"
FT VARIANT 512
FT /note="Y -> C (in NAGSD; unknown pathological significance;
FT dbSNP:rs752415489)"
FT /evidence="ECO:0000269|PubMed:27037498"
FT /id="VAR_077336"
FT VARIANT 518
FT /note="A -> T (in NAGSD; markedly decreases activity;
FT dbSNP:rs745511282)"
FT /evidence="ECO:0000269|PubMed:15878741"
FT /id="VAR_023510"
FT MUTAGEN 441
FT /note="Y->F: 15% reduction in catalytic activity."
FT /evidence="ECO:0000269|PubMed:23894642"
FT MUTAGEN 479
FT /note="N->A: 7-fold reduction in catalytic activity."
FT /evidence="ECO:0000269|PubMed:23894642"
FT MUTAGEN 485
FT /note="Y->F: 10-fold reduction in catalytic activity."
FT /evidence="ECO:0000269|PubMed:23894642"
FT CONFLICT 94
FT /note="E -> M (in Ref. 3; AAN76451)"
FT /evidence="ECO:0000305"
FT STRAND 378..382
FT /evidence="ECO:0007829|PDB:4K30"
FT HELIX 383..385
FT /evidence="ECO:0007829|PDB:4K30"
FT HELIX 388..399
FT /evidence="ECO:0007829|PDB:4K30"
FT HELIX 407..411
FT /evidence="ECO:0007829|PDB:4K30"
FT HELIX 412..414
FT /evidence="ECO:0007829|PDB:4K30"
FT STRAND 415..420
FT /evidence="ECO:0007829|PDB:4K30"
FT STRAND 424..435
FT /evidence="ECO:0007829|PDB:4K30"
FT STRAND 438..447
FT /evidence="ECO:0007829|PDB:4K30"
FT HELIX 451..467
FT /evidence="ECO:0007829|PDB:4K30"
FT STRAND 471..476
FT /evidence="ECO:0007829|PDB:4K30"
FT HELIX 482..487
FT /evidence="ECO:0007829|PDB:4K30"
FT STRAND 489..494
FT /evidence="ECO:0007829|PDB:4K30"
FT STRAND 496..503
FT /evidence="ECO:0007829|PDB:4K30"
FT HELIX 508..510
FT /evidence="ECO:0007829|PDB:4K30"
FT HELIX 511..519
FT /evidence="ECO:0007829|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
