Reviewed, UniProtKB/Swiss-Prot P00966 (ASSY_HUMAN)

Names and origin

Protein names

Recommended name:
    Argininosuccinate synthase
    EC=6.3.4.5
Alternative name(s):
    Citrulline--aspartate ligase

Gene names

Name:	ASS1
Synonyms:	ASS

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	412 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	ATP + L-citrulline + L-aspartate = AMP + diphosphate + N(omega)-(L-arginino)succinate.
Pathway	Amino-acid biosynthesis; L-arginine biosynthesis; L-arginine from L-ornithine and carbamoyl phosphate: step 2/3. Nitrogen metabolism; urea cycle; N(omega)-(L-arginino)succinic acid from L-aspartate and L-citrulline: step 1/1.
Subunit structure	Homotetramer.
Involvement in disease	Defects in ASS1 are the cause of citrullinemia type 1 (CTLN1) [MIM:215700]. Citrullinemia belongs to the urea cycle disorders. It is an autosomal recessive disease characterized primarily by elevated serum and urine citrulline levels. Ammonia intoxication is another manifestation. CTLN1 usually manifests in the first few days of life. Affected infants appear normal at birth, but as ammonia builds up in the body they present symptoms such as lethargy, poor feeding, vomiting, seizures and loss of consciousness. Less commonly, a milder CTLN1 form can develop later in childhood or adulthood. Ref.3 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17
Sequence similarities	Belongs to the argininosuccinate synthase family. Type 1 subfamily.

Ontologies

Keywords
Biological process	Amino-acid biosynthesis Arginine biosynthesis Urea cycle
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	ATP-binding Nucleotide-binding
Molecular function	Ligase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	arginine biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW urea cycle Ref.12 Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Ref.1 Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW argininosuccinate synthase activity Inferred from electronic annotation. Source: EC protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ARAF	P10398	3	EBI-536842,EBI-365961

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 412	412	Argininosuccinate synthase		PRO_0000148554
Regions
	Nucleotide binding	10 – 18	9	ATP By similarity
	Nucleotide binding	115 – 123	9	ATP By similarity
Sites
	Binding site	36	1	ATP; via amide nitrogen and carbonyl oxygen By similarity
	Binding site	87	1	Citrulline By similarity
	Binding site	92	1	Citrulline By similarity
	Binding site	119	1	Aspartate By similarity
	Binding site	123	1	Aspartate By similarity
	Binding site	123	1	Citrulline By similarity
	Binding site	124	1	Aspartate By similarity
	Binding site	127	1	Citrulline By similarity
	Binding site	180	1	Citrulline By similarity
	Binding site	189	1	Citrulline By similarity
	Binding site	270	1	Citrulline By similarity
	Binding site	282	1	Citrulline By similarity
Amino acid modifications
	Modified residue	352	1	Phosphoserine Ref.9
Natural variations
	Natural variant	14	1	G → S in CTLN1. Ref.12		VAR_000681
	Natural variant	18	1	S → L in CTLN1. Ref.13		VAR_000682
	Natural variant	19	1	C → R in CTLN1. Ref.17		VAR_015891
	Natural variant	65	1	S → I: dbSNP rs2229556.		VAR_050427
	Natural variant	69	1	V → A in CTLN1. Ref.16		VAR_016013
	Natural variant	86	1	R → C in CTLN1. Ref.13 Ref.17		VAR_000683
	Natural variant	86	1	R → H in CTLN1. Ref.13 Ref.17		VAR_015892
	Natural variant	95	1	R → S in CTLN1. Ref.17		VAR_015893
	Natural variant	96	1	P → S in CTLN1. Ref.17		VAR_015894
	Natural variant	108	1	R → L in CTLN1. dbSNP rs35269064. Ref.3 Ref.16		VAR_016014
	Natural variant	117	1	G → D in CTLN1. Ref.16 Ref.17		VAR_015896
	Natural variant	117	1	G → S in CTLN1. Ref.16 Ref.17		VAR_015895
	Natural variant	118	1	A → T in CTLN1. Ref.14		VAR_000684
	Natural variant	119	1	T → I in CTLN1. Ref.16		VAR_016015
	Natural variant	157	1	R → C in CTLN1. Ref.12 Ref.17		VAR_015897
	Natural variant	157	1	R → H in CTLN1. Ref.12 Ref.17		VAR_000685
	Natural variant	179	1	W → R in CTLN1; mild. Ref.3 Ref.17		VAR_015898
	Natural variant	180	1	S → N in CTLN1. Ref.12		VAR_000686
	Natural variant	191	1	E → K in CTLN1. Ref.17		VAR_015899
	Natural variant	192	1	A → V in CTLN1. Ref.14		VAR_000687
	Natural variant	265	1	R → H in CTLN1. Ref.17		VAR_015900
	Natural variant	269	1	V → M in CTLN1. Ref.17		VAR_015901
	Natural variant	270	1	E → Q in CTLN1. Ref.16		VAR_016007
	Natural variant	272	1	R → C in CTLN1. Ref.14 Ref.17		VAR_000688
	Natural variant	279	1	R → Q in CTLN1.		VAR_016008
	Natural variant	280	1	G → R in CTLN1. Ref.14		VAR_000689
	Natural variant	283	1	E → K in CTLN1. Ref.17		VAR_015902
	Natural variant	304	1	R → W in CTLN1. Ref.12 Ref.14 Ref.17		VAR_000690
	Natural variant	310	1	K → Q in CTLN1. Ref.17		VAR_016009
	Natural variant	310	1	K → R in CTLN1. Ref.17		VAR_015903
	Natural variant	324	1	G → S in CTLN1. Ref.12 Ref.17		VAR_000691
	Natural variant	362	1	G → V in CTLN1; mild. Ref.3 Ref.17		VAR_015904
	Natural variant	363	1	R → G in CTLN1. Ref.12 Ref.14 Ref.17		VAR_016010
	Natural variant	363	1	R → L in CTLN1. Ref.12 Ref.14 Ref.17		VAR_000692
	Natural variant	363	1	R → Q in CTLN1. Ref.12 Ref.14 Ref.17		VAR_016011
	Natural variant	363	1	R → W in CTLN1. Ref.12 Ref.14 Ref.17		VAR_000693
	Natural variant	389	1	T → I in CTLN1. Ref.17		VAR_016012
	Natural variant	390	1	G → R in CTLN1. Ref.3 Ref.12 Ref.16 Ref.17		VAR_000694
Experimental info
	Sequence conflict	325 – 327	3	FWH → LRP Ref.1
	Sequence conflict	325 – 327	3	FWH → LRP Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P00966-1 [UniParc]. Last modified April 3, 2002. Version 2. Checksum: 47CAD2373AE47E47	FASTA	412	46,530
	10 20 30 40 50 60 MSSKGSVVLA YSGGLDTSCI LVWLKEQGYD VIAYLANIGQ KEDFEEARKK ALKLGAKKVF 70 80 90 100 110 120 IEDVSREFVE EFIWPAIQSS ALYEDRYLLG TSLARPCIAR KQVEIAQREG AKYVSHGATG 130 140 150 160 170 180 KGNDQVRFEL SCYSLAPQIK VIAPWRMPEF YNRFKGRNDL MEYAKQHGIP IPVTPKNPWS 190 200 210 220 230 240 MDENLMHISY EAGILENPKN QAPPGLYTKT QDPAKAPNTP DILEIEFKKG VPVKVTNVKD 250 260 270 280 290 300 GTTHQTSLEL FMYLNEVAGK HGVGRIDIVE NRFIGMKSRG IYETPAGTIL YHAHLDIEAF 310 320 330 340 350 360 TMDREVRKIK QGLGLKFAEL VYTGFWHSPE CEFVRHCIAK SQERVEGKVQ VSVLKGQVYI 370 380 390 400 410 LGRESPLSLY NEELVSMNVQ GDYEPTDATG FININSLRLK EYHRLQSKVT AK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence for human argininosuccinate synthetase cDNA." Bock H.-G.O., Su T.-S., O'Brien W.E., Beaudet A.L. Nucleic Acids Res. 11:6505-6512(1983) [PubMed: 6194510] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Molecular structures of human argininosuccinate synthetase pseudogenes. Evolutionary and mechanistic implications." Freytag S.O., Bock H.-G.O., Beaudet A.L., O'Brien W.E. J. Biol. Chem. 259:3160-3166(1984) [PubMed: 6321498] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia." Haeberle J., Pauli S., Linnebank M., Kleijer W.J., Bakker H.D., Wanders R.J.A., Harms E., Koch H.G. Hum. Genet. 110:327-333(2002) [PubMed: 11941481] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CTLN1 LEU-108; ARG-179; VAL-362 AND ARG-390.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Small intestine.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney and Muscle.
[6]	"Structure of the 5' end region of the human argininosuccinate synthetase gene." Jinno Y., Nomiyama H., Matuo S., Shimada K., Matsuda I., Saheki T. J. Inherit. Metab. Dis. 8:157-159(1985) [PubMed: 3027451] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-24.
[7]	"Identification of essential arginine residue(s) for Mg-ATP binding of human argininosuccinate synthetase." Isashiki Y., Noda T., Kobayashi K., Sase M., Saheki T., Titani K. Protein Seq. Data Anal. 2:283-287(1989) [PubMed: 2788888] [Abstract] Cited for: PROTEIN SEQUENCE OF 148-161.
[8]	"A two-dimensional gel database of human colon carcinoma proteins." Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J. Electrophoresis 18:605-613(1997) [PubMed: 9150948] [Abstract] Cited for: PROTEIN SEQUENCE OF 200-209. Tissue: Colon carcinoma.
[9]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-352, MASS SPECTROMETRY.
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	"Structure of human argininosuccinate synthetase." Structural genomics consortium (SGC) Submitted (FEB-2008) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
[12]	"Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia." Kobayashi K., Jackson M.J., Tick D.B., O'Brien W.E., Beaudet A.L. J. Biol. Chem. 265:11361-11367(1990) [PubMed: 2358466] [Abstract] Cited for: VARIANTS CTLN1 SER-14; HIS-157; ASN-180; TRP-304; SER-324; TRP-363 AND ARG-390.
[13]	"Additional mutations in argininosuccinate synthetase causing citrullinemia." Kobayashi K., Rosenbloom C., Beaudet A.L., O'Brien W.E. Mol. Biol. Med. 8:95-100(1991) [PubMed: 1943692] [Abstract] Cited for: VARIANTS CTLN1 LEU-18 AND CYS-86.
[14]	"Mutations in argininosuccinate synthetase mRNA of Japanese patients, causing classical citrullinemia." Kobayashi K., Shaheen N., Terazono H., Saheki T. Am. J. Hum. Genet. 55:1103-1112(1994) [PubMed: 7977368] [Abstract] Cited for: VARIANTS CTLN1 THR-118; VAL-192; CYS-272; ARG-280; TRP-304 AND LEU-363.
[15]	"Characterization of human wild-type and mutant argininosuccinate synthetase proteins expressed in bacterial cells." Shaheen N., Kobayashi K., Terazono H., Fukushige T., Horiuchi M., Saheki T. Enzyme Protein 48:251-264(1995) [PubMed: 8792870] [Abstract] Cited for: CHARACTERIZATION OF SOME CTLN1 VARIANTS.
[16]	"Phenotype and genotype heterogeneity in Mediterranean citrullinemia." Vilaseca M.A., Kobayashi K., Briones P., Lambruschini N., Campistol J., Tabata A., Alomar A., Rodes M., Lluch M., Saheki T. Mol. Genet. Metab. 74:396-398(2001) [PubMed: 11708871] [Abstract] Cited for: VARIANTS CTLN1 ALA-69; LEU-108; ASP-117; ILE-119; GLN-270 AND ARG-390.
[17]	"Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients." Gao H.-Z., Kobayashi K., Tabata A., Tsuge H., Iijima M., Yasuda T., Kalkanoglu H.S., Dursun A., Tokatli A., Coskun T., Trefz F.K., Skladal D., Mandel H., Seidel J., Kodama S., Shirane S., Ichida T., Makino S. , Yoshino M., Kang J.-H., Mizuguchi M., Barshop B.A., Fuchinoue S., Seneca S., Zeesman S., Knerr I., Rodes M., Wasant P., Yoshida I., De Meirleir L., Abdul-Jalil M., Begum L., Horiuchi M., Katunuma N., Nakagawa S., Saheki T. Hum. Mutat. 22:24-34(2003) [PubMed: 12815590] [Abstract] Cited for: VARIANTS CTLN1 ARG-19; HIS-86; SER-95; SER-96; ASP-117; SER-117; CYS-157; ARG-179; LYS-191; HIS-265; MET-269; CYS-272; LYS-283; TRP-304; GLN-310; SER-324; VAL-362; GLN-363; TRP-363; ILE-389 AND ARG-390.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

X01630 mRNA. Translation: CAA25771.1.
L00084 , L00079, L00080, L00081, L00082, L00083 Genomic DNA. Translation: AAA51783.1.
AY034076 Genomic DNA. Translation: AAK67487.1.
AK027126 mRNA. No translation available.
BC009243 mRNA. Translation: AAH09243.1.
BC021676 mRNA. Translation: AAH21676.1.
BC052288 mRNA. Translation: AAH52288.1. Different initiation.
M34903 Genomic DNA. Translation: AAA51782.1.

IPI

IPI00020632.

PIR

AJHURS. A01195.

RefSeq

NP_000041.2.
NP_446464.1.

UniGene

Hs.160786

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2NZ2	X-ray	2.40	A	1-412	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P00966. 6 interactions.

PTM databases

PhosphoSite

P00966.

Proteomic databases

PRIDE

P00966.

Genome annotation databases

Ensembl

ENSG00000130707. Homo sapiens. [Contig view]

GeneID

445.

KEGG

hsa:445.

UCSC

uc004bzm.1. human.

Organism-specific databases

GeneCards

GC09P132310.

H-InvDB

HIX0008469.
HIX0025782.
HIX0035239.

HGNC

HGNC:758. ASS1.

MIM

215700. phenotype.
603470. gene.

Orphanet

187. Citrullinemia.

PharmGKB

PA30299.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P00966.

HOVERGEN

P00966.

OMA

P00966. IAPVREW.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-11304.

BRENDA

6.3.4.5. 247.

Reactome

REACT_13. Metabolism of amino acids.

Gene expression databases

ArrayExpress

P00966.

Bgee

P00966.

CleanEx

HS_ASS1.

GermOnline

ENSG00000130707. Homo sapiens.

Family and domain databases

InterPro

IPR001518. Arginosuc_synth.
IPR018223. Arginosuc_synth_CS.
IPR014729. Rossmann-like_a/b/a_fold.
[Graphical view]

Gene3D

G3DSA:3.40.50.620. Rossmann-like_a/b/a_fold. 1 hit.

PANTHER

PTHR11587. Arginosuc_synth. 1 hit.

Pfam

PF00764. Arginosuc_synth. 1 hit.
[Graphical view]

TIGRFAMs

TIGR00032. argG. 1 hit.

PROSITE

PS00564. ARGININOSUCCIN_SYN_1. 1 hit.
PS00565. ARGININOSUCCIN_SYN_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00171. Adenosine triphosphate.
DB00125. L-Arginine.
DB00128. L-Aspartic Acid.
DB00155. L-Citrulline.

NextBio

1871.

SOURCE

Search...

Entry information

Entry name

ASSY_HUMAN

Accession

Primary (citable) accession number: P00966
Secondary accession number(s): Q6LDL2, Q86UZ0, Q96GT4

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	April 3, 2002
Last modified:	July 7, 2009
This is version 114 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)