ID ARLY_HUMAN Reviewed; 464 AA.
AC P04424; Q6LDS5; Q96HS2;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 4.
DT 01-MAY-2013, entry version 157.
DE RecName: Full=Argininosuccinate lyase;
DE Short=ASAL;
DE EC=4.3.2.1;
DE AltName: Full=Arginosuccinase;
GN Name=ASL;
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 [MRNA].
RC TISSUE=Liver;
RX PubMed=3391281; DOI=10.1016/0014-5793(88)80124-8;
RA Matuo S., Tatsuno M., Kobayashi K., Saheki T., Miyata T.;
RT "Isolation of cDNA clones of human argininosuccinate lyase and
RT corrected amino acid sequence.";
RL FEBS Lett. 234:395-399(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3463959; DOI=10.1073/pnas.83.19.7211;
RA O'Brien W.E., McInnes R., Kalumuck K., Adcock M.;
RT "Cloning and sequence analysis of cDNA for human argininosuccinate
RT lyase.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:7211-7215(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2644168; DOI=10.1016/0888-7543(89)90314-5;
RA Todd S., McGill J.R., McCombs J.L., Moore C.M., Weider I.,
RA Naylor S.L.;
RT "cDNA sequence, interspecies comparison, and gene mapping analysis of
RT argininosuccinate lyase.";
RL Genomics 4:53-59(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Matuo S.;
RT "Cloning and sequence analysis of cDNA for human argininosuccinate
RT lyase.";
RL Kagoshima Daigaku Igaku Zasshi 40:147-160(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Linnebank M., Tschiedel E., Koch H.G.;
RT "Complete sequence of the human ASL gene.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Cervix;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 5-97.
RX PubMed=3368457; DOI=10.1073/pnas.85.10.3479;
RA Piatigorsky J., O'Brien W.E., Norman B.L., Kalumuck K., Wistow G.J.,
RA Borras T., Nickerson J.M., Wawrousek E.F.;
RT "Gene sharing by delta-crystallin and argininosuccinate lyase.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:3479-3483(1988).
RN [8]
RP ACETYLATION AT LYS-69 AND LYS-288, ENZYME REGULATION, MASS
RP SPECTROMETRY, AND MUTAGENESIS OF LYS-288.
RX PubMed=20167786; DOI=10.1126/science.1179689;
RA Zhao S., Xu W., Jiang W., Yu W., Lin Y., Zhang T., Yao J., Zhou L.,
RA Zeng Y., Li H., Li Y., Shi J., An W., Hancock S.M., He F., Qin L.,
RA Chin J., Yang P., Chen X., Lei Q., Xiong Y., Guan K.L.;
RT "Regulation of cellular metabolism by protein lysine acetylation.";
RL Science 327:1000-1004(2010).
RN [9]
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.,
RA Buerckstuemmer T., 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 [10]
RP X-RAY CRYSTALLOGRAPHY (4.2 ANGSTROMS).
RC TISSUE=Liver;
RX PubMed=9256435; DOI=10.1073/pnas.94.17.9063;
RA Turner M.A., Simpson A., McInnes R.R., Howell P.L.;
RT "Human argininosuccinate lyase: a structural basis for intragenic
RT complementation.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:9063-9068(1997).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF VARIANT ARG-286.
RX PubMed=11747432; DOI=10.1021/bi011525m;
RA Sampaleanu L.M., Vallee F., Thompson G.D., Howell P.L.;
RT "Three-dimensional structure of the argininosuccinate lyase frequently
RT complementing allele Q286R.";
RL Biochemistry 40:15570-15580(2001).
RN [12]
RP VARIANTS ARGINSA TRP-111; GLN-193 AND ARG-286, AND MUTAGENESIS.
RX PubMed=1705937;
RA Barbosa P., Cialkowski M., O'Brien W.E.;
RT "Analysis of naturally occurring and site-directed mutations in the
RT argininosuccinate lyase gene.";
RL J. Biol. Chem. 266:5286-5290(1991).
RN [13]
RP VARIANT ARGINSA CYS-95.
RX PubMed=2263616; DOI=10.1073/pnas.87.24.9625;
RA Walker D.C., McCloskey D.A., Simard L.R., McInnes R.R.;
RT "Molecular analysis of human argininosuccinate lyase: mutant
RT characterization and alternative splicing of the coding region.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:9625-9629(1990).
RN [14]
RP VARIANTS ARGINSA MET-178; CYS-379 AND CYS-385.
RX PubMed=12408190; DOI=10.1023/A:1020108002877;
RA Kleijer W.J., Garritsen V.H., Linnebank M., Mooyer P.,
RA Huijmans J.G.M., Mustonen A., Simola K.O.J., Arslan-Kirchner M.,
RA Battini R., Briones P., Cardo E., Mandel H., Tschiedel E.,
RA Wanders R.J.A., Koch H.G.;
RT "Clinical, enzymatic, and molecular genetic characterization of a
RT biochemical variant type of argininosuccinic aciduria: prenatal and
RT postnatal diagnosis in five unrelated families.";
RL J. Inherit. Metab. Dis. 25:399-410(2002).
RN [15]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-181 AND VAL-200.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [16]
RP VARIANTS ARGINSA ASN-31; GLN-113; MET-178; GLN-186; TRP-236; ARG-286;
RP LEU-335; ARG-382 AND TRP-456.
RX PubMed=17326097; DOI=10.1002/humu.20498;
RA Trevisson E., Salviati L., Baldoin M.C., Toldo I., Casarin A.,
RA Sacconi S., Cesaro L., Basso G., Burlina A.B.;
RT "Argininosuccinate lyase deficiency: mutational spectrum in Italian
RT patients and identification of a novel ASL pseudogene.";
RL Hum. Mutat. 28:694-702(2007).
CC -!- CATALYTIC ACTIVITY: 2-(N(omega)-L-arginino)succinate = fumarate +
CC L-arginine.
CC -!- ENZYME REGULATION: Enzyme activity is regulated by acetylation (By
CC similarity).
CC -!- PATHWAY: Amino-acid biosynthesis; L-arginine biosynthesis; L-
CC arginine from L-ornithine and carbamoyl phosphate: step 3/3.
CC -!- PATHWAY: Nitrogen metabolism; urea cycle; L-arginine and fumarate
CC from (N(omega)-L-arginino)succinate: step 1/1.
CC -!- SUBUNIT: Homotetramer.
CC -!- PTM: Acetylation modifies enzyme activity in response to
CC alterations of extracellular nutrient availability. Acetylation
CC increased with trichostin A (TSA) or with nicotinamide (NAM).
CC Glucose increases acetylation by about a factor of 3 with
CC decreasing enzyme activity. Acetylation on Lys-288 is decreased on
CC the addition of extra amino acids resulting in activation of
CC enzyme activity.
CC -!- DISEASE: Argininosuccinic aciduria (ARGINSA) [MIM:207900]: An
CC autosomal recessive disorder of the urea cycle. The disease is
CC characterized by mental and physical retardation, liver
CC enlargement, skin lesions, dry and brittle hair showing
CC trichorrhexis nodosa microscopically and fluorescing red,
CC convulsions, and episodic unconsciousness. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the lyase 1 family. Argininosuccinate lyase
CC subfamily.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA51786.1; Type=Frameshift; Positions=387, 452;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ASL";
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DR EMBL; Y00753; CAA68722.1; -; mRNA.
DR EMBL; M14218; AAA51786.1; ALT_FRAME; mRNA.
DR EMBL; J03058; AAA51787.1; -; mRNA.
DR EMBL; M57638; AAA51788.1; -; mRNA.
DR EMBL; AF376770; AAL57276.1; -; Genomic_DNA.
DR EMBL; BC008195; AAH08195.1; -; mRNA.
DR EMBL; BC033146; AAH33146.1; -; mRNA.
DR EMBL; M21007; AAA35566.1; -; Genomic_DNA.
DR EMBL; M21006; AAA35566.1; JOINED; Genomic_DNA.
DR IPI; IPI00220267; -.
DR PIR; A31658; WZHURS.
DR RefSeq; NP_000039.2; NM_000048.3.
DR RefSeq; NP_001020114.1; NM_001024943.1.
DR UniGene; Hs.632015; -.
DR PDB; 1AOS; X-ray; 4.20 A; A/B=1-464.
DR PDB; 1K62; X-ray; 2.65 A; A/B=1-464.
DR PDBsum; 1AOS; -.
DR PDBsum; 1K62; -.
DR ProteinModelPortal; P04424; -.
DR IntAct; P04424; 5.
DR STRING; 9606.ENSP00000307188; -.
DR PhosphoSite; P04424; -.
DR DMDM; 124028641; -.
DR PaxDb; P04424; -.
DR PRIDE; P04424; -.
DR DNASU; 435; -.
DR Ensembl; ENST00000304874; ENSP00000307188; ENSG00000126522.
DR Ensembl; ENST00000395332; ENSP00000378741; ENSG00000126522.
DR GeneID; 435; -.
DR KEGG; hsa:435; -.
DR UCSC; uc003tuo.3; human.
DR CTD; 435; -.
DR GeneCards; GC07P065540; -.
DR HGNC; HGNC:746; ASL.
DR HPA; CAB003696; -.
DR HPA; HPA016646; -.
DR MIM; 207900; phenotype.
DR MIM; 608310; gene.
DR neXtProt; NX_P04424; -.
DR Orphanet; 23; Argininosuccinic aciduria.
DR PharmGKB; PA25046; -.
DR eggNOG; COG0165; -.
DR HOGENOM; HOG000242744; -.
DR HOVERGEN; HBG004281; -.
DR InParanoid; P04424; -.
DR KO; K01755; -.
DR OMA; KEGIFDA; -.
DR OrthoDB; EOG418BN7; -.
DR BioCyc; MetaCyc:HS10034-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P04424; -.
DR UniPathway; UPA00068; UER00114.
DR UniPathway; UPA00158; UER00273.
DR ChiTaRS; asl; human.
DR DrugBank; DB00125; L-Arginine.
DR EvolutionaryTrace; P04424; -.
DR GenomeRNAi; 435; -.
DR NextBio; 1821; -.
DR ArrayExpress; P04424; -.
DR Bgee; P04424; -.
DR CleanEx; HS_ASL; -.
DR Genevestigator; P04424; -.
DR GermOnline; ENSG00000169910; Homo sapiens.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004056; F:argininosuccinate lyase activity; EXP:Reactome.
DR GO; GO:0042450; P:arginine biosynthetic process via ornithine; IEA:InterPro.
DR GO; GO:0006527; P:arginine catabolic process; TAS:ProtInc.
DR GO; GO:0006475; P:internal protein amino acid acetylation; IDA:UniProtKB.
DR GO; GO:0000050; P:urea cycle; TAS:Reactome.
DR Gene3D; 1.10.275.10; -; 1.
DR InterPro; IPR009049; Argininosuccinate_lyase.
DR InterPro; IPR003031; D_crystallin.
DR InterPro; IPR024083; Fumarase/histidase_N.
DR InterPro; IPR000362; Fumarate_lyase.
DR InterPro; IPR020557; Fumarate_lyase_CS.
DR InterPro; IPR022761; Fumarate_lyase_N.
DR InterPro; IPR008948; L-Aspartase-like.
DR PANTHER; PTHR11444:SF3; PTHR11444:SF3; 1.
DR Pfam; PF00206; Lyase_1; 1.
DR PRINTS; PR00145; ARGSUCLYASE.
DR PRINTS; PR00149; FUMRATELYASE.
DR SUPFAM; SSF48557; L-Aspartase-like; 1.
DR TIGRFAMs; TIGR00838; argH; 1.
DR PROSITE; PS00163; FUMARATE_LYASES; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amino-acid biosynthesis;
KW Arginine biosynthesis; Complete proteome; Disease mutation; Lyase;
KW Polymorphism; Reference proteome; Urea cycle.
FT CHAIN 1 464 Argininosuccinate lyase.
FT /FTId=PRO_0000137712.
FT MOD_RES 69 69 N6-acetyllysine.
FT MOD_RES 288 288 N6-acetyllysine.
FT VARIANT 31 31 D -> N (in ARGINSA).
FT /FTId=VAR_043106.
FT VARIANT 95 95 R -> C (in ARGINSA; dbSNP:rs28940585).
FT /FTId=VAR_000676.
FT VARIANT 111 111 R -> W (in ARGINSA).
FT /FTId=VAR_000677.
FT VARIANT 113 113 R -> Q (in ARGINSA).
FT /FTId=VAR_043107.
FT VARIANT 178 178 V -> M (in ARGINSA; dbSNP:rs28941473).
FT /FTId=VAR_017572.
FT VARIANT 181 181 T -> S (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036281.
FT VARIANT 186 186 R -> Q (in ARGINSA).
FT /FTId=VAR_043108.
FT VARIANT 193 193 R -> Q (in ARGINSA).
FT /FTId=VAR_000678.
FT VARIANT 200 200 G -> V (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036282.
FT VARIANT 236 236 R -> W (in ARGINSA).
FT /FTId=VAR_043109.
FT VARIANT 286 286 Q -> R (in ARGINSA; dbSNP:rs28941472).
FT /FTId=VAR_000679.
FT VARIANT 335 335 V -> L (in ARGINSA).
FT /FTId=VAR_043110.
FT VARIANT 379 379 R -> C (in ARGINSA; dbSNP:rs28940287).
FT /FTId=VAR_017573.
FT VARIANT 382 382 M -> R (in ARGINSA).
FT /FTId=VAR_043111.
FT VARIANT 385 385 R -> C (in ARGINSA; dbSNP:rs28940286).
FT /FTId=VAR_017574.
FT VARIANT 456 456 R -> W (in ARGINSA).
FT /FTId=VAR_043112.
FT MUTAGEN 51 51 K->N: 2-fold reduction in activity.
FT MUTAGEN 89 89 H->Q: 10-fold reduction in activity.
FT MUTAGEN 288 288 K->R: Refractory to inhibition by TSA and
FT NAM and by addition of extra amino acids.
FT No effect on protein structure.
FT CONFLICT 246 246 A -> R (in Ref. 1; CAA68722, 2; AAA51786,
FT 3; AAA51787, 4; AAA51788 and 5;
FT AAL57276).
FT CONFLICT 431 431 G -> R (in Ref. 1; CAA68722).
FT HELIX 19 25
FT HELIX 28 31
FT HELIX 32 34
FT HELIX 35 51
FT HELIX 57 76
FT HELIX 88 100
FT HELIX 101 106
FT TURN 107 110
FT HELIX 113 150
FT STRAND 154 159
FT STRAND 162 168
FT HELIX 169 194
FT STRAND 195 197
FT TURN 202 205
FT HELIX 213 219
FT STRAND 223 225
FT HELIX 229 232
FT HELIX 237 264
FT TURN 266 268
FT HELIX 291 314
FT HELIX 323 327
FT HELIX 328 352
FT HELIX 357 362
FT HELIX 366 369
FT HELIX 370 379
FT HELIX 384 400
FT HELIX 405 407
FT HELIX 410 414
FT HELIX 423 428
FT HELIX 430 434
FT STRAND 442 444
FT HELIX 445 463
SQ SEQUENCE 464 AA; 51658 MW; F751625C1A581883 CRC64;
MASESGKLWG GRFVGAVDPI MEKFNASIAY DRHLWEVDVQ GSKAYSRGLE KAGLLTKAEM
DQILHGLDKV AEEWAQGTFK LNSNDEDIHT ANERRLKELI GATAGKLHTG RSRNDQVVTD
LRLWMRQTCS TLSGLLWELI RTMVDRAEAE RDVLFPGYTH LQRAQPIRWS HWILSHAVAL
TRDSERLLEV RKRINVLPLG SGAIAGNPLG VDRELLRAEL NFGAITLNSM DATSERDFVA
EFLFWASLCM THLSRMAEDL ILYCTKEFSF VQLSDAYSTG SSLMPQKKNP DSLELIRSKA
GRVFGRCAGL LMTLKGLPST YNKDLQEDKE AVFEVSDTMS AVLQVATGVI STLQIHQENM
GQALSPDMLA TDLAYYLVRK GMPFRQAHEA SGKAVFMAET KGVALNQLSL QELQTISPLF
SGDVICVWDY GHSVEQYGAL GGTARSSVDW QIRQVRALLQ AQQA
//
