EzCatDB: T00094
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DB codeT00094
RLCP classification5.203.8000.93 : Elimination
CATH domainDomain 11.10.275.10 : Fumarase C; Chain B, domain 1
Domain 21.20.200.10 : Fumarase C; Chain A, domain 2Catalytic domain
Domain 31.10.40.30 : Ribonucleotide Reductase Protein R1; domain 1
E.C.4.3.2.1
CSA1auw

CATH domainRelated DB codes (homologues)
1.10.275.10 : Fumarase C; Chain B, domain 1D00267,T00086,T00092,T00095
1.10.40.30 : Ribonucleotide Reductase Protein R1; domain 1T00086,T00092,T00095
1.20.200.10 : Fumarase C; Chain A, domain 2D00267,T00086,T00092,T00095

Enzyme Name
UniProtKBKEGG

P11447P24058P04424
Protein nameArgininosuccinate lyaseArgininosuccinate lyaseArgininosuccinate lyaseargininosuccinate lyase
arginosuccinase
argininosuccinic acid lyase
arginine-succinate lyase
N-(L-argininosuccinate) arginine-lyase
omega-N-(L-arginino)succinate arginine-lyase
2-(omega-N-L-arginino)succinate arginine-lyase (fumarate-forming)
SynonymsASAL
EC 4.3.2.1
Arginosuccinase
ASAL
EC 4.3.2.1
Arginosuccinase
Delta crystallin II
Delta-2 crystallin
ASAL
EC 4.3.2.1
Arginosuccinase
RefSeqNP_418395.1 (Protein)
NC_000913.2 (DNA/RNA sequence)
YP_491492.1 (Protein)
NC_007779.1 (DNA/RNA sequence)

NP_000039.2 (Protein)
NM_000048.3 (DNA/RNA sequence)
NP_001020114.1 (Protein)
NM_001024943.1 (DNA/RNA sequence)
NP_001020115.1 (Protein)
NM_001024944.1 (DNA/RNA sequence)
NP_001020117.1 (Protein)
NM_001024946.1 (DNA/RNA sequence)
PfamPF00206 (Lyase_1)
[Graphical view]
PF00206 (Lyase_1)
[Graphical view]
PF00206 (Lyase_1)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00220Urea cycle and metabolism of amino groups
MAP00252Alanine and aspartate metabolism
MAP00330Arginine and proline metabolism

UniProtKB:Accession NumberP11447P24058P04424
Entry nameARLY_ECOLIARLY2_ANAPLARLY_HUMAN
Activity2-(N(omega)-L-arginino)succinate = fumarate + L-arginine.2-(N(omega)-L-arginino)succinate = fumarate + L-arginine.2-(N(omega)-L-arginino)succinate = fumarate + L-arginine.
Subunit
Homotetramer.Homotetramer.
Subcellular locationCytoplasm (Probable).

Cofactor



Compound table: links to PDB-related databases & PoSSuM

SubstratesProducts
KEGG-idC03406C00122C00062
CompoundN-(L-Arginino)succinateFumarateL-Arginine
Typeamino acids,amine group,carboxyl group,imine groupcarboxyl groupamino acids,amine group,imine group,lipid
ChEBI
18012
16467
PubChem16950
444972
21883788
6322
28782
           
1tj7A01UnboundUnboundUnbound
1tj7B01UnboundUnboundUnbound
1auwA01UnboundUnboundUnbound
1auwB01UnboundUnboundUnbound
1auwC01UnboundUnboundUnbound
1auwD01UnboundUnboundUnbound
1dcnA01UnboundUnboundUnbound
1dcnB01UnboundUnboundUnbound
1dcnC01UnboundUnboundUnbound
1dcnD01UnboundUnboundUnbound
1hy1A01UnboundUnboundUnbound
1hy1B01UnboundUnboundUnbound
1hy1C01UnboundUnboundUnbound
1hy1D01UnboundUnboundUnbound
1k7wA01UnboundUnboundUnbound
1k7wB01UnboundUnboundUnbound
1k7wC01UnboundUnboundUnbound
1k7wD01UnboundUnboundUnbound
1tjuA01UnboundUnboundUnbound
1tjuB01UnboundUnboundUnbound
1tjuC01UnboundUnboundUnbound
1tjuD01UnboundUnboundUnbound
1tjvA01UnboundUnboundUnbound
1tjvB01UnboundUnboundUnbound
1tjvC01UnboundUnboundUnbound
1tjvD01UnboundUnboundUnbound
1tjwA01UnboundUnboundUnbound
1tjwB01UnboundUnboundUnbound
1tjwC01UnboundUnboundUnbound
1tjwD01UnboundUnboundUnbound
1k62A01UnboundUnboundUnbound
1k62B01UnboundUnboundUnbound
1aosA01UnboundUnboundUnbound
1aosB01UnboundUnboundUnbound
1tj7A02UnboundUnboundUnbound
1tj7B02UnboundUnboundUnbound
1auwA02UnboundUnboundUnbound
1auwB02UnboundUnboundUnbound
1auwC02UnboundUnboundUnbound
1auwD02UnboundUnboundUnbound
1dcnA02UnboundUnboundUnbound
1dcnB02Bound:AS1UnboundUnbound
1dcnC02UnboundUnboundUnbound
1dcnD02UnboundUnboundUnbound
1hy1A02UnboundUnboundUnbound
1hy1B02UnboundUnboundUnbound
1hy1C02UnboundUnboundUnbound
1hy1D02UnboundUnboundUnbound
1k7wA02Bound:AS1UnboundUnbound
1k7wB02Bound:AS1UnboundUnbound
1k7wC02Bound:AS1UnboundUnbound
1k7wD02Bound:AS1UnboundUnbound
1tjuA02UnboundUnboundUnbound
1tjuB02UnboundUnboundUnbound
1tjuC02UnboundUnboundUnbound
1tjuD02UnboundUnboundUnbound
1tjvA02UnboundUnboundUnbound
1tjvB02UnboundUnboundUnbound
1tjvC02UnboundUnboundUnbound
1tjvD02UnboundUnboundUnbound
1tjwA02Bound:AS1UnboundUnbound
1tjwB02Bound:AS1UnboundUnbound
1tjwC02Bound:AS1UnboundUnbound
1tjwD02Bound:AS1UnboundUnbound
1k62A02UnboundUnboundUnbound
1k62B02UnboundUnboundUnbound
1aosA02UnboundUnboundUnbound
1aosB02UnboundUnboundUnbound
1tj7A03UnboundUnboundUnbound
1tj7B03UnboundUnboundUnbound
1auwA03UnboundUnboundUnbound
1auwB03UnboundUnboundUnbound
1auwC03UnboundUnboundUnbound
1auwD03UnboundUnboundUnbound
1dcnA03UnboundUnboundUnbound
1dcnB03UnboundUnboundUnbound
1dcnC03UnboundUnboundUnbound
1dcnD03UnboundUnboundUnbound
1hy1A03UnboundUnboundUnbound
1hy1B03UnboundUnboundUnbound
1hy1C03UnboundUnboundUnbound
1hy1D03UnboundUnboundUnbound
1k7wA03UnboundUnboundUnbound
1k7wB03UnboundUnboundUnbound
1k7wC03UnboundUnboundUnbound
1k7wD03UnboundUnboundUnbound
1tjuA03UnboundUnboundUnbound
1tjuB03UnboundUnboundUnbound
1tjuC03UnboundUnboundUnbound
1tjuD03UnboundUnboundUnbound
1tjvA03UnboundUnboundUnbound
1tjvB03UnboundUnboundUnbound
1tjvC03UnboundUnboundUnbound
1tjvD03UnboundUnboundUnbound
1tjwA03UnboundUnboundUnbound
1tjwB03UnboundUnboundUnbound
1tjwC03UnboundUnboundUnbound
1tjwD03UnboundUnboundUnbound
1k62A03UnboundUnboundUnbound
1k62B03UnboundUnboundUnbound
1aosA03UnboundUnboundUnbound
1aosB03UnboundUnboundUnbound

Active-site residues
resource
PDB;1auw & literature [14], [17], [21] & Catalytic Site Atlas
pdbCatalytic residuescomment
          
1tj7A01 
 
1tj7B01 
 
1auwA01 
 
1auwB01 
 
1auwC01 
 
1auwD01 
 
1dcnA01 
 
1dcnB01 
 
1dcnC01 
 
1dcnD01 
 
1hy1A01 
 
1hy1B01 
 
1hy1C01 
 
1hy1D01 
 
1k7wA01 
 
1k7wB01 
 
1k7wC01 
 
1k7wD01 
 
1tjuA01 
 
1tjuB01 
 
1tjuC01 
 
1tjuD01 
 
1tjvA01 
 
1tjvB01 
 
1tjvC01 
 
1tjvD01 
 
1tjwA01 
 
1tjwB01 
 
1tjwC01 
 
1tjwD01 
 
1k62A01 
 
1k62B01 
 
1aosA01 
 
1aosB01 
 
1tj7A02HIS 156;SER 277;LYS 283;GLU 290
 
1tj7B02HIS 156;SER 277;LYS 283;GLU 290
 
1auwA02HIS 160;SER 281;LYS 287;GLU 294
 
1auwB02HIS 160;SER 281;LYS 287;GLU 294
 
1auwC02HIS 160;SER 281;LYS 287;GLU 294
 
1auwD02HIS 160;SER 281;LYS 287;GLU 294
 
1dcnA02       ;       ;       ;GLU 296
mutant H162N, invisible 282-290
1dcnB02       ;       ;       ;GLU 296
mutant H162N, invisible 277-291
1dcnC02       ;       ;       ;GLU 296
mutant H162N, invisible 279-291
1dcnD02       ;       ;       ;GLU 296
mutant H162N, invisible 282-290
1hy1A02HIS 160;SER 281;LYS 287;GLU 294
 
1hy1B02HIS 160;SER 281;LYS 287;GLU 294
 
1hy1C02HIS 160;SER 281;LYS 287;GLU 294
 
1hy1D02HIS 160;SER 281;LYS 287;GLU 294
 
1k7wA02HIS 162;       ;LYS 289;GLU 296
mutant S283A
1k7wB02HIS 162;       ;LYS 289;GLU 296
mutant S283A
1k7wC02HIS 162;       ;LYS 289;GLU 296
mutant S283A
1k7wD02HIS 162;       ;LYS 289;GLU 296
mutant S283A
1tjuA02HIS 162;SER 283;LYS 289;GLU 296
mutant T161S
1tjuB02HIS 162;SER 283;LYS 289;GLU 296
mutant T161S
1tjuC02HIS 162;SER 283;LYS 289;GLU 296
mutant T161S
1tjuD02HIS 162;SER 283;LYS 289;GLU 296
mutant T161S
1tjvA02HIS 162;SER 283;LYS 289;GLU 296
mutant T161D
1tjvB02HIS 162;SER 283;LYS 289;GLU 296
mutant T161D
1tjvC02HIS 162;SER 283;LYS 289;GLU 296
mutant T161D
1tjvD02HIS 162;SER 283;LYS 289;GLU 296
mutant T161D
1tjwA02HIS 162;SER 283;LYS 289;GLU 296
mutant T161D
1tjwB02HIS 162;SER 283;LYS 289;GLU 296
mutant T161D
1tjwC02HIS 162;SER 283;LYS 289;GLU 296
mutant T161D
1tjwD02HIS 162;SER 283;LYS 289;GLU 296
mutant T161D
1k62A02HIS 160;SER 281;LYS 287;GLU 294
mutant Q286R
1k62B02HIS 160;SER 281;LYS 287;GLU 294
mutant Q286R
1aosA02HIS 160;SER 281;LYS 287;GLU 294
 
1aosB02HIS 160;SER 281;LYS 287;GLU 294
 
1tj7A03 
 
1tj7B03 
 
1auwA03 
 
1auwB03 
 
1auwC03 
 
1auwD03 
 
1dcnA03 
 
1dcnB03 
 
1dcnC03 
 
1dcnD03 
 
1hy1A03 
 
1hy1B03 
 
1hy1C03 
 
1hy1D03 
 
1k7wA03 
 
1k7wB03 
 
1k7wC03 
 
1k7wD03 
 
1tjuA03 
 
1tjuB03 
 
1tjuC03 
 
1tjuD03 
 
1tjvA03 
 
1tjvB03 
 
1tjvC03 
 
1tjvD03 
 
1tjwA03 
 
1tjwB03 
 
1tjwC03 
 
1tjwD03 
 
1k62A03 
 
1k62B03 
 
1aosA03 
 
1aosB03 
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[6]p.730-732
[8]p.14018-14019
[9]p.9066-9067
[10]Scheme 2, p.333-3343
[11]p.2441-2442
[12]p.2427-2429
[13]Fig.5, p.1643-16453
[14]p.2739-2741
[15]p.15575
[16]Fig.6, p.4173-41743
[18]Fig.6, p.445-446

references
[1]
PubMed ID495948
JournalAnal Biochem
Year1979
Volume95
Pages139-55
AuthorsMurakami-Murofushi K, Ratner S
TitleArgininosuccinase from bovine brain: isolation and comparison of catalytic, physical, and chemical properties with the enzymes from liver and kidney.
[2]
PubMed ID6615795
JournalBiochemistry
Year1983
Volume22
Pages3729-35
AuthorsGarrard LJ, Mathis JM, Raushel FM
TitleSubstrate-induced inactivation of argininosuccinate lyase by monofluorofumarate and difluorofumarate.
[3]
PubMed ID6722123
JournalBiochemistry
Year1984
Volume23
Pages1791-5
AuthorsRaushel FM, Garrard LJ
TitleA positional isotope exchange study of the argininosuccinate lyase reaction.
[4]
PubMed ID3522565
JournalJ Biol Chem
Year1986
Volume261
Pages8163-6
AuthorsKim SC, Raushel FM
TitleThe determination of enzyme-substrate dissociation rates by dynamic isotope exchange enhancement experiments.
[5]
PubMed ID8196062
JournalJ Mol Biol
Year1994
Volume239
Pages336-8
AuthorsTurner MA, Achyuthan AM, Hershfield MS, McInnes RR, Howell PL
TitleExpression, purification, crystallization and preliminary X-ray analysis of human argininosuccinic acid lyase.
[6]
PubMed ID7634077
JournalNat Struct Biol
Year1994
Volume1
Pages724-34
AuthorsSimpson A, Bateman O, Driessen H, Lindley P, Moss D, Mylvaganam S, Narebor E, Slingsby C
TitleThe structure of avian eye lens delta-crystallin reveals a new fold for a superfamily of oligomeric enzymes.
[7]
PubMed ID7613869
JournalStructure
Year1995
Volume3
Pages403-12
AuthorsSimpson A, Moss D, Slingsby C
TitleThe avian eye lens protein delta-crystallin shows a novel packing arrangement of tetramers in a supramolecular helix.
[8]
CommentsX-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF MUTANT ASN-91.
Medline ID98039131
PubMed ID9369472
JournalBiochemistry
Year1997
Volume36
Pages14012-22
AuthorsAbu-Abed M, Turner MA, Vallee F, Simpson A, Slingsby C, Howell PL
TitleStructural comparison of the enzymatically active and inactive forms of delta crystallin and the role of histidine 91.
Related PDB1auw
Related UniProtKBP24058
[9]
PubMed ID9256435
JournalProc Natl Acad Sci U S A
Year1997
Volume94
Pages9063-8
AuthorsTurner MA, Simpson A, McInnes RR, Howell PL
TitleHuman argininosuccinate lyase: a structural basis for intragenic complementation.
Related PDB1aos
[10]
PubMed ID9657972
JournalBiochem J
Year1998
Volume333
Pages327-34
AuthorsWu CY, Lee HJ, Wu SH, Chen ST, Chiou SH, Chang GG
TitleChemical mechanism of the endogenous argininosuccinate lyase activity of duck lens delta2-crystallin.
[11]
PubMed ID10029537
JournalBiochemistry
Year1999
Volume38
Pages2435-43
AuthorsChakraborty AR, Davidson A, Howell PL
TitleMutational analysis of amino acid residues involved in argininosuccinate lyase activity in duck delta II crystallin.
[12]
CommentsX-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ASN-162.
Medline ID99155215
PubMed ID10029536
JournalBiochemistry
Year1999
Volume38
Pages2425-34
AuthorsVallee F, Turner MA, Lindley PL, Howell PL
TitleCrystal structure of an inactive duck delta II crystallin mutant with bound argininosuccinate.
Related PDB1dcn
Related UniProtKBP24058
[13]
PubMed ID11092456
JournalCell Mol Life Sci
Year2000
Volume57
Pages1637-51
AuthorsYu B, Howell PL
TitleIntragenic complementation and the structure and function of argininosuccinate lyase.
[14]
PubMed ID11258884
JournalBiochemistry
Year2001
Volume40
Pages2732-42
AuthorsSampaleanu LM, Vallee F, Slingsby C, Howell PL
TitleStructural studies of duck delta 1 and delta 2 crystallin suggest conformational changes occur during catalysis.
Related PDB1hy1,1hy0,1i0a
[15]
PubMed ID11747432
JournalBiochemistry
Year2001
Volume40
Pages15570-80
AuthorsSampaleanu LM, Vallee F, Thompson GD, Howell PL
TitleThree-dimensional structure of the argininosuccinate lyase frequently complementing allele Q286R.
Related PDB1k62
[16]
PubMed ID11698398
JournalJ Biol Chem
Year2002
Volume277
Pages4166-75
AuthorsSampaleanu LM, Yu B, Howell PL
TitleMutational analysis of duck delta 2 crystallin and the structure of an inactive mutant with bound substrate provide insight into the enzymatic mechanism of argininosuccinate lyase.
Related PDB1k7w
[17]
PubMed ID15502303
JournalActa Crystallogr D Biol Crystallogr
Year2004
Volume60
Pages1964-70
AuthorsBhaumik P, Koski MK, Bergmann U, Wierenga RK
TitleStructure determination and refinement at 2.44 A resolution of argininosuccinate lyase from Escherichia coli.
Related PDB1tj7
[18]
PubMed ID15320872
JournalBiochem J
Year2004
Volume384
Pages437-47
AuthorsSampaleanu LM, Codding PW, Lobsanov YD, Tsai M, Smith GD, Horvatin C, Howell PL
TitleStructural studies of duck delta2 crystallin mutants provide insight into the role of Thr161 and the 280s loop in catalysis.
Related PDB1tju,1tjv,1tjw
[19]
PubMed ID15362851
JournalBiochemistry
Year2004
Volume43
Pages11672-82
AuthorsTsai M, Sampaleanu LM, Greene C, Creagh L, Haynes C, Howell PL
TitleA duck delta1 crystallin double loop mutant provides insight into residues important for argininosuccinate lyase activity.
Related PDB1u15,1u16

comments
There are two delta crystallin isoforms in duck lenses, duck delta1 crystallin (Swissprot; P24057 & PDB;1hy0, 1u15, 1u16) and duck delta2 crystallin (Swissprot; P24057), which are homologous to this enzyme, according to the literature [18]. However, only duck delta2 crystallin (d-delta-c2) is catalytically active (see [18]).
According to the literature [9] & [10], the catalytic reaction of this enzyme proceeds via E1cB-like mechanism. The reaction proceeds as follows (see [14], [16] & [18]):
(1) Glu294 (of PDB;1aos) makes His160 a general acid, by its hydrogen-bond with His160 (also called "charge-relay system").
(2) His160 abstracts a proton from the C-beta of substrate (or deprotonation site of leaving group), leading to formation of a carbanion intermediate, and a conformational change in the active-site loop (280s loop). The negative charge of the intermediate, which must be stabilized by Lys287, may induce the conformational change (see [14], [16] & [18]).
(3) Redistribution of the negative charge in the leaving group (fumarate group) gives an aci-carboxylate intermediate. This intermediate must be stabilized by Lys287, as well.
(4) Ser281 acts as a general acid, which protonates the eliminated group, guanidino group, leading to the cleavage of N1-Calpha bond.

createdupdated
2004-06-282009-02-26


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