DB code: T00094

RLCP classification 5.203.8000.93 : Elimination
CATH domain 1.10.275.10 : Fumarase C; Chain B, domain 1
1.20.200.10 : Fumarase C; Chain A, domain 2 Catalytic domain
1.10.40.30 : Ribonucleotide Reductase Protein R1; domain 1
E.C. 4.3.2.1
CSA 1auw
M-CSA 1auw
MACiE

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

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P11447 Argininosuccinate lyase
ASAL
EC 4.3.2.1
Arginosuccinase
NP_418395.1 (Protein)
NC_000913.2 (DNA/RNA sequence)
YP_491492.1 (Protein)
NC_007779.1 (DNA/RNA sequence)
PF00206 (Lyase_1)
[Graphical View]
P24058 Argininosuccinate lyase
ASAL
EC 4.3.2.1
Arginosuccinase
Delta crystallin II
Delta-2 crystallin
PF00206 (Lyase_1)
[Graphical View]
P04424 Argininosuccinate lyase
ASAL
EC 4.3.2.1
Arginosuccinase
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)
PF00206 (Lyase_1)
[Graphical View]

KEGG enzyme name
argininosuccinate 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)

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P11447 ARLY_ECOLI 2-(N(omega)-L-arginino)succinate = fumarate + L-arginine. Cytoplasm (Probable).
P24058 ARLY2_ANAPL 2-(N(omega)-L-arginino)succinate = fumarate + L-arginine. Homotetramer.
P04424 ARLY_HUMAN 2-(N(omega)-L-arginino)succinate = fumarate + L-arginine. Homotetramer.

KEGG Pathways
Map code Pathways E.C.
MAP00220 Urea cycle and metabolism of amino groups
MAP00252 Alanine and aspartate metabolism
MAP00330 Arginine and proline metabolism

Compound table
Substrates Products Intermediates
KEGG-id C03406 C00122 C00062
E.C.
Compound N-(L-Arginino)succinate Fumarate L-Arginine
Type amino acids,amine group,carboxyl group,imine group carboxyl group amino acids,amine group,imine group,lipid
ChEBI 18012
18012
16467
16467
PubChem 16950
16950
21883788
444972
21883788
444972
28782
6322
28782
6322
1tj7A01 Unbound Unbound Unbound
1tj7B01 Unbound Unbound Unbound
1auwA01 Unbound Unbound Unbound
1auwB01 Unbound Unbound Unbound
1auwC01 Unbound Unbound Unbound
1auwD01 Unbound Unbound Unbound
1dcnA01 Unbound Unbound Unbound
1dcnB01 Unbound Unbound Unbound
1dcnC01 Unbound Unbound Unbound
1dcnD01 Unbound Unbound Unbound
1hy1A01 Unbound Unbound Unbound
1hy1B01 Unbound Unbound Unbound
1hy1C01 Unbound Unbound Unbound
1hy1D01 Unbound Unbound Unbound
1k7wA01 Unbound Unbound Unbound
1k7wB01 Unbound Unbound Unbound
1k7wC01 Unbound Unbound Unbound
1k7wD01 Unbound Unbound Unbound
1tjuA01 Unbound Unbound Unbound
1tjuB01 Unbound Unbound Unbound
1tjuC01 Unbound Unbound Unbound
1tjuD01 Unbound Unbound Unbound
1tjvA01 Unbound Unbound Unbound
1tjvB01 Unbound Unbound Unbound
1tjvC01 Unbound Unbound Unbound
1tjvD01 Unbound Unbound Unbound
1tjwA01 Unbound Unbound Unbound
1tjwB01 Unbound Unbound Unbound
1tjwC01 Unbound Unbound Unbound
1tjwD01 Unbound Unbound Unbound
1k62A01 Unbound Unbound Unbound
1k62B01 Unbound Unbound Unbound
1aosA01 Unbound Unbound Unbound
1aosB01 Unbound Unbound Unbound
1tj7A02 Unbound Unbound Unbound
1tj7B02 Unbound Unbound Unbound
1auwA02 Unbound Unbound Unbound
1auwB02 Unbound Unbound Unbound
1auwC02 Unbound Unbound Unbound
1auwD02 Unbound Unbound Unbound
1dcnA02 Unbound Unbound Unbound
1dcnB02 Bound:AS1 Unbound Unbound
1dcnC02 Unbound Unbound Unbound
1dcnD02 Unbound Unbound Unbound
1hy1A02 Unbound Unbound Unbound
1hy1B02 Unbound Unbound Unbound
1hy1C02 Unbound Unbound Unbound
1hy1D02 Unbound Unbound Unbound
1k7wA02 Bound:AS1 Unbound Unbound
1k7wB02 Bound:AS1 Unbound Unbound
1k7wC02 Bound:AS1 Unbound Unbound
1k7wD02 Bound:AS1 Unbound Unbound
1tjuA02 Unbound Unbound Unbound
1tjuB02 Unbound Unbound Unbound
1tjuC02 Unbound Unbound Unbound
1tjuD02 Unbound Unbound Unbound
1tjvA02 Unbound Unbound Unbound
1tjvB02 Unbound Unbound Unbound
1tjvC02 Unbound Unbound Unbound
1tjvD02 Unbound Unbound Unbound
1tjwA02 Bound:AS1 Unbound Unbound
1tjwB02 Bound:AS1 Unbound Unbound
1tjwC02 Bound:AS1 Unbound Unbound
1tjwD02 Bound:AS1 Unbound Unbound
1k62A02 Unbound Unbound Unbound
1k62B02 Unbound Unbound Unbound
1aosA02 Unbound Unbound Unbound
1aosB02 Unbound Unbound Unbound
1tj7A03 Unbound Unbound Unbound
1tj7B03 Unbound Unbound Unbound
1auwA03 Unbound Unbound Unbound
1auwB03 Unbound Unbound Unbound
1auwC03 Unbound Unbound Unbound
1auwD03 Unbound Unbound Unbound
1dcnA03 Unbound Unbound Unbound
1dcnB03 Unbound Unbound Unbound
1dcnC03 Unbound Unbound Unbound
1dcnD03 Unbound Unbound Unbound
1hy1A03 Unbound Unbound Unbound
1hy1B03 Unbound Unbound Unbound
1hy1C03 Unbound Unbound Unbound
1hy1D03 Unbound Unbound Unbound
1k7wA03 Unbound Unbound Unbound
1k7wB03 Unbound Unbound Unbound
1k7wC03 Unbound Unbound Unbound
1k7wD03 Unbound Unbound Unbound
1tjuA03 Unbound Unbound Unbound
1tjuB03 Unbound Unbound Unbound
1tjuC03 Unbound Unbound Unbound
1tjuD03 Unbound Unbound Unbound
1tjvA03 Unbound Unbound Unbound
1tjvB03 Unbound Unbound Unbound
1tjvC03 Unbound Unbound Unbound
1tjvD03 Unbound Unbound Unbound
1tjwA03 Unbound Unbound Unbound
1tjwB03 Unbound Unbound Unbound
1tjwC03 Unbound Unbound Unbound
1tjwD03 Unbound Unbound Unbound
1k62A03 Unbound Unbound Unbound
1k62B03 Unbound Unbound Unbound
1aosA03 Unbound Unbound Unbound
1aosB03 Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
PDB;1auw & literature [14], [17], [21] & Catalytic Site Atlas

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
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
1tj7A02 HIS 156;SER 277;LYS 283;GLU 290
1tj7B02 HIS 156;SER 277;LYS 283;GLU 290
1auwA02 HIS 160;SER 281;LYS 287;GLU 294
1auwB02 HIS 160;SER 281;LYS 287;GLU 294
1auwC02 HIS 160;SER 281;LYS 287;GLU 294
1auwD02 HIS 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
1hy1A02 HIS 160;SER 281;LYS 287;GLU 294
1hy1B02 HIS 160;SER 281;LYS 287;GLU 294
1hy1C02 HIS 160;SER 281;LYS 287;GLU 294
1hy1D02 HIS 160;SER 281;LYS 287;GLU 294
1k7wA02 HIS 162;;LYS 289;GLU 296 mutant S283A
1k7wB02 HIS 162;;LYS 289;GLU 296 mutant S283A
1k7wC02 HIS 162;;LYS 289;GLU 296 mutant S283A
1k7wD02 HIS 162;;LYS 289;GLU 296 mutant S283A
1tjuA02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161S
1tjuB02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161S
1tjuC02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161S
1tjuD02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161S
1tjvA02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161D
1tjvB02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161D
1tjvC02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161D
1tjvD02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161D
1tjwA02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161D
1tjwB02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161D
1tjwC02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161D
1tjwD02 HIS 162;SER 283;LYS 289;GLU 296 mutant T161D
1k62A02 HIS 160;SER 281;LYS 287;GLU 294 mutant Q286R
1k62B02 HIS 160;SER 281;LYS 287;GLU 294 mutant Q286R
1aosA02 HIS 160;SER 281;LYS 287;GLU 294
1aosB02 HIS 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
References Sections No. of steps in catalysis
[6]
p.730-732
[8]
p.14018-14019
[9]
p.9066-9067
[10]
Scheme 2, p.333-334 3
[11]
p.2441-2442
[12]
p.2427-2429
[13]
Fig.5, p.1643-1645 3
[14]
p.2739-2741
[15]
p.15575
[16]
Fig.6, p.4173-4174 3
[18]
Fig.6, p.445-446

References
[1]
Resource
Comments
Medline ID
PubMed ID 495948
Journal Anal Biochem
Year 1979
Volume 95
Pages 139-55
Authors Murakami-Murofushi K, Ratner S
Title Argininosuccinase from bovine brain: isolation and comparison of catalytic, physical, and chemical properties with the enzymes from liver and kidney.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 6615795
Journal Biochemistry
Year 1983
Volume 22
Pages 3729-35
Authors Garrard LJ, Mathis JM, Raushel FM
Title Substrate-induced inactivation of argininosuccinate lyase by monofluorofumarate and difluorofumarate.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 6722123
Journal Biochemistry
Year 1984
Volume 23
Pages 1791-5
Authors Raushel FM, Garrard LJ
Title A positional isotope exchange study of the argininosuccinate lyase reaction.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 3522565
Journal J Biol Chem
Year 1986
Volume 261
Pages 8163-6
Authors Kim SC, Raushel FM
Title The determination of enzyme-substrate dissociation rates by dynamic isotope exchange enhancement experiments.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 8196062
Journal J Mol Biol
Year 1994
Volume 239
Pages 336-8
Authors Turner MA, Achyuthan AM, Hershfield MS, McInnes RR, Howell PL
Title Expression, purification, crystallization and preliminary X-ray analysis of human argininosuccinic acid lyase.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 7634077
Journal Nat Struct Biol
Year 1994
Volume 1
Pages 724-34
Authors Simpson A, Bateman O, Driessen H, Lindley P, Moss D, Mylvaganam S, Narebor E, Slingsby C
Title The structure of avian eye lens delta-crystallin reveals a new fold for a superfamily of oligomeric enzymes.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 7613869
Journal Structure
Year 1995
Volume 3
Pages 403-12
Authors Simpson A, Moss D, Slingsby C
Title The avian eye lens protein delta-crystallin shows a novel packing arrangement of tetramers in a supramolecular helix.
Related PDB
Related UniProtKB
[8]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF MUTANT ASN-91.
Medline ID 98039131
PubMed ID 9369472
Journal Biochemistry
Year 1997
Volume 36
Pages 14012-22
Authors Abu-Abed M, Turner MA, Vallee F, Simpson A, Slingsby C, Howell PL
Title Structural comparison of the enzymatically active and inactive forms of delta crystallin and the role of histidine 91.
Related PDB 1auw
Related UniProtKB P24058
[9]
Resource
Comments
Medline ID
PubMed ID 9256435
Journal Proc Natl Acad Sci U S A
Year 1997
Volume 94
Pages 9063-8
Authors Turner MA, Simpson A, McInnes RR, Howell PL
Title Human argininosuccinate lyase: a structural basis for intragenic complementation.
Related PDB 1aos
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 9657972
Journal Biochem J
Year 1998
Volume 333
Pages 327-34
Authors Wu CY, Lee HJ, Wu SH, Chen ST, Chiou SH, Chang GG
Title Chemical mechanism of the endogenous argininosuccinate lyase activity of duck lens delta2-crystallin.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 10029537
Journal Biochemistry
Year 1999
Volume 38
Pages 2435-43
Authors Chakraborty AR, Davidson A, Howell PL
Title Mutational analysis of amino acid residues involved in argininosuccinate lyase activity in duck delta II crystallin.
Related PDB
Related UniProtKB
[12]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ASN-162.
Medline ID 99155215
PubMed ID 10029536
Journal Biochemistry
Year 1999
Volume 38
Pages 2425-34
Authors Vallee F, Turner MA, Lindley PL, Howell PL
Title Crystal structure of an inactive duck delta II crystallin mutant with bound argininosuccinate.
Related PDB 1dcn
Related UniProtKB P24058
[13]
Resource
Comments
Medline ID
PubMed ID 11092456
Journal Cell Mol Life Sci
Year 2000
Volume 57
Pages 1637-51
Authors Yu B, Howell PL
Title Intragenic complementation and the structure and function of argininosuccinate lyase.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 11258884
Journal Biochemistry
Year 2001
Volume 40
Pages 2732-42
Authors Sampaleanu LM, Vallee F, Slingsby C, Howell PL
Title Structural studies of duck delta 1 and delta 2 crystallin suggest conformational changes occur during catalysis.
Related PDB 1hy1 1hy0 1i0a
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 11747432
Journal Biochemistry
Year 2001
Volume 40
Pages 15570-80
Authors Sampaleanu LM, Vallee F, Thompson GD, Howell PL
Title Three-dimensional structure of the argininosuccinate lyase frequently complementing allele Q286R.
Related PDB 1k62
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 11698398
Journal J Biol Chem
Year 2002
Volume 277
Pages 4166-75
Authors Sampaleanu LM, Yu B, Howell PL
Title Mutational 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 PDB 1k7w
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 15502303
Journal Acta Crystallogr D Biol Crystallogr
Year 2004
Volume 60
Pages 1964-70
Authors Bhaumik P, Koski MK, Bergmann U, Wierenga RK
Title Structure determination and refinement at 2.44 A resolution of argininosuccinate lyase from Escherichia coli.
Related PDB 1tj7
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 15320872
Journal Biochem J
Year 2004
Volume 384
Pages 437-47
Authors Sampaleanu LM, Codding PW, Lobsanov YD, Tsai M, Smith GD, Horvatin C, Howell PL
Title Structural studies of duck delta2 crystallin mutants provide insight into the role of Thr161 and the 280s loop in catalysis.
Related PDB 1tju 1tjv 1tjw
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 15362851
Journal Biochemistry
Year 2004
Volume 43
Pages 11672-82
Authors Tsai M, Sampaleanu LM, Greene C, Creagh L, Haynes C, Howell PL
Title A duck delta1 crystallin double loop mutant provides insight into residues important for argininosuccinate lyase activity.
Related PDB 1u15 1u16
Related UniProtKB

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.

Created Updated
2004-06-28 2009-02-26