DB code: S00419

RLCP classification 5.201.1651000.1453 : Elimination
CATH domain 3.40.800.10 : Arginase; Chain A Catalytic domain
E.C. 3.5.3.1
CSA 1cev
M-CSA 1cev
MACiE

CATH domain Related DB codes (homologues)

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Pfam RefSeq
P53608 Arginase
EC 3.5.3.1
PF00491 (Arginase)
[Graphical View]
P07824 Arginase-1
EC 3.5.3.1
Type I arginase
Liver-type arginase
PF00491 (Arginase)
[Graphical View] 		NP_058830.2 (Protein)
NM_017134.3 (DNA/RNA sequence)

KEGG enzyme name
arginase
arginine amidinase
canavanase
L-arginase
arginine transamidinase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P53608 ARGI_BACCD L-arginine + H(2)O = L-ornithine + urea. Homohexamer. Manganese.
P07824 ARGI1_RAT L-arginine + H(2)O = L-ornithine + urea. Homotrimer. Cytoplasm. Manganese.

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

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00034 C00062 C00001 C00077 C00086
E.C.
Compound Manganese L-Arginine H2O L-Ornithine Urea
Type heavy metal amino acids,amine group,imine group,lipid H2O amino acids,amine group,lipid amide group,amine group
ChEBI 18291
 35154
 18291
 35154
 		16467
 16467
 		15377
 15377
 		15729
 15729
 		16199
 48376
 16199
 48376
PubChem 23930
 23930
 		28782
 6322
 28782
 6322
 		22247451
 962
 22247451
 962
 		6262
 88747248
 6262
 88747248
 		1176
 1176
1cevA Bound:2x_MN Unbound Unbound Unbound
1cevB Bound:2x_MN Unbound Unbound Unbound
1cevC Bound:2x_MN Unbound Unbound Unbound
1cevD Bound:2x_MN Unbound Unbound Unbound
1cevE Bound:2x_MN Unbound Unbound Unbound
1cevF Bound:2x_MN Unbound Unbound Unbound
1d3vA Bound:2x_MN Analogue:ABH Unbound Unbound
1d3vB Bound:2x_MN Analogue:ABH Unbound Unbound
1hq5A Bound:2x_MN Analogue:S2C Unbound Unbound
1hq5B Bound:2x_MN Analogue:S2C Unbound Unbound
1hqfA Bound:2x_MN Analogue:HAR Unbound Unbound
1hqfB Bound:2x_MN Analogue:HAR Unbound Unbound
1hqfC Bound:2x_MN Analogue:HAR Unbound Unbound
1hqgA Bound:2x_MN Unbound Bound:ORN Bound:URE
1hqgB Bound:2x_MN Unbound Bound:ORN Bound:URE
1hqgC Bound:2x_MN Unbound Bound:ORN Bound:URE
1hqhA Bound:2x_MN Analogue:NNH Unbound Unbound
1hqhB Bound:2x_MN Analogue:NNH Unbound Unbound
1hqhC Bound:2x_MN Analogue:NNH Unbound Unbound
1rlaA Bound:2x_MN Unbound Unbound Unbound
1rlaB Bound:2x_MN Unbound Unbound Unbound
1rlaC Bound:2x_MN Unbound Unbound Unbound
2cevA Bound:2x_MN Unbound Unbound Unbound
2cevB Bound:2x_MN Unbound Unbound Unbound
2cevC Bound:2x_MN Unbound Unbound Unbound
2cevD Bound:2x_MN Unbound Unbound Unbound
2cevE Bound:2x_MN Unbound Unbound Unbound
2cevF Bound:2x_MN Unbound Unbound Unbound
2rlaA Bound:_MN Unbound Unbound Unbound
2rlaB Bound:_MN Unbound Unbound Unbound
2rlaC Bound:_MN Unbound Unbound Unbound
3cevA Bound:_MN Bound:ARG_407 (chain R) Unbound Unbound
3cevB Bound:_MN Bound:ARG_408 (chain R) Unbound Unbound
3cevC Bound:_MN Bound:ARG_409 (chain R) Unbound Unbound
3cevD Bound:_MN Bound:ARG_410 (chain R) Unbound Unbound
3cevE Bound:_MN Bound:ARG_411 (chain R) Unbound Unbound
3cevF Bound:_MN Bound:ARG_412 (chain R) Unbound Unbound
3rlaA Bound:2x_MN Unbound Unbound Unbound
3rlaB Bound:2x_MN Unbound Unbound Unbound
3rlaC Bound:2x_MN Unbound Unbound Unbound
4cevA Bound:2x_MN Unbound Bound:ORN Unbound
4cevB Bound:2x_MN Unbound Bound:ORN Unbound
4cevC Bound:2x_MN Unbound Bound:ORN Unbound
4cevD Bound:2x_MN Unbound Bound:ORN Unbound
4cevE Bound:2x_MN Unbound Bound:ORN Unbound
4cevF Bound:2x_MN Unbound Bound:ORN Unbound
4rlaA Bound:_MN Unbound Unbound Unbound
4rlaB Bound:_MN Unbound Unbound Unbound
4rlaC Bound:_MN Unbound Unbound Unbound
5cevA Bound:2x_MN Unbound Analogue:LYS Unbound
5cevB Bound:2x_MN Unbound Analogue:LYS Unbound
5cevC Bound:2x_MN Unbound Analogue:LYS Unbound
5cevD Bound:2x_MN Unbound Analogue:LYS Unbound
5cevE Bound:2x_MN Unbound Analogue:LYS Unbound
5cevF Bound:2x_MN Unbound Analogue:LYS Unbound
5rlaA Bound:_MN Unbound Unbound Unbound
5rlaB Bound:_MN Unbound Unbound Unbound
5rlaC Bound:_MN Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1cevA HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
1cevB HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
1cevC HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
1cevD HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
1cevE HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
1cevF HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
1d3vA HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1d3vB HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1hq5A HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1hq5B HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1hqfA HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1hqfB HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1hqfC HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1hqgA HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H141C
1hqgB HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H141C
1hqgC HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H141C
1hqhA HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1hqhB HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1hqhC HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1rlaA HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1rlaB HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
1rlaC HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
2cevA HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
2cevB HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
2cevC HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
2cevD HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
2cevE HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
2cevF HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
2rlaA HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
2rlaB HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
2rlaC HIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
3cevA HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
3cevB HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
3cevC HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
3cevD HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
3cevE HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
3cevF HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
3rlaA ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N
3rlaB ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N
3rlaC ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N
4cevA HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
4cevB HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
4cevC HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
4cevD HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
4cevE HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
4cevF HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
4rlaA ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N
4rlaB ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N
4rlaC ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N
5cevA HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
5cevB HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
5cevC HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
5cevD HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
5cevE HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
5cevF HIS 99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228
5rlaA ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N
5rlaB ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N
5rlaC ;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234 mutant H101N

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
Fig.3b, p.556 4
[2]
p.10563-10564
[4]
p.8548-8549, Scheme 4 4
[5]
p.443-445
[6]
Fig.1a, p.1045 4
[8]
Fig.9, p.420-423 4
[9]
Fig.11, p.45-50
[11]
Fig.6, p.2697-2699

References
[1]
Resource
Comments X-ray crystallography (2.1 Angstroms)
Medline ID 97002331
PubMed ID 8849731
Journal Nature
Year 1996
Volume 383
Pages 554-7
Authors Kanyo ZF, Scolnick LR, Ash DE, Christianson DW
Title Structure of a unique binuclear manganese cluster in arginase.
Related PDB 1rla
Related UniProtKB P07824
[2]
Resource
Comments X-ray crystallography (3.0 Angstroms)
Medline ID 97410344
PubMed ID 9265637
Journal Biochemistry
Year 1997
Volume 36
Pages 10558-65
Authors Scolnick LR, Kanyo ZF, Cavalli RC, Ash DE, Christianson DW
Title Altering the binuclear manganese cluster of arginase diminishes thermostability and catalytic function.
Related PDB 2rla 3rla 4rla 5rla
Related UniProtKB P07824
[3]
Resource
Comments
Medline ID
PubMed ID 9507056
Journal Biochim Biophys Acta
Year 1998
Volume 1382
Pages 23-37
Authors Perozich J, Hempel J, Morris SM Jr
Title Roles of conserved residues in the arginase family.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 9622506
Journal Biochemistry
Year 1998
Volume 37
Pages 8539-50
Authors Khangulov SV, Sossong TM Jr, Ash DE, Dismukes GC
Title L-arginine binding to liver arginase requires proton transfer to gateway residue His141 and coordination of the guanidinium group to the dimanganese(II,II) center.
Related PDB
Related UniProtKB
[5]
Resource
Comments X-ray crystallography (2.4 Angstroms)
Medline ID 99216539
PubMed ID 10196128
Journal Structure Fold Des
Year 1999
Volume 7
Pages 435-48
Authors Bewley MC, Jeffrey PD, Patchett ML, Kanyo ZF, Baker EN
Title Crystal structures of Bacillus caldovelox arginase in complex with substrate and inhibitors reveal new insights into activation, inhibition and catalysis in the arginase superfamily.
Related PDB 1cev 2cev 3cev 4cev 5cev
Related UniProtKB P53608
[6]
Resource
Comments X-ray crystallography (1.7 Angstroms)
Medline ID
PubMed ID 10542097
Journal Nat Struct Biol
Year 1999
Volume 6
Pages 1043-7
Authors Cox JD, Kim NN, Traish AM, Christianson DW
Title Arginase-boronic acid complex highlights a physiological role in erectile function.
Related PDB 1d3v
Related UniProtKB P07824
[7]
Resource
Comments
Medline ID
PubMed ID 10643656
Journal J Inorg Biochem
Year 1999
Volume 77
Pages 163-7
Authors Carvajal N, Salas M, Lopez V, Uribe E, Herrera P, Cerpa J, Fuentes M
Title Manganese-dependent inhibition of human liver arginase by borate.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 10693141
Journal Met Ions Biol Syst
Year 2000
Volume 37
Pages 407-28
Authors Ash DE, Cox JD, Christianson DW
Title Arginase: a binuclear manganese metalloenzyme.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 10872443
Journal Annu Rev Biochem
Year 1999
Volume 68
Pages 33-57
Authors Christianson DW, Cox JD
Title Catalysis by metal-activated hydroxide in zinc and manganese metalloenzymes.
Related PDB
Related UniProtKB
[10]
Resource
Comments X-ray crystallography (2.3 Angstroms)
Medline ID
PubMed ID 11258879
Journal Biochemistry
Year 2001
Volume 40
Pages 2678-88
Authors Kim NN, Cox JD, Baggio RF, Emig FA, Mistry SK, Harper SL, Speicher DW, Morris SM Jr, Ash DE, Traish A, Christianson DW
Title Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum.
Related PDB 1hq5
Related UniProtKB
[11]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 11258880
Journal Biochemistry
Year 2001
Volume 40
Pages 2689-701
Authors Cox JD, Cama E, Colleluori DM, Pethe S, Boucher JL, Mansuy D, Ash DE, Christianson DW
Title Mechanistic and metabolic inferences from the binding of substrate analogues and products to arginase.
Related PDB 1hqf 1hqg 1hqh
Related UniProtKB
[12]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 11278703
Journal J Biol Chem
Year 2001
Volume 276
Pages 14242-8
Authors Lavulo LT, Sossong TM Jr, Brigham-Burke MR, Doyle ML, Cox JD, Christianson DW, Ash DE
Title Subunit-subunit interactions in trimeric arginase. Generation of active monomers by mutation of a single amino acid.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 11470277
Journal FEBS Lett
Year 2001
Volume 501
Pages 161-5
Authors Sabio G, Mora A, Rangel MA, Quesada A, Marcos CF, Alonso JC, Soler G, Centeno F
Title Glu-256 is a main structural determinant for oligomerisation of human arginase I.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 11883902
Journal Arch Biochem Biophys
Year 2002
Volume 399
Pages 49-55
Authors Lavulo LT, Emig FA, Ash DE
Title Functional consequences of the G235R mutation in liver arginase leading to hyperargininemia.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 11904441
Journal Proc Natl Acad Sci U S A
Year 2002
Volume 99
Pages 3914-9
Authors Huang J, DeGraves FJ, Lenz SD, Gao D, Feng P, Li D, Schlapp T, Kaltenboeck B
Title The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 12679340
Journal J Biol Chem
Year 2003
Volume 278
Pages 21550-8
Authors El Alami M, Dubois E, Oudjama Y, Tricot C, Wouters J, Stalon V, Messenguy F
Title Yeast epiarginase regulation, an enzyme-enzyme activity control: identification of residues of ornithine carbamoyltransferase and arginase responsible for enzyme catalytic and regulatory activities.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 12820884
Journal Biochemistry
Year 2003
Volume 42
Pages 7748-58
Authors Cama E, Emig FA, Ash DE, Christianson DW
Title Structural and functional importance of first-shell metal ligands in the binuclear manganese cluster of arginase I.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 12859189
Journal Biochemistry
Year 2003
Volume 42
Pages 8445-51
Authors Cama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW
Title Human arginase II: crystal structure and physiological role in male and female sexual arousal.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 14570477
Journal J Am Chem Soc
Year 2003
Volume 125
Pages 13052-7
Authors Cama E, Shin H, Christianson DW
Title Design of amino acid sulfonamides as transition-state analogue inhibitors of arginase.
Related PDB
Related UniProtKB

Comments
This enzyme belongs to the arginase family.
Taken together, this enzyme catalyzes two successive reactions (rather than hydrolysis) as follows:
(A) Water addition to Imine carbon (C=N) to form a tetrahedral intermediate.
(B) Elimination of amine group from the intermediate, forming a carbonyl group.
##
Papers [1] & [4] proposed two different catalytic mechanisms. According to the paper [4], the differences between the two mechanisms are as follows:
(1) The character of nucleophilic water: The paper [1] suggested that bridging hydroxide ion could attack the guanidinium carbon, whilst the paper [4] proposed that aquo, water molecule bound to a Mn2+ ion, would attack the carbon.
(2) The role of His141: His141 can be a proton shuttle, which mediates proton transfer to and from bulk solvent water, according to the paper [1], whilst the other paper proposed His141 might be involved in deprotonation of the substrate.
(3) The binding mode of substrate L-arginine to Glu277 and to Mn2+ ion: The paper [1] suggested a bidenate binding mode between arginine and Glu277, whilst the paper [4] reported a monodentate binding mode. In terms of interaction between the substrate and Mn2+ ion, the paper [4] suggested that the substrate is bound directly to Mn2+ ion, whilst the other paper did not.
However, several papers, such as [8], [9] & [11], supported mainly the proposal by [1]. One of the most recent papers, [11], proposed the following catalytic mechanism, based on crystal structures of the ligand-bound enzymes.
(A) Water addition to Imine carbon (C=N) to form a tetrahedral intermediate.
(A1) His141 acts as a base-acid (or proton shuttle), mediating the proton transfer from metal-bridging water to bulk solvent.
(A2) Metal-bridging hydroxide makes a nucleophilic attack on the carbon atom of the substrate guanidinium group, resulting in the formation of a tetrahedral intermediate, stabilized by Glu277 and two metal ions.
(B) Elimination of amine group from the intermediate, forming a carbonyl group.
(B1) Asp128 mediates a proton transfer from the hydroxyl group of the tetrahedral intermediate to the leaving group, E-amino group of product ornithine.
(B2) The tetrahedral intermediate collapses, yielding the two products, ornithine and urea. The oxygen atom of urea is coordinated to both the metal ions.
(B3) A water molecule enters to bridge the two metal ions, causing the urea to move to a terminal coordination site on Mn2+A. This product dissociation facilitates ionization of the metal-binding water to yield the next hydroxide ion. (Getting back to A1 stage)

Created Updated
2003-02-03 2009-02-26