EzCatDB: S00419

DB codeS00419
RLCP classification5.201.1651000.1453
CATH domainDomain 13.40.800.10Catalytic domain
E.C.3.5.3.1
CSA1cev


Enzyme Name
Swiss-protKEGG

P53608P07824
Protein nameArginaseArginase-1arginase
arginine amidinase
canavanase
L-arginase
arginine transamidinase
SynonymsEC 3.5.3.1
EC 3.5.3.1
Type I arginase
Liver-type arginase

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

Swiss-prot:Accession NumberP53608P07824
Entry nameARGI_BACCDARGI1_RAT
ActivityL-arginine + H(2)O = L-ornithine + urea.L-arginine + H(2)O = L-ornithine + urea.
SubunitHomohexamer.Homotrimer.
Subcellular location
Cytoplasm.
CofactorManganese.Manganese.


CofactorsSubstratesProducts
KEGG-idC00034C00062C00001C00077C00086
CompoundManganeseL-ArginineH2OL-OrnithineUrea
Typeheavy metalamino acids,amine group,imine group,lipidH2Oamino acids,amine group,lipidamide group,amine group
1cevABound:2x_MNUnbound
UnboundUnbound
1cevBBound:2x_MNUnbound
UnboundUnbound
1cevCBound:2x_MNUnbound
UnboundUnbound
1cevDBound:2x_MNUnbound
UnboundUnbound
1cevEBound:2x_MNUnbound
UnboundUnbound
1cevFBound:2x_MNUnbound
UnboundUnbound
1d3vABound:2x_MNAnalogue:ABH
UnboundUnbound
1d3vBBound:2x_MNAnalogue:ABH
UnboundUnbound
1hq5ABound:2x_MNAnalogue:S2C
UnboundUnbound
1hq5BBound:2x_MNAnalogue:S2C
UnboundUnbound
1hqfABound:2x_MNAnalogue:HAR
UnboundUnbound
1hqfBBound:2x_MNAnalogue:HAR
UnboundUnbound
1hqfCBound:2x_MNAnalogue:HAR
UnboundUnbound
1hqgABound:2x_MNUnbound
Bound:ORNBound:URE
1hqgBBound:2x_MNUnbound
Bound:ORNBound:URE
1hqgCBound:2x_MNUnbound
Bound:ORNBound:URE
1hqhABound:2x_MNAnalogue:NNH
UnboundUnbound
1hqhBBound:2x_MNAnalogue:NNH
UnboundUnbound
1hqhCBound:2x_MNAnalogue:NNH
UnboundUnbound
1rlaABound:2x_MNUnbound
UnboundUnbound
1rlaBBound:2x_MNUnbound
UnboundUnbound
1rlaCBound:2x_MNUnbound
UnboundUnbound
2cevABound:2x_MNUnbound
UnboundUnbound
2cevBBound:2x_MNUnbound
UnboundUnbound
2cevCBound:2x_MNUnbound
UnboundUnbound
2cevDBound:2x_MNUnbound
UnboundUnbound
2cevEBound:2x_MNUnbound
UnboundUnbound
2cevFBound:2x_MNUnbound
UnboundUnbound
2rlaABound:_MNUnbound
UnboundUnbound
2rlaBBound:_MNUnbound
UnboundUnbound
2rlaCBound:_MNUnbound
UnboundUnbound
3cevABound:_MNBound:ARG 407(chain R)
UnboundUnbound
3cevBBound:_MNBound:ARG 408(chain R)
UnboundUnbound
3cevCBound:_MNBound:ARG 409(chain R)
UnboundUnbound
3cevDBound:_MNBound:ARG 410(chain R)
UnboundUnbound
3cevEBound:_MNBound:ARG 411(chain R)
UnboundUnbound
3cevFBound:_MNBound:ARG 412(chain R)
UnboundUnbound
3rlaABound:2x_MNUnbound
UnboundUnbound
3rlaBBound:2x_MNUnbound
UnboundUnbound
3rlaCBound:2x_MNUnbound
UnboundUnbound
4cevABound:2x_MNUnbound
Bound:ORNUnbound
4cevBBound:2x_MNUnbound
Bound:ORNUnbound
4cevCBound:2x_MNUnbound
Bound:ORNUnbound
4cevDBound:2x_MNUnbound
Bound:ORNUnbound
4cevEBound:2x_MNUnbound
Bound:ORNUnbound
4cevFBound:2x_MNUnbound
Bound:ORNUnbound
4rlaABound:_MNUnbound
UnboundUnbound
4rlaBBound:_MNUnbound
UnboundUnbound
4rlaCBound:_MNUnbound
UnboundUnbound
5cevABound:2x_MNUnbound
Analogue:LYSUnbound
5cevBBound:2x_MNUnbound
Analogue:LYSUnbound
5cevCBound:2x_MNUnbound
Analogue:LYSUnbound
5cevDBound:2x_MNUnbound
Analogue:LYSUnbound
5cevEBound:2x_MNUnbound
Analogue:LYSUnbound
5cevFBound:2x_MNUnbound
Analogue:LYSUnbound
5rlaABound:_MNUnbound
UnboundUnbound
5rlaBBound:_MNUnbound
UnboundUnbound
5rlaCBound:_MNUnbound
UnboundUnbound

Active-site residues
pdbCofactor-binding residuescomment
1cevAHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

1cevBHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

1cevCHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

1cevDHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

1cevEHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

1cevFHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

1d3vAHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1d3vBHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1hq5AHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1hq5BHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1hqfAHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1hqfBHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1hqfCHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1hqgAHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
mutant H141C
1hqgBHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
mutant H141C
1hqgCHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234
mutant H141C
1hqhAHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1hqhBHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1hqhCHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1rlaAHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1rlaBHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

1rlaCHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

2cevAHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

2cevBHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

2cevCHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

2cevDHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

2cevEHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

2cevFHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

2rlaAHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

2rlaBHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

2rlaCHIS 101;ASP 124;HIS 126;ASP 128;ASP 232;ASP 234

3cevAHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

3cevBHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

3cevCHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

3cevDHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

3cevEHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

3cevFHIS  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
4cevAHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

4cevBHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

4cevCHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

4cevDHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

4cevEHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

4cevFHIS  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
5cevAHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

5cevBHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

5cevCHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

5cevDHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

5cevEHIS  99;ASP 122;HIS 124;ASP 126;ASP 226;ASP 228

5cevFHIS  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
ReferencesSectionsNo. of steps in catalysis
[1]Fig.3b, p.5564
[2]p.10563-10564
[4]p.8548-8549, Scheme 44
[5]p.443-445
[6]Fig.1a, p.10454
[8]Fig.9, p.420-4234
[9]Fig.11, p.45-50
[11]Fig.6, p.2697-2699

references
[1]
CommentsX-ray crystallography (2.1 Angstroms)
Medline ID97002331
PubMed ID8849731
JournalNature
Year1996
Volume383
Pages554-7
AuthorsKanyo ZF, Scolnick LR, Ash DE, Christianson DW
TitleStructure of a unique binuclear manganese cluster in arginase.
Related PDB1rla
Related Swiss-protP07824
[2]
CommentsX-ray crystallography (3.0 Angstroms)
Medline ID97410344
PubMed ID9265637
JournalBiochemistry
Year1997
Volume36
Pages10558-65
AuthorsScolnick LR, Kanyo ZF, Cavalli RC, Ash DE, Christianson DW
TitleAltering the binuclear manganese cluster of arginase diminishes thermostability and catalytic function.
Related PDB2rla,3rla,4rla,5rla
Related Swiss-protP07824
[3]
PubMed ID9507056
JournalBiochim Biophys Acta
Year1998
Volume1382
Pages23-37
AuthorsPerozich J, Hempel J, Morris SM Jr
TitleRoles of conserved residues in the arginase family.
[4]
PubMed ID9622506
JournalBiochemistry
Year1998
Volume37
Pages8539-50
AuthorsKhangulov SV, Sossong TM Jr, Ash DE, Dismukes GC
TitleL-arginine binding to liver arginase requires proton transfer to gateway residue His141 and coordination of the guanidinium group to the dimanganese(II,II) center.
[5]
CommentsX-ray crystallography (2.4 Angstroms)
Medline ID99216539
PubMed ID10196128
JournalStructure Fold Des
Year1999
Volume7
Pages435-48
AuthorsBewley MC, Jeffrey PD, Patchett ML, Kanyo ZF, Baker EN
TitleCrystal structures of Bacillus caldovelox arginase in complex with substrate and inhibitors reveal new insights into activation, inhibition and catalysis in the arginase superfamily.
Related PDB1cev,2cev,3cev,4cev,5cev
Related Swiss-protP53608
[6]
CommentsX-ray crystallography (1.7 Angstroms)
PubMed ID10542097
JournalNat Struct Biol
Year1999
Volume6
Pages1043-7
AuthorsCox JD, Kim NN, Traish AM, Christianson DW
TitleArginase-boronic acid complex highlights a physiological role in erectile function.
Related PDB1d3v
Related Swiss-protP07824
[7]
PubMed ID10643656
JournalJ Inorg Biochem
Year1999
Volume77
Pages163-7
AuthorsCarvajal N, Salas M, Lopez V, Uribe E, Herrera P, Cerpa J, Fuentes M
TitleManganese-dependent inhibition of human liver arginase by borate.
[8]
PubMed ID10693141
JournalMet Ions Biol Syst
Year2000
Volume37
Pages407-28
AuthorsAsh DE, Cox JD, Christianson DW
TitleArginase: a binuclear manganese metalloenzyme.
[9]
PubMed ID10872443
JournalAnnu Rev Biochem
Year1999
Volume68
Pages33-57
AuthorsChristianson DW, Cox JD
TitleCatalysis by metal-activated hydroxide in zinc and manganese metalloenzymes.
[10]
CommentsX-ray crystallography (2.3 Angstroms)
PubMed ID11258879
JournalBiochemistry
Year2001
Volume40
Pages2678-88
AuthorsKim NN, Cox JD, Baggio RF, Emig FA, Mistry SK, Harper SL, Speicher DW, Morris SM Jr, Ash DE, Traish A, Christianson DW
TitleProbing 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 PDB1hq5
[11]
CommentsX-ray crystallography
PubMed ID11258880
JournalBiochemistry
Year2001
Volume40
Pages2689-701
AuthorsCox JD, Cama E, Colleluori DM, Pethe S, Boucher JL, Mansuy D, Ash DE, Christianson DW
TitleMechanistic and metabolic inferences from the binding of substrate analogues and products to arginase.
Related PDB1hqf,1hqg,1hqh
[12]
CommentsX-ray crystallography
PubMed ID11278703
JournalJ Biol Chem
Year2001
Volume276
Pages14242-8
AuthorsLavulo LT, Sossong TM Jr, Brigham-Burke MR, Doyle ML, Cox JD, Christianson DW, Ash DE
TitleSubunit-subunit interactions in trimeric arginase. Generation of active monomers by mutation of a single amino acid.
[13]
PubMed ID11470277
JournalFEBS Lett
Year2001
Volume501
Pages161-5
AuthorsSabio G, Mora A, Rangel MA, Quesada A, Marcos CF, Alonso JC, Soler G, Centeno F
TitleGlu-256 is a main structural determinant for oligomerisation of human arginase I.
[14]
PubMed ID11883902
JournalArch Biochem Biophys
Year2002
Volume399
Pages49-55
AuthorsLavulo LT, Emig FA, Ash DE
TitleFunctional consequences of the G235R mutation in liver arginase leading to hyperargininemia.
[15]
PubMed ID11904441
JournalProc Natl Acad Sci U S A
Year2002
Volume99
Pages3914-9
AuthorsHuang J, DeGraves FJ, Lenz SD, Gao D, Feng P, Li D, Schlapp T, Kaltenboeck B
TitleThe quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease.
[16]
PubMed ID12679340
JournalJ Biol Chem
Year2003
Volume278
Pages21550-8
AuthorsEl Alami M, Dubois E, Oudjama Y, Tricot C, Wouters J, Stalon V, Messenguy F
TitleYeast epiarginase regulation, an enzyme-enzyme activity control: identification of residues of ornithine carbamoyltransferase and arginase responsible for enzyme catalytic and regulatory activities.
[17]
PubMed ID12820884
JournalBiochemistry
Year2003
Volume42
Pages7748-58
AuthorsCama E, Emig FA, Ash DE, Christianson DW
TitleStructural and functional importance of first-shell metal ligands in the binuclear manganese cluster of arginase I.
[18]
PubMed ID12859189
JournalBiochemistry
Year2003
Volume42
Pages8445-51
AuthorsCama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW
TitleHuman arginase II: crystal structure and physiological role in male and female sexual arousal.
[19]
PubMed ID14570477
JournalJ Am Chem Soc
Year2003
Volume125
Pages13052-7
AuthorsCama E, Shin H, Christianson DW
TitleDesign of amino acid sulfonamides as transition-state analogue inhibitors of arginase.

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)

createdupdated
2003-02-032009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2010)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)

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