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| Enzyme Name | | Swiss-prot | KEGG |
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| P53608 | P07824 |
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| Protein name | Arginase | Arginase-1 | arginasearginine amidinasecanavanaseL-arginasearginine transamidinase |
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| Synonyms | EC 3.5.3.1 | EC 3.5.3.1Type I arginaseLiver-type arginase |
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| KEGG pathways | | MAP code | Pathways |
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| MAP00220 | Urea cycle and metabolism of amino groups | | MAP00330 | Arginine and proline metabolism |
| Swiss-prot:Accession Number | P53608 | P07824 |
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| Entry name | ARGI_BACCD | ARGI1_RAT |
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| Activity | L-arginine + H(2)O = L-ornithine + urea. | L-arginine + H(2)O = L-ornithine + urea. |
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| Subunit | Homohexamer. | Homotrimer. |
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| Subcellular location |
| Cytoplasm. |
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| Cofactor | Manganese. | Manganese. |
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| References for Catalytic Mechanism | | References | Sections | No. of steps in catalysis |
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| [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 |
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| references | | [1] |
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| Comments | X-ray crystallography (2.1 Angstroms) |
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| Medline ID | 97002331 |
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| PubMed ID | 8849731 |
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| Journal | Nature |
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| Year | 1996 |
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| Volume | 383 |
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| Pages | 554-7 |
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| Authors | Kanyo ZF, Scolnick LR, Ash DE, Christianson DW |
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| Title | Structure of a unique binuclear manganese cluster in arginase. |
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| Related PDB | 1rla |
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| Related Swiss-prot | P07824 |
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| [2] |
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| Comments | X-ray crystallography (3.0 Angstroms) |
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| Medline ID | 97410344 |
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| PubMed ID | 9265637 |
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| Journal | Biochemistry |
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| Year | 1997 |
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| Volume | 36 |
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| Pages | 10558-65 |
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| Authors | Scolnick LR, Kanyo ZF, Cavalli RC, Ash DE, Christianson DW |
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| Title | Altering the binuclear manganese cluster of arginase diminishes thermostability and catalytic function. |
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| Related PDB | 2rla,3rla,4rla,5rla |
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| Related Swiss-prot | P07824 |
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| [3] |
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| PubMed ID | 9507056 |
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| Journal | Biochim Biophys Acta |
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| Year | 1998 |
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| Volume | 1382 |
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| Pages | 23-37 |
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| Authors | Perozich J, Hempel J, Morris SM Jr |
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| Title | Roles of conserved residues in the arginase family. |
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| [4] |
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| PubMed ID | 9622506 |
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| Journal | Biochemistry |
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| Year | 1998 |
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| Volume | 37 |
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| Pages | 8539-50 |
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| Authors | Khangulov SV, Sossong TM Jr, Ash DE, Dismukes GC |
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| 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. |
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| [5] |
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| Comments | X-ray crystallography (2.4 Angstroms) |
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| Medline ID | 99216539 |
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| PubMed ID | 10196128 |
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| Journal | Structure Fold Des |
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| Year | 1999 |
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| Volume | 7 |
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| Pages | 435-48 |
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| Authors | Bewley MC, Jeffrey PD, Patchett ML, Kanyo ZF, Baker EN |
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| 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. |
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| Related PDB | 1cev,2cev,3cev,4cev,5cev |
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| Related Swiss-prot | P53608 |
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| [6] |
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| Comments | X-ray crystallography (1.7 Angstroms) |
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| PubMed ID | 10542097 |
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| Journal | Nat Struct Biol |
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| Year | 1999 |
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| Volume | 6 |
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| Pages | 1043-7 |
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| Authors | Cox JD, Kim NN, Traish AM, Christianson DW |
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| Title | Arginase-boronic acid complex highlights a physiological role in erectile function. |
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| Related PDB | 1d3v |
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| Related Swiss-prot | P07824 |
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| [7] |
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| PubMed ID | 10643656 |
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| Journal | J Inorg Biochem |
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| Year | 1999 |
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| Volume | 77 |
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| Pages | 163-7 |
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| Authors | Carvajal N, Salas M, Lopez V, Uribe E, Herrera P, Cerpa J, Fuentes M |
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| Title | Manganese-dependent inhibition of human liver arginase by borate. |
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| [8] |
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| PubMed ID | 10693141 |
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| Journal | Met Ions Biol Syst |
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| Year | 2000 |
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| Volume | 37 |
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| Pages | 407-28 |
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| Authors | Ash DE, Cox JD, Christianson DW |
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| Title | Arginase: a binuclear manganese metalloenzyme. |
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| [9] |
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| PubMed ID | 10872443 |
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| Journal | Annu Rev Biochem |
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| Year | 1999 |
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| Volume | 68 |
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| Pages | 33-57 |
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| Authors | Christianson DW, Cox JD |
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| Title | Catalysis by metal-activated hydroxide in zinc and manganese metalloenzymes. |
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| [10] |
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| Comments | X-ray crystallography (2.3 Angstroms) |
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| PubMed ID | 11258879 |
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| Journal | Biochemistry |
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| Year | 2001 |
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| Volume | 40 |
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| Pages | 2678-88 |
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| Authors | Kim NN, Cox JD, Baggio RF, Emig FA, Mistry SK, Harper SL, Speicher DW, Morris SM Jr, Ash DE, Traish A, Christianson DW |
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| 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. |
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| Related PDB | 1hq5 |
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| [11] |
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| Comments | X-ray crystallography |
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| PubMed ID | 11258880 |
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| Journal | Biochemistry |
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| Year | 2001 |
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| Volume | 40 |
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| Pages | 2689-701 |
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| Authors | Cox JD, Cama E, Colleluori DM, Pethe S, Boucher JL, Mansuy D, Ash DE, Christianson DW |
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| Title | Mechanistic and metabolic inferences from the binding of substrate analogues and products to arginase. |
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| Related PDB | 1hqf,1hqg,1hqh |
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| [12] |
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| Comments | X-ray crystallography |
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| PubMed ID | 11278703 |
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| Journal | J Biol Chem |
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| Year | 2001 |
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| Volume | 276 |
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| Pages | 14242-8 |
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| Authors | Lavulo LT, Sossong TM Jr, Brigham-Burke MR, Doyle ML, Cox JD, Christianson DW, Ash DE |
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| Title | Subunit-subunit interactions in trimeric arginase. Generation of active monomers by mutation of a single amino acid. |
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| [13] |
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| PubMed ID | 11470277 |
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| Journal | FEBS Lett |
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| Year | 2001 |
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| Volume | 501 |
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| Pages | 161-5 |
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| Authors | Sabio G, Mora A, Rangel MA, Quesada A, Marcos CF, Alonso JC, Soler G, Centeno F |
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| Title | Glu-256 is a main structural determinant for oligomerisation of human arginase I. |
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| [14] |
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| PubMed ID | 11883902 |
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| Journal | Arch Biochem Biophys |
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| Year | 2002 |
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| Volume | 399 |
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| Pages | 49-55 |
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| Authors | Lavulo LT, Emig FA, Ash DE |
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| Title | Functional consequences of the G235R mutation in liver arginase leading to hyperargininemia. |
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| [15] |
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| PubMed ID | 11904441 |
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| Journal | Proc Natl Acad Sci U S A |
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| Year | 2002 |
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| Volume | 99 |
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| Pages | 3914-9 |
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| Authors | Huang J, DeGraves FJ, Lenz SD, Gao D, Feng P, Li D, Schlapp T, Kaltenboeck B |
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| Title | The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease. |
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| [16] |
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| PubMed ID | 12679340 |
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| Journal | J Biol Chem |
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| Year | 2003 |
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| Volume | 278 |
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| Pages | 21550-8 |
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| Authors | El Alami M, Dubois E, Oudjama Y, Tricot C, Wouters J, Stalon V, Messenguy F |
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| Title | Yeast epiarginase regulation, an enzyme-enzyme activity control: identification of residues of ornithine carbamoyltransferase and arginase responsible for enzyme catalytic and regulatory activities. |
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| [17] |
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| PubMed ID | 12820884 |
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| Journal | Biochemistry |
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| Year | 2003 |
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| Volume | 42 |
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| Pages | 7748-58 |
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| Authors | Cama E, Emig FA, Ash DE, Christianson DW |
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| Title | Structural and functional importance of first-shell metal ligands in the binuclear manganese cluster of arginase I. |
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| [18] |
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| PubMed ID | 12859189 |
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| Journal | Biochemistry |
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| Year | 2003 |
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| Volume | 42 |
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| Pages | 8445-51 |
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| Authors | Cama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW |
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| Title | Human arginase II: crystal structure and physiological role in male and female sexual arousal. |
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| [19] |
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| PubMed ID | 14570477 |
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| Journal | J Am Chem Soc |
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| Year | 2003 |
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| Volume | 125 |
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| Pages | 13052-7 |
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| Authors | Cama E, Shin H, Christianson DW |
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| Title | Design of amino acid sulfonamides as transition-state analogue inhibitors of arginase. |
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| 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)
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| created | updated |
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| 2003-02-03 | 2009-02-26 |
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