DB code: S00393

RLCP classification	1.15.36100.51 : Hydrolysis
CATH domain	3.40.250.10 : Oxidized Rhodanese; domain 1	Catalytic domain
E.C.	3.1.3.48
CSA
M-CSA
MACiE

CATH domain	Related DB codes (homologues)

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	RefSeq	Pfam
P30304	M-phase inducer phosphatase 1	EC 3.1.3.48 Dual specificity phosphatase Cdc25A	NP_001780.2 (Protein) NM_001789.2 (DNA/RNA sequence) NP_963861.1 (Protein) NM_201567.1 (DNA/RNA sequence)	PF06617 (M-inducer_phosp) PF00581 (Rhodanese) [Graphical View]
P30305	M-phase inducer phosphatase 2	EC 3.1.3.48 Dual specificity phosphatase Cdc25B	NP_004349.1 (Protein) NM_004358.3 (DNA/RNA sequence) NP_068658.1 (Protein) NM_021872.2 (DNA/RNA sequence) NP_068659.1 (Protein) NM_021873.2 (DNA/RNA sequence)	PF06617 (M-inducer_phosp) PF00581 (Rhodanese) [Graphical View]

KEGG enzyme name
protein-tyrosine-phosphatase phosphotyrosine phosphatase phosphoprotein phosphatase (phosphotyrosine) phosphotyrosine histone phosphatase protein phosphotyrosine phosphatase tyrosylprotein phosphatase phosphotyrosine protein phosphatase phosphotyrosylprotein phosphatase tyrosine O-phosphate phosphatase PPT-phosphatase PTPase [phosphotyrosine]protein phosphatase PTP-phosphatase

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
P30304	MPIP1_HUMAN	Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.	Interacts with CCNB1/cyclin B1. Interacts with YWHAE/14- 3-3 epsilon when phosphorylated. Interacts with CUL1 specifically when CUL1 is neddylated and active. Interacts with BTRC/BTRCP1 and FBXW11/BTRCP2. Interactions with CUL1, BTRC and FBXW11 are enhanced upon DNA damage.
P30305	MPIP2_HUMAN	Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.		Centrosome.

KEGG Pathways
Map code	Pathways	E.C.

Compound table
	Substrates		Products		Intermediates
KEGG-id	C01167	C00001	C00585	C00009
E.C.
Compound	Protein tyrosine phosphate	H2O	Protein tyrosine	Orthophosphate
Type	aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion	H2O	aromatic ring (only carbon atom),peptide/protein	phosphate group/phosphate ion
ChEBI		15377 15377		26078 26078
PubChem		22247451 962 22247451 962		1004 22486802 1004 22486802

1c25A	Unbound		Unbound	Unbound
1cwrA	Unbound		Unbound	Unbound
1qb0A	Unbound		Unbound	Analogue:SO4

Reference for Active-site residues
resource	references	E.C.
literature [2],[3]

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

1c25A	CYS 430;GLU 431;SER 433;ARG 436
1cwrA	CYS 473;GLU 474;SER 476;ARG 479
1qb0A	CYS 473;GLU 474;SER 476;ARG 479

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[1]	p.7-8
[2]	p.5119-5120
[3]	p.620-621
[4]	p.561-564
[6]	p.10781
[7]	Fig.4, Fig.5	3
[9]	Fig.9	4

References
[1]
Resource
Comments
Medline ID
PubMed ID	8771191
Journal	Protein Sci
Year	1996
Volume	5
Pages	5-12
Authors	Eckstein JW, Beer-Romero P, Berdo I
Title	Identification of an essential acidic residue in Cdc25 protein phosphatase and a general three-dimensional model for a core region in protein phosphatases.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID	8617791
Journal	J Biol Chem
Year	1996
Volume	271
Pages	5118-24
Authors	Xu X, Burke SP
Title	Roles of active site residues and the NH2-terminal domain in the catalysis and substrate binding of human Cdc25.
Related PDB
Related UniProtKB
[3]
Resource
Comments	X-ray crystallography (2.3 Angstroms)
Medline ID
PubMed ID	9604936
Journal	Cell
Year	1998
Volume	93
Pages	617-625
Authors	Fauman EB, Cogswell JP, Lovejoy B, Rocque WJ, Holmes W, Montana VG, Piwnica-Worms H, Rink MJ, Saper MA
Title	Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A.
Related PDB	1c25
Related UniProtKB	P30304
[4]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	10543950
Journal	J Mol Biol
Year	1999
Volume	293
Pages	559-568
Authors	Reynolds RA, Yem AW, Wolfe CL, Deibel MR Jr, Chidester CG, Watenpaugh KD
Title	Crystal structure of the catalytic subunit of Cdc25B required for G2/M phase transition of the cell cycle.
Related PDB	1cwr 1qb0
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID	10788330
Journal	J Mol Biol
Year	2000
Volume	298
Pages	691-704
Authors	Bordo D, Deriu D, Colnaghi R, Carpen A, Pagani S, Bolognesi M
Title	The crystal structure of a sulfurtransferase from Azotobacter vinelandii highlights the evolutionary relationship between the rhodanese and phosphatase enzyme families.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID	10978163
Journal	Biochemistry
Year	2000
Volume	39
Pages	10781-9
Authors	Chen W, Wilborn M, Rudolph J
Title	Dual-specific Cdc25B phosphatase: in search of the catalytic acid.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID	11805096
Journal	J Biol Chem
Year	2002
Volume	277
Pages	11190-200
Authors	McCain DF, Catrina IE, Hengge AC, Zhang ZY
Title	The catalytic mechanism of Cdc25A phosphatase.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID	12151332
Journal	EMBO Rep
Year	2002
Volume	3
Pages	741-6
Authors	Bordo D, Bork P
Title	The rhodanese/Cdc25 phosphatase superfamily. Sequence-structure-function relations.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID	12463761
Journal	Biochemistry
Year	2002
Volume	41
Pages	14613-23
Authors	Rudolph J
Title	Catalytic mechanism of Cdc25.
Related PDB
Related UniProtKB

Comments
According to the literature [3], Cys430 plays a catalytic role, with its thiolate ion, as nucleophile. Whilst the paper [1] identified Asp383 (PDB; 1c25) as the catalytic acid, another paper [3] reported that Glu431 may act as a general acid. However, more recent papers, [6], [7] & [9], mentioned alternative catalytic mechanisms. The literature [6] mentioned that the catalytic acid does not seem to be located within the enzym itself, and may lie on its protein substrate. The paper [7] suggested the two possible catalytic mechanisms dependent on the pKa of the leaving group. In both mechanisms, for the substrates with lower leaving group pKa, the catalysis can proceed without catalytic acid. In contrast, in the first catalytic mechanism model, the attainment of the transition state is so slow that protonation of the leaving group occurs at or before the transition state. On the other hand, in the second model, the conformational change will bring Glu431 (PDB; 1c25) into proper position to serve as a catalytic acid for the higher leaving group pKa substrates. The most recent literature [9] proposed another catalytic mechanism, in which the monoprotonated phosphate of the protein substrate provides the critical proton to the leaving group. In this proposed mechanism, the residue corresponding to Glu431 (PDB; 1c25) functions as a catalytic base in the transfer of the proton from the phosphate to the leaving group.

Comments

According to the literature [3], Cys430 plays a catalytic role, with its thiolate ion, as nucleophile.
Whilst the paper [1] identified Asp383 (PDB; 1c25) as the catalytic acid, another paper [3] reported that Glu431 may act as a general acid. However, more recent papers, [6], [7] & [9], mentioned alternative catalytic mechanisms.
The literature [6] mentioned that the catalytic acid does not seem to be located within the enzym itself, and may lie on its protein substrate.
The paper [7] suggested the two possible catalytic mechanisms dependent on the pKa of the leaving group. In both mechanisms, for the substrates with lower leaving group pKa, the catalysis can proceed without catalytic acid. In contrast, in the first catalytic mechanism model, the attainment of the transition state is so slow that protonation of the leaving group occurs at or before the transition state. On the other hand, in the second model, the conformational change will bring Glu431 (PDB; 1c25) into proper position to serve as a catalytic acid for the higher leaving group pKa substrates.
The most recent literature [9] proposed another catalytic mechanism, in which the monoprotonated phosphate of the protein substrate provides the critical proton to the leaving group. In this proposed mechanism, the residue corresponding to Glu431 (PDB; 1c25) functions as a catalytic base in the transfer of the proton from the phosphate to the leaving group.

Created	Updated
2002-09-27	2009-02-26