DB code: S00458

RLCP classification	1.15.36030.52 : Hydrolysis
CATH domain	3.90.190.10 : Protein-Tyrosine Phosphatase; Chain A	Catalytic domain
E.C.	3.1.3.16 3.1.3.48
CSA
M-CSA
MACiE

CATH domain	Related DB codes (homologues)
3.90.190.10 : Protein-Tyrosine Phosphatase; Chain A	M00169 D00154 M00149 T00221

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	RefSeq	Pfam
P51452	Dual specificity protein phosphatase 3	EC 3.1.3.48 EC 3.1.3.16 Dual specificity protein phosphatase VHR	NP_004081.1 (Protein) NM_004090.3 (DNA/RNA sequence)	PF00782 (DSPc) [Graphical View]

KEGG enzyme name
phosphoprotein phosphatase (EC 3.1.3.16 ) protein phosphatase-1 (EC 3.1.3.16 ) protein phosphatase-2A (EC 3.1.3.16 ) protein phosphatase-2B (EC 3.1.3.16 ) protein phosphatase-2C (EC 3.1.3.16 ) protein D phosphatase (EC 3.1.3.16 ) phosphospectrin phosphatase (EC 3.1.3.16 ) casein phosphatase (EC 3.1.3.16 ) Aspergillus awamori acid protein phosphatase (EC 3.1.3.16 ) calcineurin (EC 3.1.3.16 ) phosphatase 2A (EC 3.1.3.16 ) phosphatase 2B (EC 3.1.3.16 ) phosphatase II (EC 3.1.3.16 ) phosphatase IB (EC 3.1.3.16 ) phosphatase C-II (EC 3.1.3.16 ) polycation modulated (PCM-) phosphatase (EC 3.1.3.16 ) phosphopyruvate dehydrogenase phosphatase (EC 3.1.3.16 ) phosphatase SP (EC 3.1.3.16 ) branched-chain alpha-keto acid dehydrogenase phosphatase (EC 3.1.3.16 ) BCKDH phosphatase (EC 3.1.3.16 ) 3-hydroxy 3-methylglutaryl coenzymeA reductase phosphatase (EC 3.1.3.16 ) HMG-CoA reductase phosphatase (EC 3.1.3.16 ) phosphatase H-II (EC 3.1.3.16 ) phosphatase III (EC 3.1.3.16 ) phosphatase I (EC 3.1.3.16 ) protein phosphatase (EC 3.1.3.16 ) phosphatase IV (EC 3.1.3.16 ) protein-tyrosine-phosphatase (EC 3.1.3.48 ) phosphotyrosine phosphatase (EC 3.1.3.48 ) phosphoprotein phosphatase (phosphotyrosine) (EC 3.1.3.48 ) phosphotyrosine histone phosphatase (EC 3.1.3.48 ) protein phosphotyrosine phosphatase (EC 3.1.3.48 ) tyrosylprotein phosphatase (EC 3.1.3.48 ) phosphotyrosine protein phosphatase (EC 3.1.3.48 ) phosphotyrosylprotein phosphatase (EC 3.1.3.48 ) tyrosine O-phosphate phosphatase (EC 3.1.3.48 ) PPT-phosphatase (EC 3.1.3.48 ) PTPase (EC 3.1.3.48 ) [phosphotyrosine]protein phosphatase (EC 3.1.3.48 ) PTP-phosphatase (EC 3.1.3.48 )

KEGG enzyme name

phosphoprotein phosphatase
(EC 3.1.3.16 )
protein phosphatase-1
(EC 3.1.3.16 )
protein phosphatase-2A
(EC 3.1.3.16 )
protein phosphatase-2B
(EC 3.1.3.16 )
protein phosphatase-2C
(EC 3.1.3.16 )
protein D phosphatase
(EC 3.1.3.16 )
phosphospectrin phosphatase
(EC 3.1.3.16 )
casein phosphatase
(EC 3.1.3.16 )
Aspergillus awamori acid protein phosphatase
(EC 3.1.3.16 )
calcineurin
(EC 3.1.3.16 )
phosphatase 2A
(EC 3.1.3.16 )
phosphatase 2B
(EC 3.1.3.16 )
phosphatase II
(EC 3.1.3.16 )
phosphatase IB
(EC 3.1.3.16 )
phosphatase C-II
(EC 3.1.3.16 )
polycation modulated (PCM-) phosphatase
(EC 3.1.3.16 )
phosphopyruvate dehydrogenase phosphatase
(EC 3.1.3.16 )
phosphatase SP
(EC 3.1.3.16 )
branched-chain alpha-keto acid dehydrogenase phosphatase
(EC 3.1.3.16 )
BCKDH phosphatase
(EC 3.1.3.16 )
3-hydroxy 3-methylglutaryl coenzymeA reductase phosphatase
(EC 3.1.3.16 )
HMG-CoA reductase phosphatase
(EC 3.1.3.16 )
phosphatase H-II
(EC 3.1.3.16 )
phosphatase III
(EC 3.1.3.16 )
phosphatase I
(EC 3.1.3.16 )
protein phosphatase
(EC 3.1.3.16 )
phosphatase IV
(EC 3.1.3.16 )
protein-tyrosine-phosphatase
(EC 3.1.3.48 )
phosphotyrosine phosphatase
(EC 3.1.3.48 )
phosphoprotein phosphatase (phosphotyrosine)
(EC 3.1.3.48 )
phosphotyrosine histone phosphatase
(EC 3.1.3.48 )
protein phosphotyrosine phosphatase
(EC 3.1.3.48 )
tyrosylprotein phosphatase
(EC 3.1.3.48 )
phosphotyrosine protein phosphatase
(EC 3.1.3.48 )
phosphotyrosylprotein phosphatase
(EC 3.1.3.48 )
tyrosine O-phosphate phosphatase
(EC 3.1.3.48 )
PPT-phosphatase
(EC 3.1.3.48 )
PTPase
(EC 3.1.3.48 )
[phosphotyrosine]protein phosphatase
(EC 3.1.3.48 )
PTP-phosphatase
(EC 3.1.3.48 )

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
P51452	DUS3_HUMAN	Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate. A phosphoprotein + H(2)O = a protein + phosphate.

KEGG Pathways
Map code	Pathways	E.C.

Compound table
	Cofactors		Substrates			Products			Intermediates
KEGG-id	C00076	C00391	C00562	C01167	C00001	C00017	C00585	C00009
E.C.	3.1.3.16	3.1.3.16	3.1.3.16	3.1.3.48	3.1.3.16 3.1.3.48	3.1.3.16	3.1.3.48	3.1.3.16 3.1.3.48
Compound	Calcium	Calmodulin	Phosphoprotein	Protein tyrosine phosphate	H2O	Protein	Protein tyrosine	Orthophosphate
Type	divalent metal (Ca2+, Mg2+)	peptide/protein	peptide/protein,phosphate group/phosphate ion	aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion	H2O	peptide/protein	aromatic ring (only carbon atom),peptide/protein	phosphate group/phosphate ion
ChEBI	29108 29108				15377 15377			26078 26078
PubChem	271 271				22247451 962 22247451 962			1004 22486802 1004 22486802

1vhrA	Unbound	Unbound	Analogue:EPE	Unbound		Unbound	Unbound	Unbound
1vhrB	Unbound	Unbound	Unbound	Unbound		Unbound	Unbound	Analogue:SO4
1f5dA	Unbound	Unbound	Bound:PTR (chain D)	Bound:PTR (chain D)		Unbound	Unbound	Unbound
1j4xA	Unbound	Unbound	Bound:PTR (chain D)	Bound:PTR (chain D)		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

1vhrA	ASP 92;CYS 124;ARG 130;SER 131			ARG 125;GLU 126;TYR 128;SER 129;ARG 130
1vhrB	ASP 92;CYS 124;ARG 130;SER 131			ARG 125;GLU 126;TYR 128;SER 129;ARG 130
1f5dA	ASP 92; ;ARG 130;SER 131			ARG 125;GLU 126;TYR 128;SER 129;ARG 130	mutant C124S
1j4xA	ASP 92; ;ARG 130;SER 131			ARG 125;GLU 126;TYR 128;SER 129;ARG 130	mutant C124S

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[1]	Fig.4, p.5913-5914	2
[2]	Fig.2, Fig.3, p.7088-7091
[3]	p.1330
[5]	Scheme.1, p.27574	4
[6]	p.3011

References
[1]
Resource
Comments
Medline ID
PubMed ID	7597052
Journal	Proc Natl Acad Sci U S A
Year	1995
Volume	92
Pages	5910-4
Authors	Denu JM, Dixon JE
Title	A catalytic mechanism for the dual-specific phosphatases.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID	8679534
Journal	Biochemistry
Year	1996
Volume	35
Pages	7084-92
Authors	Hengge AC, Denu JM, Dixon JE
Title	Transition-state structures for the native dual-specific phosphatase VHR and D92N and S131A mutants. Contributions to the driving force for catalysis.
Related PDB
Related UniProtKB
[3]
Resource
Comments	X-ray crystallography (2.1 Angstroms)
Medline ID	96243129
PubMed ID	8650541
Journal	Science
Year	1996
Volume	272
Pages	1328-1331
Authors	Yuvaniyama J, Denu JM, Dixon JE, Saper MA
Title	Crystal structure of the dual specificity protein phosphatase VHR.
Related PDB	1vhr
Related UniProtKB	P51452
[4]
Resource
Comments
Medline ID
PubMed ID	8969212
Journal	J Biol Chem
Year	1996
Volume	271
Pages	33486-92
Authors	Wiland AM, Denu JM, Mourey RJ, Dixon JE
Title	Purification and kinetic characterization of the mitogen-activated protein kinase phosphatase rVH6.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID	11346639
Journal	J Biol Chem
Year	2001
Volume	276
Pages	27568-74
Authors	Kim JH, Shin DY, Han MH, Choi MU
Title	Mutational and kinetic evaluation of conserved His-123 in dual specificity protein-tyrosine phosphatase vaccinia H1-related phosphatase: participation of Tyr-78 and Thr-73 residues in tuning the orientation of His-123.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID	11863439
Journal	Biochemistry
Year	2002
Volume	41
Pages	3009-17
Authors	Schumacher MA, Todd JL, Rice AE, Tanner KG, Denu JM
Title	Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein Phosphatase.
Related PDB	1f5d 1j4x
Related UniProtKB

Comments
According to the papers [1] & [2], Cys124 functions as nucleophile, which attacks the phosphate on a phosphotyrosine to form a thiol-phosphate intermediate, whilst Asp92 serves a role as general acid, protonating the phenolate leaving group in the first step. This intermediate formation is rate-limiting in the reaction mechanism [1]. In the second step, the same acidic residue, Asp92, might acts as the general base, which would activate a water molecule by proton abstraction, and the activated water would hydrolyze the thiol-phosphate [1]. In this breakdown of the phosphoenzyme, Ser131 facilitates the hydrolysis, by its hydroxyl group interacting with the catalytic thiol of Cys124 [1]. Moreover, the residue corresponding to Arg130 seems to be critical for transition-state stabilization [1]. Along with the sidechain of Arg130, mainchain amide groups of loop 125-130 seems to stabilize the phosphate group. The paper [2] indicated that the catalytic mechanism of this enzyme involved a highly dissociative transition state (SN1-like reaction), in which bond cleavage and protonation of the leaving group by the acid seem well advanced.

Comments

According to the papers [1] & [2], Cys124 functions as nucleophile, which attacks the phosphate on a phosphotyrosine to form a thiol-phosphate intermediate, whilst Asp92 serves a role as general acid, protonating the phenolate leaving group in the first step. This intermediate formation is rate-limiting in the reaction mechanism [1].
In the second step, the same acidic residue, Asp92, might acts as the general base, which would activate a water molecule by proton abstraction, and the activated water would hydrolyze the thiol-phosphate [1]. In this breakdown of the phosphoenzyme, Ser131 facilitates the hydrolysis, by its hydroxyl group interacting with the catalytic thiol of Cys124 [1].
Moreover, the residue corresponding to Arg130 seems to be critical for transition-state stabilization [1]. Along with the sidechain of Arg130, mainchain amide groups of loop 125-130 seems to stabilize the phosphate group.
The paper [2] indicated that the catalytic mechanism of this enzyme involved a highly dissociative transition state (SN1-like reaction), in which bond cleavage and protonation of the leaving group by the acid seem well advanced.

Created	Updated
2002-07-09	2009-02-26