EzCatDB: S00254

DB codeS00254
RLCP classification5.12.1132000.75
CATH domainDomain 13.30.1360.20Catalytic domain
E.C.4.2.1.96
CSA1dco
MACiEM0073


Enzyme Name
Swiss-protKEGG

P61459
Protein namePterin-4-alpha-carbinolamine dehydratase4a-hydroxytetrahydrobiopterin dehydratase
4alpha-hydroxy-tetrahydropterin dehydratase
pterin-4alpha-carbinolamine dehydratase
4a-hydroxytetrahydrobiopterin hydro-lyase
SynonymsPHS
EC 4.2.1.96
4-alpha-hydroxy-tetrahydropterin dehydratase
Phenylalanine hydroxylase-stimulating protein
Pterin carbinolamine dehydratase
PCD
Dimerization cofactor of hepatocyte nuclear factor 1-alpha
Dimerization cofactor of HNF1
DCoH


Swiss-prot:Accession NumberP61459
Entry namePHS_RAT
Activity(6R)-6-(L-erythro-1,2-dihydroxypropyl)- 5,6,7,8-tetrahydro-4a-hydroxypterin = (6R)-6-(L-erythro-1,2- dihydroxypropyl)-7,8-dihydro-6H-pterin + H(2)O.
SubunitHomotetramer or homodimer.
Subcellular locationCytoplasm. Nucleus. Note=Cytoplasmic and/or nuclear.
Cofactor


SubstratesProducts
KEGG-idC15522C00268C00001
Compound4a-Hydroxytetrahydrobiopterin6,7-DihydrobiopterinH2O
Typeamine group,aromatic ring (with nitrogen atoms),carbohydrateamide group,amine group,aromatic ring (with nitrogen atoms),carbohydrateH2O
1dchAUnboundUnbound
1dchBUnboundUnbound
1dchCUnboundUnbound
1dchDUnboundUnbound
1dchEUnboundUnbound
1dchFUnboundUnbound
1dchGUnboundUnbound
1dchHUnboundUnbound
1dcoAUnboundUnbound
1dcoBUnboundUnbound
1dcoCUnboundUnbound
1dcoDUnboundUnbound
1dcoEUnboundUnbound
1dcoFUnboundUnbound
1dcoGUnboundUnbound
1dcoHUnboundUnbound
1dcpAUnboundBound:HBI
1dcpBUnboundBound:HBI
1dcpCUnboundBound:HBI
1dcpDUnboundBound:HBI
1dcpEUnboundBound:HBI
1dcpFUnboundBound:HBI
1dcpGUnboundBound:HBI
1dcpHUnboundBound:HBI

Active-site residues
resource
literature [7], [11] & [14]
pdbCatalytic residuesMain-chain involved in catalysis
1dchAGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dchBGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dchCGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dchDGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dchEGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dchFGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dchGGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dchHGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcoAGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcoBGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcoCGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcoDGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcoEGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcoFGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcoGGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcoHGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcpAGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcpBGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcpCGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcpDGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcpEGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcpFGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcpGGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81
1dcpHGLU 58;HIS 62;HIS 63;HIS 80;ASP 89
HIS 80;GLU 81

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[7]p.558
[9]Scheme 2, p.861-8632
[11]Fig.6, p.1969-1970
[14]Fig.7, p.11252-11254
[15]Fig.4, p.14305

references
[1]
CommentsVARIANT HYPERPHENYLALANINEMIA ARG-81.
Medline ID93356171
PubMed ID8352282
JournalAm J Hum Genet
Year1993
Volume53
Pages768-74
AuthorsCitron BA, Kaufman S, Milstien S, Naylor EW, Greene CL, Davis MD
TitleMutation in the 4a-carbinolamine dehydratase gene leads to mild hyperphenylalaninemia with defective cofactor metabolism.
Related Swiss-protP61459
[2]
PubMed ID8504250
JournalCurr Opin Genet Dev
Year1993
Volume3
Pages246-53
AuthorsHansen LP, Crabtree GR
TitleRegulation of the HNF-1 homeodomain proteins by DCoH.
[3]
PubMed ID7727440
JournalBiochemistry
Year1995
Volume34
Pages5801-10
AuthorsRebrin I, Bailey SW, Boerth SR, Ardell MD, Ayling JE
TitleCatalytic characterization of 4a-hydroxytetrahydropterin dehydratase.
[4]
CommentsX-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
Medline ID95262643
PubMed ID7744010
JournalEMBO J
Year1995
Volume14
Pages2034-42
AuthorsFicner R, Sauer UH, Stier G, Suck D
TitleThree-dimensional structure of the bifunctional protein PCD/DCoH, a cytoplasmic enzyme interacting with transcription factor HNF1.
Related Swiss-protP61459
[5]
PubMed ID7635153
JournalEur J Biochem
Year1995
Volume231
Pages414-23
AuthorsKoster S, Thony B, Macheroux P, Curtius HC, Heizmann CW, Pfleiderer W, Ghisla S
TitleHuman pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1 alpha. Characterization and kinetic analysis of wild-type and mutant enzymes.
[6]
PubMed ID8001680
JournalFEBS Lett
Year1995
Volume357
Pages62-4
AuthorsFicner R, Sauer UH, Ceska TA, Stier G, Suck D
TitleCrystallization and preliminary crystallographic studies of recombinant dimerization cofactor of transcription factor HNF1/pterin-4 alpha-carbinolamine dehydratase from liver.
[7]
CommentsX-ray crystallography
PubMed ID7725101
JournalScience
Year1995
Volume268
Pages556-9
AuthorsEndrizzi JA, Cronk JD, Wang W, Crabtree GR, Alber T
TitleCrystal structure of DCoH, a bifunctional, protein-binding transcriptional coactivator.
Related PDB1dch
[8]
PubMed ID8590013
JournalStructure
Year1995
Volume3
Pages531-4
AuthorsKim JL, Burley SK
TitlePCD/DCoH: more than a second molecular saddle.
[9]
PubMed ID8944775
JournalEur J Biochem
Year1996
Volume241
Pages858-64
AuthorsKoster S, Stier G, Ficner R, Holzer M, Curtius HC, Suck D, Ghisla S
TitleLocation of the active site and proposed catalytic mechanism of pterin-4a-carbinolamine dehydratase.
[10]
PubMed ID8682201
JournalFEBS Lett
Year1996
Volume389
Pages35-9
AuthorsSuck D, Ficner R
TitleStructure and function of PCD/DCoH, an enzyme with regulatory properties.
[11]
CommentsX-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
Medline ID97052967
PubMed ID8897596
JournalProtein Sci
Year1996
Volume5
Pages1963-72
AuthorsCronk JD, Endrizzi JA, Alber T
TitleHigh-resolution structures of the bifunctional enzyme and transcriptional coactivator DCoH and its complex with a product analogue.
Related PDB1dco,1dcp
Related Swiss-protP61459
[12]
PubMed ID8995521
JournalJ Mol Biol
Year1997
Volume265
Pages20-9
AuthorsRhee KH, Stier G, Becker PB, Suck D, Sandaltzopoulos R
TitleThe bifunctional protein DCoH modulates interactions of the homeodomain transcription factor HNF1 with nucleic acids.
[13]
PubMed ID9391049
JournalProc Natl Acad Sci U S A
Year1997
Volume94
Pages13469-74
AuthorsJohnen G, Kaufman S
TitleStudies on the enzymatic and transcriptional activity of the dimerization cofactor for hepatocyte nuclear factor 1.
[14]
PubMed ID9698371
JournalBiochemistry
Year1998
Volume37
Pages11246-54
AuthorsRebrin I, Thony B, Bailey SW, Ayling JE
TitleStereospecificity and catalytic function of histidine residues in 4a-hydroxy-tetrahydropterin dehydratase/DCoH.
[15]
PubMed ID9894810
JournalBiol Chem
Year1998
Volume379
Pages1427-32
AuthorsKoster S, Stier G, Kubasch N, Curtius HC, Ghisla S
TitlePterin-4a-carbinolamine dehydratase from Pseudomonas aeruginosa: characterization, catalytic mechanism and comparison to the human enzyme.
[16]
PubMed ID10966642
JournalNat Struct Biol
Year2000
Volume7
Pages744-8
AuthorsRose RB, Bayle JH, Endrizzi JA, Cronk JD, Crabtree GR, Alber T
TitleStructural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha.

comments
According to the literature, the true substrate and products are 4a-hydroxy-tetrahydrobiopterin and dihydrobiopterin (C00268 in KEGG), plus water, although different compounds are annotated in the Swiss-prot and KEGG data.
According to the literature [11] & [14], the catalytic reaction seems to proceed as follows:
(1) The catalytic dyad, Glu58-His63, acts as a general base, which abstracts the N8 proton on the opposite side of the eliminated group, 4a-hydroxyl group, leading to the formation of an oxyanion, with the negative charge on the O4 atom next to the eliminated group. The negative charge is stabilized by the mainchain amide groups of His80 and Glu81.
(2) A general acid should protonate the eliminated, 4a-hydroxyl group, to facilitate the elimination reaction. For 4a(R)-hydroxyl group, the catalytic dyad, Asp89-His62, acts as the general acid, whilst His80 functions for the 4a(S)-enantiomer (see [14]). (The 4a-carbon is tetrahedral in the substrate.)
(3) The remaining proton at N5 must be abstracted by a solvent water, considering the active-site structure (see [14]). This protonation leads to the protonation to the N8 atom by His63, releasing the final product.

createdupdated
2004-04-042009-02-26
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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