DB code: S00254

RLCP classification 5.12.1132000.75 : Elimination
CATH domain 3.30.1360.20 : Gyrase A; domain 2 Catalytic domain
E.C. 4.2.1.96
CSA 1dco
M-CSA 1dco
MACiE M0073

CATH domain Related DB codes (homologues)

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P61459 Pterin-4-alpha-carbinolamine dehydratase
PHS
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
NP_001007602.1 (Protein)
NM_001007601.1 (DNA/RNA sequence)
PF01329 (Pterin_4a)
[Graphical View]

KEGG enzyme name
4a-hydroxytetrahydrobiopterin dehydratase
4alpha-hydroxy-tetrahydropterin dehydratase
pterin-4alpha-carbinolamine dehydratase
4a-hydroxytetrahydrobiopterin hydro-lyase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P61459 PHS_RAT (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. Homotetramer or homodimer. Cytoplasm. Nucleus. Note=Cytoplasmic and/or nuclear.

KEGG Pathways
Map code Pathways E.C.

Compound table
Substrates Products Intermediates
KEGG-id C15522 C00268 C00001
E.C.
Compound 4a-Hydroxytetrahydrobiopterin 6,7-Dihydrobiopterin H2O
Type amine group,aromatic ring (with nitrogen atoms),carbohydrate amide group,amine group,aromatic ring (with nitrogen atoms),carbohydrate H2O
ChEBI 15377
PubChem 46173804
133246
22247451
962
1dchA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dchB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dchC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dchD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dchE Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dchF Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dchG Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dchH Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcoA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcoB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcoC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcoD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcoE Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcoF Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcoG Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcoH Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound
1dcpA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:HBI
1dcpB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:HBI
1dcpC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:HBI
1dcpD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:HBI
1dcpE Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:HBI
1dcpF Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:HBI
1dcpG Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:HBI
1dcpH Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:HBI

Reference for Active-site residues
resource references E.C.
literature [7], [11] & [14]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1dchA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dchB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dchC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dchD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dchE Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dchF Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dchG Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dchH Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcoA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcoB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcoC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcoD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcoE Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcoF Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcoG Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcoH Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcpA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcpB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcpC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcpD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcpE Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcpF Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcpG Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81
1dcpH Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 58;HIS 62;HIS 63;HIS 80;ASP 89 HIS 80;GLU 81

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[7]
p.558
[9]
Scheme 2, p.861-863 2
[11]
Fig.6, p.1969-1970
[14]
Fig.7, p.11252-11254
[15]
Fig.4, p.1430 5

References
[1]
Resource
Comments VARIANT HYPERPHENYLALANINEMIA ARG-81.
Medline ID 93356171
PubMed ID 8352282
Journal Am J Hum Genet
Year 1993
Volume 53
Pages 768-74
Authors Citron BA, Kaufman S, Milstien S, Naylor EW, Greene CL, Davis MD
Title Mutation in the 4a-carbinolamine dehydratase gene leads to mild hyperphenylalaninemia with defective cofactor metabolism.
Related PDB
Related UniProtKB P61459
[2]
Resource
Comments
Medline ID
PubMed ID 8504250
Journal Curr Opin Genet Dev
Year 1993
Volume 3
Pages 246-53
Authors Hansen LP, Crabtree GR
Title Regulation of the HNF-1 homeodomain proteins by DCoH.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 7727440
Journal Biochemistry
Year 1995
Volume 34
Pages 5801-10
Authors Rebrin I, Bailey SW, Boerth SR, Ardell MD, Ayling JE
Title Catalytic characterization of 4a-hydroxytetrahydropterin dehydratase.
Related PDB
Related UniProtKB
[4]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
Medline ID 95262643
PubMed ID 7744010
Journal EMBO J
Year 1995
Volume 14
Pages 2034-42
Authors Ficner R, Sauer UH, Stier G, Suck D
Title Three-dimensional structure of the bifunctional protein PCD/DCoH, a cytoplasmic enzyme interacting with transcription factor HNF1.
Related PDB
Related UniProtKB P61459
[5]
Resource
Comments
Medline ID
PubMed ID 7635153
Journal Eur J Biochem
Year 1995
Volume 231
Pages 414-23
Authors Koster S, Thony B, Macheroux P, Curtius HC, Heizmann CW, Pfleiderer W, Ghisla S
Title Human pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1 alpha. Characterization and kinetic analysis of wild-type and mutant enzymes.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 8001680
Journal FEBS Lett
Year 1995
Volume 357
Pages 62-4
Authors Ficner R, Sauer UH, Ceska TA, Stier G, Suck D
Title Crystallization and preliminary crystallographic studies of recombinant dimerization cofactor of transcription factor HNF1/pterin-4 alpha-carbinolamine dehydratase from liver.
Related PDB
Related UniProtKB
[7]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 7725101
Journal Science
Year 1995
Volume 268
Pages 556-9
Authors Endrizzi JA, Cronk JD, Wang W, Crabtree GR, Alber T
Title Crystal structure of DCoH, a bifunctional, protein-binding transcriptional coactivator.
Related PDB 1dch
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 8590013
Journal Structure
Year 1995
Volume 3
Pages 531-4
Authors Kim JL, Burley SK
Title PCD/DCoH: more than a second molecular saddle.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 8944775
Journal Eur J Biochem
Year 1996
Volume 241
Pages 858-64
Authors Koster S, Stier G, Ficner R, Holzer M, Curtius HC, Suck D, Ghisla S
Title Location of the active site and proposed catalytic mechanism of pterin-4a-carbinolamine dehydratase.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 8682201
Journal FEBS Lett
Year 1996
Volume 389
Pages 35-9
Authors Suck D, Ficner R
Title Structure and function of PCD/DCoH, an enzyme with regulatory properties.
Related PDB
Related UniProtKB
[11]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
Medline ID 97052967
PubMed ID 8897596
Journal Protein Sci
Year 1996
Volume 5
Pages 1963-72
Authors Cronk JD, Endrizzi JA, Alber T
Title High-resolution structures of the bifunctional enzyme and transcriptional coactivator DCoH and its complex with a product analogue.
Related PDB 1dco 1dcp
Related UniProtKB P61459
[12]
Resource
Comments
Medline ID
PubMed ID 8995521
Journal J Mol Biol
Year 1997
Volume 265
Pages 20-9
Authors Rhee KH, Stier G, Becker PB, Suck D, Sandaltzopoulos R
Title The bifunctional protein DCoH modulates interactions of the homeodomain transcription factor HNF1 with nucleic acids.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 9391049
Journal Proc Natl Acad Sci U S A
Year 1997
Volume 94
Pages 13469-74
Authors Johnen G, Kaufman S
Title Studies on the enzymatic and transcriptional activity of the dimerization cofactor for hepatocyte nuclear factor 1.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 9698371
Journal Biochemistry
Year 1998
Volume 37
Pages 11246-54
Authors Rebrin I, Thony B, Bailey SW, Ayling JE
Title Stereospecificity and catalytic function of histidine residues in 4a-hydroxy-tetrahydropterin dehydratase/DCoH.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 9894810
Journal Biol Chem
Year 1998
Volume 379
Pages 1427-32
Authors Koster S, Stier G, Kubasch N, Curtius HC, Ghisla S
Title Pterin-4a-carbinolamine dehydratase from Pseudomonas aeruginosa: characterization, catalytic mechanism and comparison to the human enzyme.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 10966642
Journal Nat Struct Biol
Year 2000
Volume 7
Pages 744-8
Authors Rose RB, Bayle JH, Endrizzi JA, Cronk JD, Crabtree GR, Alber T
Title Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha.
Related PDB
Related UniProtKB

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.

Created Updated
2004-04-04 2009-02-26