S00329
type: Enzyme
rlcp: p8010
cath: Rossmann fold
ec: https://purl.uniprot.org/enzyme/1.1.1.153
uniprot: Q64105
uniprot: P35270
kegg enzyme: sepiapterin reductase
kegg enzyme: SR
kegg pathway: Folate biosynthesis
kegg substrate: Sepiapterin
kegg substrate: NADPH
kegg substrate: H+
kegg substrate: 6-pyruvoyl-5,6,7,8-tetrahydropterin
kegg product: 7,8-Dihydrobiopterin
kegg product: NADP+
kegg product: Tetrahydrobiopterin
kegg intermediate: 6-(1'-hydroxy-2'-oxopropyl)-tetrahydropterin
kegg intermediate: 6-lactoyl-tetrahydropterin
pdb: 1nasA
pdb: 1oaaA
pdb: 1sepA
pdb: 1z6zA
pdb: 1z6zB
pdb: 1z6zC
pdb: 1z6zD
pdb: 1z6zE
pdb: 1z6zF
pdb bound state: Unbound
  compound: Sepiapterin
  pdb: 1nasA
pdb bound state: Unbound
  compound: Sepiapterin
  pdb: 1oaaA
pdb bound state: Analogue
  compound: Sepiapterin
  pdb: 1sepA
  ligand het code: BIO
pdb bound state: Unbound
  compound: Sepiapterin
  pdb: 1z6zA
pdb bound state: Unbound
  compound: Sepiapterin
  pdb: 1z6zB
pdb bound state: Unbound
  compound: Sepiapterin
  pdb: 1z6zC
pdb bound state: Unbound
  compound: Sepiapterin
  pdb: 1z6zD
pdb bound state: Unbound
  compound: Sepiapterin
  pdb: 1z6zE
pdb bound state: Unbound
  compound: Sepiapterin
  pdb: 1z6zF
pdb bound state: Unbound
  compound: NADPH
  pdb: 1nasA
pdb bound state: Unbound
  compound: NADPH
  pdb: 1oaaA
pdb bound state: Unbound
  compound: NADPH
  pdb: 1sepA
pdb bound state: Unbound
  compound: NADPH
  pdb: 1z6zA
pdb bound state: Unbound
  compound: NADPH
  pdb: 1z6zB
pdb bound state: Unbound
  compound: NADPH
  pdb: 1z6zC
pdb bound state: Unbound
  compound: NADPH
  pdb: 1z6zD
pdb bound state: Unbound
  compound: NADPH
  pdb: 1z6zE
pdb bound state: Unbound
  compound: NADPH
  pdb: 1z6zF
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1nasA
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1oaaA
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1sepA
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1z6zA
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1z6zB
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1z6zC
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1z6zD
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1z6zE
pdb bound state: Unbound
  compound: 6-pyruvoyl-5,6,7,8-tetrahydropterin
  pdb: 1z6zF
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1nasA
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1oaaA
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1sepA
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1z6zA
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1z6zB
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1z6zC
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1z6zD
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1z6zE
pdb bound state: Unbound
  compound: 7,8-Dihydrobiopterin
  pdb: 1z6zF
pdb bound state: Unbound
  compound: Tetrahydrobiopterin
  pdb: 1nasA
pdb bound state: Unbound
  compound: Tetrahydrobiopterin
  pdb: 1oaaA
active site residues resources: Tetrahydrobiopterin biosynthesis, regeneration and functions.
active site residues resources: http://ezcatdb.cbrc.jp/EzCatDB/reference/S00329#14
references: Direct inhibition of brain sepiapterin reductase by a catecholamine and an indoleamine.
references: Dyspropterin, an intermediate formed from dihydroneopterin triphosphate in the biosynthetic pathway of tetrahydrobiopterin.
references: Tetrahydrobiopterin biosynthesis. Studies with specifically labeled (2H)NAD(P)H and 2H2O and of the enzymes involved.
references: Isomerization of 6-lactoyl tetrahydropterin by sepiapterin reductase.
references: New inhibitors of sepiapterin reductase. Lack of an effect of intracellular tetrahydrobiopterin depletion upon in vitro proliferation of two human cell lines.
references: The pathway from GTP to tetrahydrobiopterin: three-dimensional structures of GTP cyclohydrolase I and 6-pyruvoyl tetrahydropterin synthase.
references: The 1.25 A crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters.
references: Biosynthesis of pteridines. NMR studies on the reaction mechanisms of GTP cyclohydrolase I, pyruvoyltetrahydropterin synthase, and sepiapterin reductase.
references: Sepiapterin reductase producing L-threo-dihydrobiopterin from Chlorobium tepidum.
references: Functionally important residues tyrosine-171 and serine-158 in sepiapterin reductase.
references: Tetrahydrobiopterin biosynthesis, regeneration and functions.
references: Role of the conserved Ser-Tyr-Lys triad of the SDR family in sepiapterin reductase.
comment: This enzyme belongs to the short-chain dehydrogenase/reductase (SDR) superfamily, along with Drosophia alcohol dehydrogenase (S00319 in EzCatDB). This enzyme has got a catalytic triad composed of conserved residues, Ser, Tyr, and Lys. The conformation of these residues, compared to that of the NAD molecule, seems to be similar to that of the homologous enzymes. Thus, its catalytic mechanism must be similar to those of the homologous enzymes. According to the literature [7] and [11], this enzyme catalyzes three reactions, including the two reduction steps for the diketo substrate (C03684), as follows: (A) Reduction of C1'-keto group of the substrate by NADPH, forming 1'-hydroxyl intermediate (I00093): (B) Isomerization of 1'-hydroxyl intermediate, forming 1'-keto-2'hydroxyl intermediate (I00094): (C) Reduction of C1'-keto group of the intermediate by NADPH: The first and last reactions must be catalyzed by the catalytic triad, as in the other homologous enzymes.

Rossmann fold
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/3.40.50.720
catalytic domain: index.html

Folate biosynthesis
type: KeggPathway
references: KEGG:MAP00790

Sepiapterin
type: KeggSubstrate
references: KEGG:C00835
compound type: amide group
compound type: amine group
compound type: imine group
compound type: carbohydrate
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

NADPH
type: KeggSubstrate
references: KEGG:C00005
compound type: amide group
compound type: amine group
compound type: nucleotide
references: CHEBI:16474
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

H+
type: KeggSubstrate
references: KEGG:C00080
compound type: others
references: CHEBI:15378
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

6-pyruvoyl-5,6,7,8-tetrahydropterin
type: KeggSubstrate
references: KEGG:C03684
compound type: amide group
compound type: amine group
compound type: aromatic ring (with nitrogen atoms)
compound type: carbohydrate
references: CHEBI:17804
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

7,8-Dihydrobiopterin
type: KeggProduct
references: KEGG:C02953
compound type: amide group
compound type: amine group
compound type: aromatic ring (with nitrogen atoms)
compound type: carbohydrate
references: CHEBI:43029
references: CHEBI:64277
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

NADP+
type: KeggProduct
references: KEGG:C00006
compound type: amide group
compound type: amine group
compound type: nucleotide
references: CHEBI:18009
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

Tetrahydrobiopterin
type: KeggProduct
references: KEGG:C00272
compound type: amide group
compound type: amine group
compound type: aromatic ring (with nitrogen atoms)
compound type: carbohydrate
references: CHEBI:59560
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

6-(1'-hydroxy-2'-oxopropyl)-tetrahydropterin
type: KeggIntermediate
references: KEGG:I00093

6-lactoyl-tetrahydropterin
type: KeggIntermediate
references: KEGG:I00094

1nasA
type: Pdb
references: 1nas
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1nas
catalytic residue: SER 158;TYR 171;LYS 175

1oaaA
type: Pdb
references: 1oaa
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1oaa
catalytic residue: SER 158;TYR 171;LYS 175

1sepA
type: Pdb
references: 1sep
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1sep
catalytic residue: SER 158;TYR 171;LYS 175

1z6zA
type: Pdb
references: 1z6z
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1z6z
catalytic residue: SER 154;TYR 167;LYS 171

1z6zB
type: Pdb
references: 1z6z
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1z6z
catalytic residue: SER 154;TYR 167;LYS 171

1z6zC
type: Pdb
references: 1z6z
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1z6z
catalytic residue: SER 154;TYR 167;LYS 171

1z6zD
type: Pdb
references: 1z6z
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1z6z
catalytic residue: SER 154;TYR 167;LYS 171

1z6zE
type: Pdb
references: 1z6z
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1z6z
catalytic residue: SER 154;TYR 167;LYS 171

1z6zF
type: Pdb
references: 1z6z
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1z6z
catalytic residue: SER 154;TYR 167;LYS 171

Direct inhibition of brain sepiapterin reductase by a catecholamine and an indoleamine.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/7046745
journal: Biochem Biophys Res Commun
volume: 105
pages: 75-81
published year: 1982
authors:
  item: Katoh S
  item: Sueoka T
  item: Yamada S

Dyspropterin, an intermediate formed from dihydroneopterin triphosphate in the biosynthetic pathway of tetrahydrobiopterin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/3888282
journal: Biochim Biophys Acta
volume: 840
pages: 235-44
published year: 1985
authors:
  item: Masada M
  item: Akino M
  item: Sueoka T
  item: Katoh S

Tetrahydrobiopterin biosynthesis. Studies with specifically labeled (2H)NAD(P)H and 2H2O and of the enzymes involved.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/3888618
journal: Eur J Biochem
volume: 148
pages: 413-9
published year: 1985
authors:
  item: Curtius HC
  item: Heintel D
  item: Ghisla S
  item: Kuster T
  item: Leimbacher W
  item: Niederwieser A

Isomerization of 6-lactoyl tetrahydropterin by sepiapterin reductase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/3553175
journal: J Biochem (Tokyo)
volume: 101
pages: 275-8
published year: 1987
authors:
  item: Katoh S
  item: Sueoka T

New inhibitors of sepiapterin reductase. Lack of an effect of intracellular tetrahydrobiopterin depletion upon in vitro proliferation of two human cell lines.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/1544933
journal: J Biol Chem
volume: 267
pages: 5599-607
published year: 1992
authors:
  item: Smith GK
  item: Duch DS
  item: Edelstein MP
  item: Bigham EC

The pathway from GTP to tetrahydrobiopterin: three-dimensional structures of GTP cyclohydrolase I and 6-pyruvoyl tetrahydropterin synthase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9165069
journal: Biol Chem
volume: 378
pages: 185-92
published year: 1997
authors:
  item: Auerbach G
  item: Nar H

The 1.25 A crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS)
medline id: 98070299
references: http://www.ncbi.nlm.nih.gov/pubmed/9405351
journal: EMBO J
volume: 16
pages: 7219-30
published year: 1997
authors:
  item: Auerbach G
  item: Herrmann A
  item: Gutlich M
  item: Fischer M
  item: Jacob U
  item: Bacher A
  item: Huber R
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: Q64105

Biosynthesis of pteridines. NMR studies on the reaction mechanisms of GTP cyclohydrolase I, pyruvoyltetrahydropterin synthase, and sepiapterin reductase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9774432
journal: J Biol Chem
volume: 273
pages: 28132-41
published year: 1998
authors:
  item: Bracher A
  item: Eisenreich W
  item: Schramek N
  item: Ritz H
  item: Gotze E
  item: Herrmann A
  item: Gutlich M
  item: Bacher A

Sepiapterin reductase producing L-threo-dihydrobiopterin from Chlorobium tepidum.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10333495
journal: Biochem J
volume: 340
pages: 497-503
published year: 1999
authors:
  item: Cho SH
  item: Na JU
  item: Youn H
  item: Hwang CS
  item: Lee CH
  item: Kang SO

Functionally important residues tyrosine-171 and serine-158 in sepiapterin reductase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10350607
journal: Biochim Biophys Acta
volume: 1431
pages: 306-14
published year: 1999
authors:
  item: Fujimoto K
  item: Ichinose H
  item: Nagatsu T
  item: Nonaka T
  item: Mitsui Y
  item: Katoh S

Tetrahydrobiopterin biosynthesis, regeneration and functions.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10727395
journal: Biochem J
volume: 347 Pt 1
pages: 1-16
published year: 2000
authors:
  item: Thony B
  item: Auerbach G
  item: Blau N

Role of the conserved Ser-Tyr-Lys triad of the SDR family in sepiapterin reductase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11306098
journal: Chem Biol Interact
volume: 130-132
pages: 825-32
published year: 2001
authors:
  item: Fujimoto K
  item: Hara M
  item: Yamada H
  item: Sakurai M
  item: Inaba A
  item: Tomomura A
  item: Katoh S

ReferenceForCatalyticMechanism
reference index: 7
reference section: p.7224-7225

ReferenceForCatalyticMechanism
reference index: 8
reference section: Fig.11

ReferenceForCatalyticMechanism
reference index: 10
reference section: p.311-313

ReferenceForCatalyticMechanism
reference index: 12
reference section: Fig.5