M00210
type: Enzyme
cath: Rossmann fold
cath: Leucine Dehydrogenase; Chain A, domain 1
cath: http://ezcatdb.cbrc.jp/EzCatDB/cath/3.30.-.-
cath: http://ezcatdb.cbrc.jp/EzCatDB/cath/3.10.-.-
ec: https://purl.uniprot.org/enzyme/1.5.1.5
ec: https://purl.uniprot.org/enzyme/3.5.4.9
ec: https://purl.uniprot.org/enzyme/6.3.4.3
csa: 1a4i
uniprot: P11586
kegg enzyme: methylenetetrahydrofolate dehydrogenase (NADP+)
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/1.5.1.5
kegg enzyme: N5,N10-methylenetetrahydrofolate dehydrogenase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/1.5.1.5
kegg enzyme: 5,10-methylenetetrahydrofolate:NADP oxidoreductase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/1.5.1.5
kegg enzyme: 5,10-methylenetetrahydrofolate dehydrogenase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/1.5.1.5
kegg enzyme: methylenetetrahydrofolate dehydrogenase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/1.5.1.5
kegg enzyme: methylenetetrahydrofolate dehydrogenase (NADP)
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/1.5.1.5
kegg enzyme: methenyltetrahydrofolate cyclohydrolase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/3.5.4.9
kegg enzyme: Citrovorum factor cyclodehydrase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/3.5.4.9
kegg enzyme: cyclohydrolase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/3.5.4.9
kegg enzyme: formyl-methenyl-methylenetetrahydrofolate synthetase (combined)
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/3.5.4.9
kegg enzyme: formate---tetrahydrofolate ligase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/6.3.4.3
kegg enzyme: formyltetrahydrofolate synthetase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/6.3.4.3
kegg enzyme: 10-formyltetrahydrofolate synthetase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/6.3.4.3
kegg enzyme: tetrahydrofolic formylase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/6.3.4.3
kegg enzyme: tetrahydrofolate formylase
  type: KeggEnzyme
  ec: https://purl.uniprot.org/enzyme/6.3.4.3
kegg pathway: Glyoxylate and dicarboxylate metabolism
kegg pathway: One carbon pool by folate
kegg substrate: 5,10-Methylenetetrahydrofolate
kegg substrate: NADP+
kegg substrate: 5,10-Methenyltetrahydrofolate
kegg substrate: H2O
kegg substrate: ATP
kegg substrate: Formate
kegg substrate: Tetrahydrofolate
kegg product: 5,10-Methenyltetrahydrofolate
kegg product: NADPH
kegg product: H+
kegg product: 10-Formyltetrahydrofolate
kegg product: ADP
kegg product: Orthophosphate
pdb: 1a4iA01
pdb: 1a4iB01
pdb: 1diaA01
pdb: 1diaB01
pdb: 1dibA01
pdb: 1dibB01
pdb: 1digA01
pdb: 1digB01
pdb: 1a4iA02
pdb: 1a4iB02
pdb: 1diaA02
pdb: 1diaB02
pdb: 1dibA02
pdb: 1dibB02
pdb: 1digA02
pdb: 1digB02
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1a4iA01
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1a4iB01
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1diaA01
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1diaB01
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1dibA01
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1dibB01
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1digA01
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1digB01
pdb bound state: Unbound
  compound: 5,10-Methylenetetrahydrofolate
  pdb: 1a4iA02
active site residues resources: The X-ray structure of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
active site residues resources: http://ezcatdb.cbrc.jp/EzCatDB/reference/M00210#12
references: Site-directed mutagenesis of yeast C1-tetrahydrofolate synthase: analysis of an overlapping active site in a multifunctional enzyme.
references: Synthesis of (6S)-5-formyltetrahydropteroyl-polyglutamates and interconversion to other reduced pteroylpolyglutamate derivatives.
references: Crystallization of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
references: Purification, crystallization, and preliminary x-ray studies of a bifunctional 5,10-methenyl/methylene-tetrahydrofolate cyclohydrolase/dehydrogenase from Escherichia coli.
references: The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution.
references: The crystal structure of a bacterial, bifunctional 5,10 methylene-tetrahydrofolate dehydrogenase/cyclohydrolase.
references: Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase.
references: The X-ray structure of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
references: Re-face stereospecificity of methylenetetrahydromethanopterin and methylenetetrahydrofolate dehydrogenases is predetermined by intrinsic properties of the substrate.
references: Mammalian mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase derived from a trifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase.
references: Residues involved in the mechanism of the bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase: the roles of glutamine 100 and aspartate 125.
comment: This protein is multifunctional enzyme with three distinct domains, which corerspond to methylenetetrahydrofolate dehydrogenase/cyclohydrolase (EC 1.5.1.5 & 3.5.4.9) and formyltetrahydrofolate synthetase (EC 6.3.4.3). Out of the three domains, the C-terminal formyltetrahydrofolate synthetase domain has not been determined yet.

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

Leucine Dehydrogenase; Chain A, domain 1
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/3.40.192.10
catalytic domain: index.html

Rossmann fold
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/3.40.50.-

Glyoxylate and dicarboxylate metabolism
type: KeggPathway
references: KEGG:MAP00630
ec: https://purl.uniprot.org/enzyme/1.5.1.5
ec: https://purl.uniprot.org/enzyme/3.5.4.9
ec: https://purl.uniprot.org/enzyme/6.3.4.3

One carbon pool by folate
type: KeggPathway
references: KEGG:MAP00670
ec: https://purl.uniprot.org/enzyme/1.5.1.5
ec: https://purl.uniprot.org/enzyme/3.5.4.9
ec: https://purl.uniprot.org/enzyme/6.3.4.3

5,10-Methylenetetrahydrofolate
type: KeggSubstrate
references: KEGG:C00143
ec: https://purl.uniprot.org/enzyme/1.5.1.5
compound type: amino acids
compound type: amide group
compound type: amine group
compound type: aromatic ring (only carbon atom)
compound type: aromatic ring (with nitrogen atoms)
compound type: carboxyl group
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

NADP+
type: KeggSubstrate
references: KEGG:C00006
ec: https://purl.uniprot.org/enzyme/1.5.1.5
compound type: amide group
compound type: amine group
compound type: nucleotide
references: CHEBI:18009
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

5,10-Methenyltetrahydrofolate
type: KeggSubstrate
references: KEGG:C00445
ec: https://purl.uniprot.org/enzyme/3.5.4.9
compound type: amino acids
compound type: amide group
compound type: amine group
compound type: aromatic ring (only carbon atom)
compound type: aromatic ring (with nitrogen atoms)
compound type: carboxyl group
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi
type: KeggProduct
ec: https://purl.uniprot.org/enzyme/1.5.1.5

H2O
type: KeggSubstrate
references: KEGG:C00001
ec: https://purl.uniprot.org/enzyme/3.5.4.9
compound type: H2O
references: CHEBI:15377
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

ATP
type: KeggSubstrate
references: KEGG:C00002
ec: https://purl.uniprot.org/enzyme/6.3.4.3
compound type: amine group
compound type: nucleotide
references: CHEBI:15422
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

Formate
type: KeggSubstrate
references: KEGG:C00058
ec: https://purl.uniprot.org/enzyme/6.3.4.3
compound type: carboxyl group
references: CHEBI:30751
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

Tetrahydrofolate
type: KeggSubstrate
references: KEGG:C00101
ec: https://purl.uniprot.org/enzyme/6.3.4.3
compound type: amino acids
compound type: amide group
compound type: amine group
compound type: aromatic ring (only carbon atom)
compound type: aromatic ring (with nitrogen atoms)
compound type: carboxyl group
references: CHEBI:15635
references: CHEBI:20506
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

NADPH
type: KeggProduct
references: KEGG:C00005
ec: https://purl.uniprot.org/enzyme/1.5.1.5
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: KeggProduct
references: KEGG:C00080
ec: https://purl.uniprot.org/enzyme/1.5.1.5
compound type: others
references: CHEBI:15378
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

10-Formyltetrahydrofolate
type: KeggProduct
references: KEGG:C00234
ec: https://purl.uniprot.org/enzyme/3.5.4.9
ec: https://purl.uniprot.org/enzyme/6.3.4.3
compound type: amino acids
compound type: amide group
compound type: amine group
compound type: aromatic ring (only carbon atom)
compound type: aromatic ring (with nitrogen atoms)
compound type: carboxyl group
references: CHEBI:15637
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

ADP
type: KeggProduct
references: KEGG:C00008
ec: https://purl.uniprot.org/enzyme/6.3.4.3
compound type: amine group
compound type: nucleotide
references: CHEBI:16761
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

Orthophosphate
type: KeggProduct
references: KEGG:C00009
ec: https://purl.uniprot.org/enzyme/6.3.4.3
compound type: phosphate group/phosphate ion
references: CHEBI:26078
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

1a4iA02
type: Pdb
references: 1a4i
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1a4i
catalytic residue: LYS 56;GLN 100

1a4iB02
type: Pdb
references: 1a4i
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1a4i
catalytic residue: LYS 56;GLN 100

1diaA02
type: Pdb
references: 1dia
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1dia
catalytic residue: LYS 56;GLN 100

1diaB02
type: Pdb
references: 1dia
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1dia
catalytic residue: LYS 1056;GLN 1100

1dibA02
type: Pdb
references: 1dib
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1dib
catalytic residue: LYS 56;GLN 100

1dibB02
type: Pdb
references: 1dib
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1dib
catalytic residue: LYS 1056;GLN 1100

1digA02
type: Pdb
references: 1dig
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1dig
catalytic residue: LYS 56;GLN 100

1digB02
type: Pdb
references: 1dig
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1dig
catalytic residue: LYS 1056;GLN 1100

Site-directed mutagenesis of yeast C1-tetrahydrofolate synthase: analysis of an overlapping active site in a multifunctional enzyme.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/2541774
journal: Biochemistry
volume: 28
pages: 2099-106
published year: 1989
authors:
  item: Barlowe CK
  item: Williams ME
  item: Rabinowitz JC
  item: Appling DR

Synthesis of (6S)-5-formyltetrahydropteroyl-polyglutamates and interconversion to other reduced pteroylpolyglutamate derivatives.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/1621989
journal: Biochemistry
volume: 202
pages: 82-8
published year: 1992
authors:
  item: Stover P
  item: Schirch V

Crystallization of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8990502
journal: Proteins
volume: 26
pages: 481-2
published year: 1996
authors:
  item: Monzingo AF
  item: West MG
  item: Schelp E
  item: Appling DR
  item: Robertus JD

Purification, crystallization, and preliminary x-ray studies of a bifunctional 5,10-methenyl/methylene-tetrahydrofolate cyclohydrolase/dehydrogenase from Escherichia coli.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9061797
journal: Proteins
volume: 27
pages: 322-4
published year: 1997
authors:
  item: Cheung E
  item: D'Ari L
  item: Rabinowitz JC
  item: Dyer DH
  item: Huang JY
  item: Stoddard BL

The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 1-301
medline id: 98179934
references: http://www.ncbi.nlm.nih.gov/pubmed/9519408
journal: Structure
volume: 6
pages: 173-82
published year: 1998
authors:
  item: Allaire M
  item: Li Y
  item: MacKenzie RE
  item: Cygler M
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P11586

The crystal structure of a bacterial, bifunctional 5,10 methylene-tetrahydrofolate dehydrogenase/cyclohydrolase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10386884
journal: Protein Sci
volume: 8
pages: 1342-9
published year: 1999
authors:
  item: Shen BW
  item: Dyer DH
  item: Huang JY
  item: D'Ari L
  item: Rabinowitz J
  item: Stoddard BL

Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase.
type: BibliographicResource
comment: X-ray crystallography
references: http://www.ncbi.nlm.nih.gov/pubmed/10828945
journal: Biochemistry
volume: 39
pages: 6325-35
published year: 2000
authors:
  item: Schmidt A
  item: Wu H
  item: MacKenzie RE
  item: Chen VJ
  item: Bewly JR
  item: Ray JE
  item: Toth JE
  item: Cygler M
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl

The X-ray structure of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10933503
journal: Protein Sci
volume: 9
pages: 1374-81
published year: 2000
authors:
  item: Monzingo AF
  item: Breksa A
  item: Ernst S
  item: Appling DR
  item: Robertus JD

Re-face stereospecificity of methylenetetrahydromethanopterin and methylenetetrahydrofolate dehydrogenases is predetermined by intrinsic properties of the substrate.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11828486
journal: Chembiochem
volume: 2
pages: 530-41
published year: 2001
authors:
  item: Bartoschek S
  item: Buurman G
  item: Thauer RK
  item: Geierstanger BH
  item: Weyrauch JP
  item: Griesinger C
  item: Nilges M
  item: Hutter MC
  item: Helms V

Mammalian mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase derived from a trifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/12061812
journal: Arch Biochem Biophys
volume: 403
pages: 145-8
published year: 2002
authors:
  item: Patel H
  item: Christensen KE
  item: Mejia N
  item: MacKenzie RE

Residues involved in the mechanism of the bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase: the roles of glutamine 100 and aspartate 125.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11904299
journal: J Biol Chem
volume: 277
pages: 18703-9
published year: 2002
authors:
  item: Sundararajan S
  item: MacKenzie RE

Analogue
compound: 5,10-Methylenetetrahydrofolate
pdb: 1dibA02
ligand het code: L34

Analogue
compound: 10-Formyltetrahydrofolate
pdb: 1diaA02
ligand het code: L24

Analogue
compound: 10-Formyltetrahydrofolate
pdb: 1digA02
ligand het code: L37

ReferenceForCatalyticMechanism
reference index: 5
reference section: p.178-180

ReferenceForCatalyticMechanism
reference index: 6

ReferenceForCatalyticMechanism
reference index: 7
reference section: Fig.8, p.6332-6334

ReferenceForCatalyticMechanism
reference index: 8

ReferenceForCatalyticMechanism
reference index: 9
reference section: p.538-539

ReferenceForCatalyticMechanism
reference index: 11
reference section: Fig.3, p.18706-18708