DB code: M00210

CATH domain 3.40.50.720 : Rossmann fold Catalytic domain
3.40.192.10 : Leucine Dehydrogenase; Chain A, domain 1 Catalytic domain
3.40.50.- : Rossmann fold
3.30.-.- :
3.10.-.- :
E.C. 1.5.1.5 3.5.4.9 6.3.4.3
CSA 1a4i
M-CSA 1a4i
MACiE

CATH domain Related DB codes (homologues)
3.40.50.720 : Rossmann fold S00543 S00551 S00552 S00553 S00602 S00604 S00605 S00608 S00610 S00625 S00319 S00328 S00329 S00330 S00331 S00332 D00456 D00457 D00458 S00324 S00320 S00325 S00326 S00327 D00459 S00335 S00336 S00334 T00219 S00339 D00513 D00001 D00002 D00003 D00005 D00007 D00008 D00010 D00012 D00017 D00018 D00023 D00027 D00028 D00031 D00032 D00033 D00034 D00035 D00037 D00048 D00071 D00476 D00481 D00482 D00490 D00492 D00494 D00545 D00601 D00603 D00604 D00605 D00615 D00845 D00857 D00858 M00161 M00171 T00002 T00010 T00011 T00015 T00227 T00247 T00408 T00414 D00827 D00262 D00274 D00275 M00035 T00109
3.40.192.10 : Leucine Dehydrogenase; Chain A, domain 1 D00458 D00032 D00033 D00035 D00605 D00845 D00857 D00858 T00010 T00011 T00414

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Includes RefSeq Pfam
P11586 C-1-tetrahydrofolate synthase, cytoplasmic
C1-THF synthase
Methylenetetrahydrofolate dehydrogenase
EC 1.5.1.5
Methenyltetrahydrofolate cyclohydrolase
EC 3.5.4.9
Formyltetrahydrofolate synthetase
EC 6.3.4.3
NP_005947.3 (Protein)
NM_005956.3 (DNA/RNA sequence)
PF01268 (FTHFS)
PF00763 (THF_DHG_CYH)
PF02882 (THF_DHG_CYH_C)
[Graphical View]

KEGG enzyme name
methylenetetrahydrofolate dehydrogenase (NADP+)
(EC 1.5.1.5 )
N5,N10-methylenetetrahydrofolate dehydrogenase
(EC 1.5.1.5 )
5,10-methylenetetrahydrofolate:NADP oxidoreductase
(EC 1.5.1.5 )
5,10-methylenetetrahydrofolate dehydrogenase
(EC 1.5.1.5 )
methylenetetrahydrofolate dehydrogenase
(EC 1.5.1.5 )
methylenetetrahydrofolate dehydrogenase (NADP)
(EC 1.5.1.5 )
methenyltetrahydrofolate cyclohydrolase
(EC 3.5.4.9 )
Citrovorum factor cyclodehydrase
(EC 3.5.4.9 )
cyclohydrolase
(EC 3.5.4.9 )
formyl-methenyl-methylenetetrahydrofolate synthetase (combined)
(EC 3.5.4.9 )
formate---tetrahydrofolate ligase
(EC 6.3.4.3 )
formyltetrahydrofolate synthetase
(EC 6.3.4.3 )
10-formyltetrahydrofolate synthetase
(EC 6.3.4.3 )
tetrahydrofolic formylase
(EC 6.3.4.3 )
tetrahydrofolate formylase
(EC 6.3.4.3 )

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P11586 C1TC_HUMAN 5,10-methylenetetrahydrofolate + NADP(+) = 5,10-methenyltetrahydrofolate + NADPH. 5,10-methenyltetrahydrofolate + H(2)O = 10- formyltetrahydrofolate. ATP + formate + tetrahydrofolate = ADP + phosphate + 10-formyltetrahydrofolate. Homodimer. Cytoplasm.

KEGG Pathways
Map code Pathways E.C.
MAP00670 One carbon pool by folate 1.5.1.5 3.5.4.9 6.3.4.3
MAP00630 Glyoxylate and dicarboxylate metabolism 1.5.1.5 3.5.4.9 6.3.4.3

Compound table
Substrates Products Intermediates
KEGG-id C00143 C00006 C00445 C00001 C00002 C00058 C00101 C00445 C00005 C00080 C00234 C00008 C00009
E.C. 1.5.1.5
1.5.1.5
3.5.4.9
3.5.4.9
6.3.4.3
6.3.4.3
6.3.4.3
1.5.1.5
1.5.1.5
1.5.1.5
3.5.4.9
6.3.4.3
6.3.4.3
6.3.4.3
Compound 5,10-Methylenetetrahydrofolate NADP+ 5,10-Methenyltetrahydrofolate H2O ATP Formate Tetrahydrofolate 5,10-Methenyltetrahydrofolate NADPH H+ 10-Formyltetrahydrofolate ADP Orthophosphate
Type amino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group amide group,amine group,nucleotide amino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group H2O amine group,nucleotide carboxyl group amino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group amino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group amide group,amine group,nucleotide others amino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group amine group,nucleotide phosphate group/phosphate ion
ChEBI 18009
15377
15422
30751
20506
15635
16474
15378
15637
16761
26078
PubChem 439175
5886
439237
962
22247451
5957
284
18971002
91443
5460413
439237
5884
1038
6326742
122347
6022
22486802
1004
1a4iA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Bound:NDP Unbound Unbound Unbound
1a4iB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Bound:NDP Unbound Unbound Unbound
1diaA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1diaB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1dibA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1dibB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1digA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1digB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1a4iA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1a4iB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1diaA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Analogue:L24 Unbound Unbound
1diaB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1dibA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Analogue:L34 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1dibB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1digA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Analogue:L37 Unbound Unbound
1digB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound

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

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1a4iA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1a4iB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1diaA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1diaB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1dibA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1dibB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1digA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1digB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1a4iA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain LYS 56;GLN 100
1a4iB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain LYS 56;GLN 100
1diaA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain LYS 56;GLN 100
1diaB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain LYS 1056;GLN 1100
1dibA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain LYS 56;GLN 100
1dibB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain LYS 1056;GLN 1100
1digA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain LYS 56;GLN 100
1digB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain LYS 1056;GLN 1100

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[5]
p.178-180
[6]
[7]
Fig.8, p.6332-6334
[8]
[9]
p.538-539
[11]
Fig.3, p.18706-18708

References
[1]
Resource
Comments
Medline ID
PubMed ID 2541774
Journal Biochemistry
Year 1989
Volume 28
Pages 2099-106
Authors Barlowe CK, Williams ME, Rabinowitz JC, Appling DR
Title Site-directed mutagenesis of yeast C1-tetrahydrofolate synthase: analysis of an overlapping active site in a multifunctional enzyme.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 1621989
Journal Biochemistry
Year 1992
Volume 202
Pages 82-8
Authors Stover P, Schirch V
Title Synthesis of (6S)-5-formyltetrahydropteroyl-polyglutamates and interconversion to other reduced pteroylpolyglutamate derivatives.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 8990502
Journal Proteins
Year 1996
Volume 26
Pages 481-2
Authors Monzingo AF, West MG, Schelp E, Appling DR, Robertus JD
Title Crystallization of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 9061797
Journal Proteins
Year 1997
Volume 27
Pages 322-4
Authors Cheung E, D'Ari L, Rabinowitz JC, Dyer DH, Huang JY, Stoddard BL
Title Purification, crystallization, and preliminary x-ray studies of a bifunctional 5,10-methenyl/methylene-tetrahydrofolate cyclohydrolase/dehydrogenase from Escherichia coli.
Related PDB
Related UniProtKB
[5]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 1-301
Medline ID 98179934
PubMed ID 9519408
Journal Structure
Year 1998
Volume 6
Pages 173-82
Authors Allaire M, Li Y, MacKenzie RE, Cygler M
Title The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution.
Related PDB 1a4i 1dig
Related UniProtKB P11586
[6]
Resource
Comments
Medline ID
PubMed ID 10386884
Journal Protein Sci
Year 1999
Volume 8
Pages 1342-9
Authors Shen BW, Dyer DH, Huang JY, D'Ari L, Rabinowitz J, Stoddard BL
Title The crystal structure of a bacterial, bifunctional 5,10 methylene-tetrahydrofolate dehydrogenase/cyclohydrolase.
Related PDB
Related UniProtKB
[7]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 10828945
Journal Biochemistry
Year 2000
Volume 39
Pages 6325-35
Authors Schmidt A, Wu H, MacKenzie RE, Chen VJ, Bewly JR, Ray JE, Toth JE, Cygler M
Title Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase.
Related PDB 1dia 1dib
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 10933503
Journal Protein Sci
Year 2000
Volume 9
Pages 1374-81
Authors Monzingo AF, Breksa A, Ernst S, Appling DR, Robertus JD
Title The X-ray structure of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 11828486
Journal Chembiochem
Year 2001
Volume 2
Pages 530-41
Authors Bartoschek S, Buurman G, Thauer RK, Geierstanger BH, Weyrauch JP, Griesinger C, Nilges M, Hutter MC, Helms V
Title Re-face stereospecificity of methylenetetrahydromethanopterin and methylenetetrahydrofolate dehydrogenases is predetermined by intrinsic properties of the substrate.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 12061812
Journal Arch Biochem Biophys
Year 2002
Volume 403
Pages 145-8
Authors Patel H, Christensen KE, Mejia N, MacKenzie RE
Title Mammalian mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase derived from a trifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 11904299
Journal J Biol Chem
Year 2002
Volume 277
Pages 18703-9
Authors Sundararajan S, MacKenzie RE
Title Residues involved in the mechanism of the bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase: the roles of glutamine 100 and aspartate 125.
Related PDB
Related UniProtKB

Comments
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.

Created Updated
2004-03-23 2009-02-26