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)
3.40.192.10 : Leucine Dehydrogenase; Chain A, domain 1 D00458 D00032 D00033 D00035 D00605 D00845 D00857 D00858 T00010 T00011 T00414
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

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.
MAP00630 Glyoxylate and dicarboxylate metabolism 1.5.1.5 3.5.4.9 6.3.4.3
MAP00670 One carbon pool by folate 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
 18009
 		15377
 15377
 		15422
 15422
 		30751
 30751
 		15635
 20506
 15635
 20506
 		16474
 16474
 		15378
 15378
 		15637
 15637
 		16761
 16761
 		26078
 26078
PubChem 439175
 439175
 		5886
 5886
 		439237
 439237
 		22247451
 962
 22247451
 962
 		5957
 5957
 		18971002
 284
 18971002
 284
 		5460413
 91443
 5460413
 91443
 		439237
 439237
 		5884
 5884
 		1038
 1038
 		122347
 6326742
 122347
 6326742
 		6022
 6022
 		1004
 22486802
 1004
 22486802
1a4iA01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Bound:NDP Unbound Unbound Unbound
1a4iB01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Bound:NDP Unbound Unbound Unbound
1diaA01 Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1diaB01 Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1dibA01 Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1dibB01 Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1digA01 Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1digB01 Unbound Bound:NAP Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1a4iA02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1a4iB02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1diaA02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Analogue:L24 Unbound Unbound
1diaB02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1dibA02 Analogue:L34 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1dibB02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1digA02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Analogue:L37 Unbound Unbound
1digB02 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
1a4iB01
1diaA01
1diaB01
1dibA01
1dibB01
1digA01
1digB01
1a4iA02 LYS 56;GLN 100
1a4iB02 LYS 56;GLN 100
1diaA02 LYS 56;GLN 100
1diaB02 LYS 1056;GLN 1100
1dibA02 LYS 56;GLN 100
1dibB02 LYS 1056;GLN 1100
1digA02 LYS 56;GLN 100
1digB02 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