EzCatDB: M00210
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DB codeM00210
CATH domainDomain 13.40.50.720 : Rossmann foldCatalytic domain
Domain 23.40.192.10 : Leucine Dehydrogenase; Chain A, domain 1Catalytic domain
Domain 33.40.50.- : Rossmann fold
Domain 43.30.-.-
Domain 53.10.-.-
E.C.1.5.1.5,3.5.4.9,6.3.4.3
CSA1a4i

CATH domainRelated DB codes (homologues)
3.40.192.10 : Leucine Dehydrogenase; Chain A, domain 1D00458,D00032,D00033,D00035,D00605,D00845,D00857,D00858,T00010,T00011,T00414
3.40.50.720 : Rossmann foldS00543,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

Enzyme Name
UniProtKBKEGG

P11586
Protein nameC-1-tetrahydrofolate synthase, cytoplasmicmethylenetetrahydrofolate 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)

SynonymsC1-THF synthase
IncludesMethylenetetrahydrofolate dehydrogenase
   EC 1.5.1.5
Methenyltetrahydrofolate cyclohydrolase
   EC 3.5.4.9
Formyltetrahydrofolate synthetase
   EC 6.3.4.3
RefSeqNP_005947.3 (Protein)
NM_005956.3 (DNA/RNA sequence)
PfamPF01268 (FTHFS)
PF00763 (THF_DHG_CYH)
PF02882 (THF_DHG_CYH_C)
[Graphical view]

KEGG pathways
MAP codePathwaysE.C.
MAP00630Glyoxylate and dicarboxylate metabolism1.5.1.5,3.5.4.9,6.3.4.3
MAP00670One carbon pool by folate1.5.1.5,3.5.4.9,6.3.4.3

UniProtKB:Accession NumberP11586
Entry nameC1TC_HUMAN
Activity5,10-methylenetetrahydrofolate + NADP(+) = 5,10-methenyltetrahydrofolate + NADPH.,5,10-methenyltetrahydrofolate + H(2)O = 10- formyltetrahydrofolate.,ATP + formate + tetrahydrofolate = ADP + phosphate + 10-formyltetrahydrofolate.
SubunitHomodimer.
Subcellular locationCytoplasm.
Cofactor

Compound table: links to PDB-related databases & PoSSuM

SubstratesProducts
KEGG-idC00143C00006C00445C00001C00002C00058C00101C00445C00005C00080C00234C00008C00009
E.C.1.5.1.51.5.1.53.5.4.93.5.4.96.3.4.36.3.4.36.3.4.31.5.1.51.5.1.51.5.1.53.5.4.9,6.3.4.36.3.4.36.3.4.3
Compound5,10-MethylenetetrahydrofolateNADP+5,10-MethenyltetrahydrofolateH2OATPFormateTetrahydrofolate5,10-MethenyltetrahydrofolateNADPHH+10-FormyltetrahydrofolateADPOrthophosphate
Typeamino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl groupamide group,amine group,nucleotideamino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl groupH2Oamine group,nucleotidecarboxyl groupamino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl groupamino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl groupamide group,amine group,nucleotideothersamino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl groupamine group,nucleotidephosphate group/phosphate ion
ChEBI
18009

15377
15422
30751
15635
20506

16474
15378
15637
16761
26078
PubChem439175
5886
439237
962
22247451
5957
284
18971002
91443
5460413
439237
5884
1038
6326742
122347
6022
22486802
1004
                     
1a4iA01UnboundUnboundUnbound UnboundUnboundUnboundUnboundBound:NDP UnboundUnboundUnbound
1a4iB01UnboundUnboundUnbound UnboundUnboundUnboundUnboundBound:NDP UnboundUnboundUnbound
1diaA01UnboundBound:NAPUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1diaB01UnboundBound:NAPUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1dibA01UnboundBound:NAPUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1dibB01UnboundBound:NAPUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1digA01UnboundBound:NAPUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1digB01UnboundBound:NAPUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1a4iA02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1a4iB02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1diaA02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound Analogue:L24UnboundUnbound
1diaB02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1dibA02Analogue:L34UnboundUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1dibB02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound
1digA02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound Analogue:L37UnboundUnbound
1digB02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound UnboundUnboundUnbound

Active-site residues
resource
literature [7] & [11]
pdbCatalytic residues
         
1a4iA01 
1a4iB01 
1diaA01 
1diaB01 
1dibA01 
1dibB01 
1digA01 
1digB01 
1a4iA02LYS   56;GLN  100
1a4iB02LYS   56;GLN  100
1diaA02LYS   56;GLN  100
1diaB02LYS 1056;GLN 1100
1dibA02LYS   56;GLN  100
1dibB02LYS 1056;GLN 1100
1digA02LYS   56;GLN  100
1digB02LYS 1056;GLN 1100

References for Catalytic Mechanism
ReferencesSectionsNo. 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]
PubMed ID2541774
JournalBiochemistry
Year1989
Volume28
Pages2099-106
AuthorsBarlowe CK, Williams ME, Rabinowitz JC, Appling DR
TitleSite-directed mutagenesis of yeast C1-tetrahydrofolate synthase: analysis of an overlapping active site in a multifunctional enzyme.
[2]
PubMed ID1621989
JournalBiochemistry
Year1992
Volume202
Pages82-8
AuthorsStover P, Schirch V
TitleSynthesis of (6S)-5-formyltetrahydropteroyl-polyglutamates and interconversion to other reduced pteroylpolyglutamate derivatives.
[3]
PubMed ID8990502
JournalProteins
Year1996
Volume26
Pages481-2
AuthorsMonzingo AF, West MG, Schelp E, Appling DR, Robertus JD
TitleCrystallization of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
[4]
PubMed ID9061797
JournalProteins
Year1997
Volume27
Pages322-4
AuthorsCheung E, D'Ari L, Rabinowitz JC, Dyer DH, Huang JY, Stoddard BL
TitlePurification, crystallization, and preliminary x-ray studies of a bifunctional 5,10-methenyl/methylene-tetrahydrofolate cyclohydrolase/dehydrogenase from Escherichia coli.
[5]
CommentsX-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 1-301
Medline ID98179934
PubMed ID9519408
JournalStructure
Year1998
Volume6
Pages173-82
AuthorsAllaire M, Li Y, MacKenzie RE, Cygler M
TitleThe 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution.
Related PDB1a4i,1dig
Related UniProtKBP11586
[6]
PubMed ID10386884
JournalProtein Sci
Year1999
Volume8
Pages1342-9
AuthorsShen BW, Dyer DH, Huang JY, D'Ari L, Rabinowitz J, Stoddard BL
TitleThe crystal structure of a bacterial, bifunctional 5,10 methylene-tetrahydrofolate dehydrogenase/cyclohydrolase.
[7]
CommentsX-ray crystallography
PubMed ID10828945
JournalBiochemistry
Year2000
Volume39
Pages6325-35
AuthorsSchmidt A, Wu H, MacKenzie RE, Chen VJ, Bewly JR, Ray JE, Toth JE, Cygler M
TitleStructures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase.
Related PDB1dia,1dib
[8]
PubMed ID10933503
JournalProtein Sci
Year2000
Volume9
Pages1374-81
AuthorsMonzingo AF, Breksa A, Ernst S, Appling DR, Robertus JD
TitleThe X-ray structure of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.
[9]
PubMed ID11828486
JournalChembiochem
Year2001
Volume2
Pages530-41
AuthorsBartoschek S, Buurman G, Thauer RK, Geierstanger BH, Weyrauch JP, Griesinger C, Nilges M, Hutter MC, Helms V
TitleRe-face stereospecificity of methylenetetrahydromethanopterin and methylenetetrahydrofolate dehydrogenases is predetermined by intrinsic properties of the substrate.
[10]
PubMed ID12061812
JournalArch Biochem Biophys
Year2002
Volume403
Pages145-8
AuthorsPatel H, Christensen KE, Mejia N, MacKenzie RE
TitleMammalian mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase derived from a trifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase.
[11]
PubMed ID11904299
JournalJ Biol Chem
Year2002
Volume277
Pages18703-9
AuthorsSundararajan S, MacKenzie RE
TitleResidues involved in the mechanism of the bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase: the roles of glutamine 100 and aspartate 125.

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.

createdupdated
2004-03-232009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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