Metabolism of folate and pterines (Homo sapiens)

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15, 207, 2913, 1713, 178, 294, 12, 1825, 298, 2921119, 1613, 178, 297, 296, 26, 27213, 17310, 2325, 291, 196, 26, 275, 225, 14, 2224, 284, 12, 18313, 1710, 231, 19mitochondrial matrixcytosolmitochondrial intermembrane spaceNADP+FOLR2MTHFD1 CO2THFPiALDH1L1 ATPMTHFD1L dimerATPGlyL-SerH+NAD+5-methyl-THF10-formyl-THFPGNADP+H+2xMTHFD1ADPDHFR5-methyl-THFH+DHFRL1 NADPHH2OGluPiGlyNADP+PiL-SerNADP+HCOOHHCOOHNADP+FPGS-15-methyl-THFPGFOLR2 MTHFD2 SLC19A1THFPGADPDHFR NADPHSHMT2 tetramerATPSHMT1 tetramerL-GluH+ADH1L2 tetramerH2ONADHMTHFD1L MTHFD2L ADPPiADPSHMT2 ATPNADPHMTHFD2, D2LPXLP-SHMT1 5-formyl-THFPGH2O5,10-methenyl-THFPGH2ONADP+PiCO2H+SLC46A1FOLR2:FOLA10-formyl-THF2xMTHFRMTHFR ADPTHFPGFOLANADPHTHFFPGS-25,10-methylene-THFPG10-formyl-THFPGMTHFSH+H2OTHFPGALDH1L1 tetramerALDH1L2 H+ATPFOLA5,10-methylene-THFNADPHDHFSLC25A32FOLA ADP5,10-methenyl-THFNADPHPi1, 191, 191, 191, 19


Description

Folates are essential cofactors that provide one-carbon moieties in various states of reduction for biosynthetic reactions. Processes annotated here include transport reactions by which folates are taken up by cells and moved intracellularly, folate conjugation with glutamate (required for folate retention within a cell), and some of the key reactions in the generation of reduced folates and one-carbon derivatives of folate. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 196757
Reactome-version 
Reactome version: 61

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Ontology Terms

 

Bibliography

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  1. Walkup AS, Appling DR.; ''Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase.''; PubMed Europe PMC
  2. Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J, Nienhuis AW.; ''The functional human dihydrofolate reductase gene.''; PubMed Europe PMC
  3. Hum DW, Bell AW, Rozen R, MacKenzie RE.; ''Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase.''; PubMed Europe PMC
  4. Villar E, Schuster B, Peterson D, Schirch V.; ''C1-Tetrahydrofolate synthase from rabbit liver. Structural and kinetic properties of the enzyme and its two domains.''; PubMed Europe PMC
  5. Dayan A, Bertrand R, Beauchemin M, Chahla D, Mamo A, Filion M, Skup D, Massie B, Jolivet J.; ''Cloning and characterization of the human 5,10-methenyltetrahydrofolate synthetase-encoding cDNA.''; PubMed Europe PMC
  6. Titus SA, Moran RG.; ''Retrovirally mediated complementation of the glyB phenotype. Cloning of a human gene encoding the carrier for entry of folates into mitochondria.''; PubMed Europe PMC
  7. Strickland KC, Krupenko NI, Dubard ME, Hu CJ, Tsybovsky Y, Krupenko SA.; ''Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase.''; PubMed Europe PMC
  8. Bolusani S, Young BA, Cole NA, Tibbetts AS, Momb J, Bryant JD, Solmonson A, Appling DR.; ''Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues.''; PubMed Europe PMC
  9. Ferguson PL, Flintoff WF.; ''Topological and functional analysis of the human reduced folate carrier by hemagglutinin epitope insertion.''; PubMed Europe PMC
  10. Bertrand R, MacKenzie RE, Jolivet J.; ''Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates.''; PubMed Europe PMC
  11. Tibbetts AS, Appling DR.; ''Compartmentalization of Mammalian folate-mediated one-carbon metabolism.''; PubMed Europe PMC
  12. Krupenko NI, Dubard ME, Strickland KC, Moxley KM, Oleinik NV, Krupenko SA.; ''ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase.''; PubMed Europe PMC
  13. Yang XM, MacKenzie RE.; ''NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is the mammalian homolog of the mitochondrial enzyme encoded by the yeast MIS1 gene.''; PubMed Europe PMC
  14. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID.; ''Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.''; PubMed Europe PMC
  15. Garrow TA, Admon A, Shane B.; ''Expression cloning of a human cDNA encoding folylpoly(gamma-glutamate) synthetase and determination of its primary structure.''; PubMed Europe PMC
  16. Lucock M.; ''Folic acid: nutritional biochemistry, molecular biology, and role in disease processes.''; PubMed Europe PMC
  17. Chen L, Qi H, Korenberg J, Garrow TA, Choi YJ, Shane B.; ''Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene.''; PubMed Europe PMC
  18. Wibowo AS, Singh M, Reeder KM, Carter JJ, Kovach AR, Meng W, Ratnam M, Zhang F, Dann CE.; ''Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition.''; PubMed Europe PMC
  19. Antony AC, Kane MA, Portillo RM, Elwood PC, Kolhouse JF.; ''Studies of the role of a particulate folate-binding protein in the uptake of 5-methyltetrahydrofolate by cultured human KB cells.''; PubMed Europe PMC
  20. Prasannan P, Pike S, Peng K, Shane B, Appling DR.; ''Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls.''; PubMed Europe PMC
  21. Scott JM.; ''Folate and vitamin B12.''; PubMed Europe PMC
  22. Davies JF, Delcamp TJ, Prendergast NJ, Ashford VA, Freisheim JH, Kraut J.; ''Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate.''; PubMed Europe PMC
  23. Pike ST, Rajendra R, Artzt K, Appling DR.; ''Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos.''; PubMed Europe PMC
  24. Williams FM, Flintoff WF.; ''Isolation of a human cDNA that complements a mutant hamster cell defective in methotrexate uptake.''; PubMed Europe PMC
  25. Goyette P, Frosst P, Rosenblatt DS, Rozen R.; ''Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency.''; PubMed Europe PMC
  26. Shin M, Bryant JD, Momb J, Appling DR.; ''Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues.''; PubMed Europe PMC
  27. Ratnam M, Marquardt H, Duhring JL, Freisheim JH.; ''Homologous membrane folate binding proteins in human placenta: cloning and sequence of a cDNA.''; PubMed Europe PMC
  28. Anderson DD, Quintero CM, Stover PJ.; ''Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria.''; PubMed Europe PMC
  29. Renwick SB, Snell K, Baumann U.; ''The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101365view11:25, 1 November 2018ReactomeTeamreactome version 66
100903view21:00, 31 October 2018ReactomeTeamreactome version 65
100444view19:34, 31 October 2018ReactomeTeamreactome version 64
99993view16:18, 31 October 2018ReactomeTeamreactome version 63
99547view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93817view13:38, 16 August 2017ReactomeTeamreactome version 61
93363view11:21, 9 August 2017ReactomeTeamreactome version 61
86968view13:50, 15 July 2016MkutmonOntology Term : 'folate metabolic pathway' added !
86447view09:18, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
10-formyl-THFMetaboliteCHEBI:15637 (ChEBI)
10-formyl-THFPGMetaboliteCHEBI:28010 (ChEBI)
2xMTHFD1ComplexR-HSA-200667 (Reactome)
2xMTHFRComplexR-HSA-200713 (Reactome)
5,10-methenyl-THFMetaboliteCHEBI:15638 (ChEBI)
5,10-methenyl-THFPGMetaboliteCHEBI:65049 (ChEBI)
5,10-methylene-THFMetaboliteCHEBI:12071 (ChEBI)
5,10-methylene-THFPGMetaboliteCHEBI:60473 (ChEBI)
5-formyl-THFPGMetaboliteCHEBI:63907 (ChEBI)
5-methyl-THFMetaboliteCHEBI:15641 (ChEBI)
5-methyl-THFPGMetaboliteCHEBI:63907 (ChEBI)
ADH1L2 tetramerComplexR-HSA-6808504 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ALDH1L1 ProteinO75891 (Uniprot-TrEMBL)
ALDH1L1 tetramerComplexR-HSA-6808495 (Reactome)
ALDH1L2 ProteinQ3SY69 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
DHFMetaboliteCHEBI:15633 (ChEBI)
DHFR ProteinP00374 (Uniprot-TrEMBL)
DHFRL1 ProteinQ86XF0 (Uniprot-TrEMBL)
DHFRComplexR-HSA-2975817 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
FOLA MetaboliteCHEBI:27470 (ChEBI)
FOLAMetaboliteCHEBI:27470 (ChEBI)
FOLR2 ProteinP14207 (Uniprot-TrEMBL)
FOLR2:FOLAComplexR-HSA-8940118 (Reactome)
FOLR2ProteinP14207 (Uniprot-TrEMBL)
FPGS-1ProteinQ05932-1 (Uniprot-TrEMBL)
FPGS-2ProteinQ05932-2 (Uniprot-TrEMBL)
GluMetaboliteCHEBI:29985 (ChEBI)
GlyMetaboliteCHEBI:57305 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCOOHMetaboliteCHEBI:30751 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
L-SerMetaboliteCHEBI:33384 (ChEBI)
MTHFD1 ProteinP11586 (Uniprot-TrEMBL)
MTHFD1L ProteinQ6UB35 (Uniprot-TrEMBL)
MTHFD1L dimerComplexR-HSA-5696840 (Reactome)
MTHFD2 ProteinP13995 (Uniprot-TrEMBL)
MTHFD2, D2LComplexR-HSA-6801461 (Reactome)
MTHFD2L ProteinQ9H903 (Uniprot-TrEMBL)
MTHFR ProteinP42898 (Uniprot-TrEMBL)
MTHFSProteinP49914 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
PXLP-SHMT1 ProteinP34896 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SHMT1 tetramerComplexR-HSA-71243 (Reactome)
SHMT2 ProteinP34897 (Uniprot-TrEMBL)
SHMT2 tetramerComplexR-HSA-5694100 (Reactome)
SLC19A1ProteinP41440 (Uniprot-TrEMBL)
SLC25A32ProteinQ9H2D1 (Uniprot-TrEMBL)
SLC46A1ProteinQ96NT5 (Uniprot-TrEMBL)
THFMetaboliteCHEBI:15635 (ChEBI)
THFPGMetaboliteCHEBI:28624 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
10-formyl-THFArrowR-HSA-5696839 (Reactome)
10-formyl-THFArrowR-HSA-6801462 (Reactome)
10-formyl-THFPGArrowR-HSA-200711 (Reactome)
10-formyl-THFPGArrowR-HSA-200740 (Reactome)
10-formyl-THFPGR-HSA-200661 (Reactome)
10-formyl-THFPGR-HSA-6808487 (Reactome)
10-formyl-THFPGR-HSA-6808496 (Reactome)
10-formyl-THFR-HSA-6801456 (Reactome)
2xMTHFD1mim-catalysisR-HSA-200644 (Reactome)
2xMTHFD1mim-catalysisR-HSA-200661 (Reactome)
2xMTHFD1mim-catalysisR-HSA-200711 (Reactome)
2xMTHFD1mim-catalysisR-HSA-200718 (Reactome)
2xMTHFD1mim-catalysisR-HSA-200740 (Reactome)
2xMTHFRmim-catalysisR-HSA-200676 (Reactome)
5,10-methenyl-THFArrowR-HSA-6801328 (Reactome)
5,10-methenyl-THFPGArrowR-HSA-200644 (Reactome)
5,10-methenyl-THFPGArrowR-HSA-200661 (Reactome)
5,10-methenyl-THFPGArrowR-HSA-6801342 (Reactome)
5,10-methenyl-THFPGR-HSA-200718 (Reactome)
5,10-methenyl-THFPGR-HSA-200740 (Reactome)
5,10-methenyl-THFR-HSA-6801462 (Reactome)
5,10-methylene-THFPGArrowR-HSA-200718 (Reactome)
5,10-methylene-THFPGArrowR-HSA-200735 (Reactome)
5,10-methylene-THFPGR-HSA-200644 (Reactome)
5,10-methylene-THFPGR-HSA-200651 (Reactome)
5,10-methylene-THFPGR-HSA-200676 (Reactome)
5,10-methylene-THFR-HSA-5694137 (Reactome)
5,10-methylene-THFR-HSA-6801328 (Reactome)
5-formyl-THFPGR-HSA-6801342 (Reactome)
5-methyl-THFArrowR-HSA-200652 (Reactome)
5-methyl-THFPGArrowR-HSA-200676 (Reactome)
5-methyl-THFPGArrowR-HSA-200681 (Reactome)
5-methyl-THFR-HSA-200652 (Reactome)
5-methyl-THFR-HSA-200681 (Reactome)
ADH1L2 tetramermim-catalysisR-HSA-6808487 (Reactome)
ADPArrowR-HSA-197958 (Reactome)
ADPArrowR-HSA-200681 (Reactome)
ADPArrowR-HSA-200682 (Reactome)
ADPArrowR-HSA-200711 (Reactome)
ADPArrowR-HSA-5696839 (Reactome)
ADPArrowR-HSA-6801342 (Reactome)
ADPR-HSA-6801456 (Reactome)
ALDH1L1 tetramermim-catalysisR-HSA-6808496 (Reactome)
ATPArrowR-HSA-6801456 (Reactome)
ATPR-HSA-197958 (Reactome)
ATPR-HSA-200681 (Reactome)
ATPR-HSA-200682 (Reactome)
ATPR-HSA-200711 (Reactome)
ATPR-HSA-5696839 (Reactome)
ATPR-HSA-6801342 (Reactome)
CO2ArrowR-HSA-6808487 (Reactome)
CO2ArrowR-HSA-6808496 (Reactome)
DHFArrowR-HSA-197963 (Reactome)
DHFR-HSA-197972 (Reactome)
DHFRmim-catalysisR-HSA-197963 (Reactome)
DHFRmim-catalysisR-HSA-197972 (Reactome)
FOLAArrowR-HSA-200646 (Reactome)
FOLAArrowR-HSA-200729 (Reactome)
FOLAArrowR-HSA-8942344 (Reactome)
FOLAR-HSA-197963 (Reactome)
FOLAR-HSA-200646 (Reactome)
FOLAR-HSA-200729 (Reactome)
FOLAR-HSA-8940134 (Reactome)
FOLR2:FOLAArrowR-HSA-8940134 (Reactome)
FOLR2:FOLAR-HSA-8942344 (Reactome)
FOLR2ArrowR-HSA-8942344 (Reactome)
FOLR2R-HSA-8940134 (Reactome)
FPGS-1mim-catalysisR-HSA-200682 (Reactome)
FPGS-2mim-catalysisR-HSA-197958 (Reactome)
FPGS-2mim-catalysisR-HSA-200681 (Reactome)
GluR-HSA-200682 (Reactome)
GlyArrowR-HSA-200735 (Reactome)
GlyR-HSA-200651 (Reactome)
GlyR-HSA-5694137 (Reactome)
H+ArrowR-HSA-200644 (Reactome)
H+ArrowR-HSA-6801342 (Reactome)
H+ArrowR-HSA-6808487 (Reactome)
H+ArrowR-HSA-6808496 (Reactome)
H+R-HSA-197963 (Reactome)
H+R-HSA-197972 (Reactome)
H+R-HSA-200676 (Reactome)
H+R-HSA-200718 (Reactome)
H2OArrowR-HSA-200661 (Reactome)
H2OR-HSA-200740 (Reactome)
H2OR-HSA-5694137 (Reactome)
H2OR-HSA-6801462 (Reactome)
H2OR-HSA-6808487 (Reactome)
H2OR-HSA-6808496 (Reactome)
HCOOHArrowR-HSA-6801456 (Reactome)
HCOOHArrowR-HSA-6803255 (Reactome)
HCOOHR-HSA-200711 (Reactome)
HCOOHR-HSA-5696839 (Reactome)
HCOOHR-HSA-6803255 (Reactome)
L-GluR-HSA-197958 (Reactome)
L-GluR-HSA-200681 (Reactome)
L-SerArrowR-HSA-200651 (Reactome)
L-SerArrowR-HSA-5694137 (Reactome)
L-SerR-HSA-200735 (Reactome)
MTHFD1L dimermim-catalysisR-HSA-5696839 (Reactome)
MTHFD1L dimermim-catalysisR-HSA-6801456 (Reactome)
MTHFD2, D2Lmim-catalysisR-HSA-6801328 (Reactome)
MTHFD2, D2Lmim-catalysisR-HSA-6801462 (Reactome)
MTHFSmim-catalysisR-HSA-6801342 (Reactome)
NAD+R-HSA-6801328 (Reactome)
NADHArrowR-HSA-6801328 (Reactome)
NADP+ArrowR-HSA-197963 (Reactome)
NADP+ArrowR-HSA-197972 (Reactome)
NADP+ArrowR-HSA-200676 (Reactome)
NADP+ArrowR-HSA-200718 (Reactome)
NADP+R-HSA-200644 (Reactome)
NADP+R-HSA-6808487 (Reactome)
NADP+R-HSA-6808496 (Reactome)
NADPHArrowR-HSA-200644 (Reactome)
NADPHArrowR-HSA-6808487 (Reactome)
NADPHArrowR-HSA-6808496 (Reactome)
NADPHR-HSA-197963 (Reactome)
NADPHR-HSA-197972 (Reactome)
NADPHR-HSA-200676 (Reactome)
NADPHR-HSA-200718 (Reactome)
PiArrowR-HSA-197958 (Reactome)
PiArrowR-HSA-200681 (Reactome)
PiArrowR-HSA-200682 (Reactome)
PiArrowR-HSA-200711 (Reactome)
PiArrowR-HSA-5696839 (Reactome)
PiArrowR-HSA-6801342 (Reactome)
PiR-HSA-6801456 (Reactome)
R-HSA-197958 (Reactome) Cytosolic folylpolyglutamate synthase catalyzes the reaction of THF-glutamate(n), L-glutamate, and ATP to form THF-glutamate(n+1), ADP, and orthophosphate. (The first glutamate residue is attached to the glutamate moiety of THF itself; for convenience the process is annotated here as if it proceeded in a single concerted step.) The extent of conjugation is variable, but the commonest cytosolic form of THF has five added glutamate residues. Although its properties as a donor of one-carbon units are not affected by glutamate addition, THF that lacks added glutamate residues cannot be retained in the cytosol so this reaction is needed for normal THF function under physiological conditions (Garrow et al. 1992; Chen et al. 1996).
R-HSA-197963 (Reactome) Cytosolic dihydrofolate reductase catalyzes the reaction of folate, NADPH, and H+ to form dihydrofolate and NADP+ (Chen et al. 1984; Davies et al. 1990).
R-HSA-197972 (Reactome) Cytosolic dihydrofolate reductase catalyzes the reaction of dihydrofolate, NADPH, and H+ to form tetrahydrofolate (THF) and NADP+ (Chen et al. 1984; Davies et al. 1990).
R-HSA-200644 (Reactome) The methylenetetrahydrofolate dehydrogenase activity of the trifunctional MTHFD1 enzyme catalyzes the reversible reaction of 5,10-methyleneTHF polyglutamate and NADP+ to form 5,10-methenylTHF polyglutamate, NADPH, and H+. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985).
R-HSA-200646 (Reactome) SLC46A1 protein in the plasma membrane mediates the reversible transport of folate between the extracellular space and the cytosol. Retention of folate within the cell is dependent on polyglutamate addition (Qiu et al. 2006; Chen et al. 1996).
R-HSA-200651 (Reactome) Cytosolic serine hydroxymethyltransferase catalyzes the reversible reaction of 5,10-methyleneTHF polyglutamate and glycine to form tetrahydrofolate polyglutamate (THF polyglutamate) and serine. The active form of the enzyme is a tetramer (Renwick et al. 1998).
R-HSA-200652 (Reactome) SLC19A1 protein, associated with the plasma membrane, mediates the uptake of extracellular 5-methyltetrahydrofolate and other reduced folates (Williams and Flintoff 1995; Ferguson and Flintoff 1999).
R-HSA-200661 (Reactome) The methenyltetrahydrofolate cyclohydrolase activity of the trifunctional MTHFD1 enzyme catalyzes the reversible reaction of 10-formylTHF polyglutamate to form 5,10-methenylTHF polyglutamate and H2O. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985).
R-HSA-200676 (Reactome) Cytosolic MTHFR dimer catalyzes the reaction of 5,10-methyleneTHF polyglutamate, NADPH, and H+ to form 5-methylTHF polyglutamate and NADP+. The specificity and importance of this reaction in vivo have been established through the study of patients deficient in the enzyme (Goyette et al. 1995).
R-HSA-200680 (Reactome) SLC25A32 protein in the inner mitochondrial membrane mediates the reversible transport of tetrahydrofolate between the cytosol and the mitochondrial matrix. Retention of tetrahydrofolate within the mitochondrial matrix is dependent on mitochondrial polyglutamate addition (Titus and Moran 2000; Chen et al. 1996).
R-HSA-200681 (Reactome) Cytosolic folylpolyglutamate synthase catalyzes the reaction of 5-methylTHF-glutamate(n), L-glutamate, and ATP to form 5-methylTHF-glutamate(n+1), ADP, and orthophosphate. (The first glutamate residue is attached to the glutamate moiety of 5-methylTHF itself; for convenience the process is annotated here as if it proceeded in a single concerted step.) The extent of conjugation is variable, but the commonest cytosolic form of 5-methylTHF has five added glutamate residues. Although its properties as a donor of one-carbon units are not affected by glutamate addition, 5-methylTHF that lacks added glutamate residues cannot be retained in the cytosol so this reaction is needed for normal 5-methylTHF function under physiological conditions (Garrow et al. 1992; Chen et al. 1996).
R-HSA-200682 (Reactome) Mitochondrial folylpolyglutamate synthase catalyzes the reaction of THF-glutamate(n), L-glutamate, and ATP to form THF-glutamate(n+1), ADP, and orthophosphate. (The first glutamate residue is attached to the glutamate moiety of THF itself; for convenience the process is annotated here as if it proceeded in a single concerted step.) The extent of conjugation is variable, but the commonest mitochondrial form of THF has six added glutamate residues. Although its properties as a donor of one-carbon units are not affected by glutamate addition, THF that lacks added glutamate residues cannot be retained in the mitochondrial matrix so this reaction is needed for normal THF function under physiological conditions. The mitochondrial and cytosolic forms of folylpolyglutamate synthase are encoded by the same gene - alternative splicing generates mRNA with or without an initial exon encoding a mitochondrial targeting sequence (Garrow et al. 1992; Chen et al. 1996).
R-HSA-200711 (Reactome) The formate-tetrahydrofolate ligase activity of the trifunctional MTHFD1 enzyme catalyzes the reaction of THF polyglutamate, formate, and ATP to form 10-formylTHF polyglutamate, ADP, and orthophosphate. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985).
R-HSA-200718 (Reactome) The methylenetetrahydrofolate dehydrogenase activity of the trifunctional MTHFD1 enzyme catalyzes the reversible reaction of 5,10-methenylTHF polyglutamate, NADPH, and H+ to form 5,10-methyleneTHF polyglutamate and NADP+. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985).
R-HSA-200720 (Reactome) SLC25A32 protein in the inner mitochondrial membrane mediates the reversible transport of tetrahydrofolate between the cytosol and the mitochondrial matrix. Retention of tetrahydrofolate within the mitochondrial matrix is dependent on mitochondrial polyglutamate addition (Titus and Moran 2000; Chen et al. 1996).
R-HSA-200729 (Reactome) SLC46A1 protein in the plasma membrane mediates the reversible transport of folate between the extracellular space and the cytosol. Retention of folate within the cell is dependent on polyglutamate addition. Although the SLC46A1 gene is expressed in several tissues in the body, this transporter appears to be primarily needed for absorption of dietary folate from the intestinal lumen (Qiu et al. 2006; Chen et al. 1996).
R-HSA-200735 (Reactome) Cytosolic serine hydroxymethyltransferase catalyzes the reversible reaction of tetrahydrofolate polyglutamate (THF polyglutamate) and serine to form 5,10-methyleneTHF polyglutamate and glycine. The active form of the enzyme is a tetramer (Renwick et al. 1998). In the body, this reaction is a major source of 5,10-methyleneTHF, which in turn is a critical precursor in the synthesis of dTMP.
R-HSA-200740 (Reactome) The methenyltetrahydrofolate cyclohydrolase activity of the trifunctional MTHFD1 enzyme catalyzes the reversible reaction of 5,10-methenylTHF polyglutamate and H2O to form 10-formylTHF polyglutamate. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985).
R-HSA-5694137 (Reactome) Mitochondrial serine hydroxymethyltransferase (SHMT2) contributes to the de novo mitochondrial thymidylate biosynthesis pathway which is essential for mitochondrial DNA (mtDNA) integrity. It is associated with the inner mitochondrial membrane and is functional as a homotetramer. SHMT2 transfers a hydroxymethyl group from 5,10-methylenetetrahydrofolate (5,10MTHF) to glycine (Gly), forming tetrahydrofolate (THF) and L-serine (L-Ser) (Anderson et al. 2011).
R-HSA-5696839 (Reactome) All C1-tetrahydrofolate (C1-THF) synthases characterised to date are trifunctional, containing the activities of 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase. Mitochondrial monofunctional C1-tetrahydrofolate synthase (MTHFD1L) only possesses 10-formyl-THF synthetase activity and it reversibly ligates formate (HCOOH) to tetrahydrofolate (THF), forming 10-formyltetrahydrofolate (10-formyl-THF) (Prasannan et al. 2003, Walkup & Appling 2005). MTHFD1L is functional as a homodimer and could be a missing reaction in one-carbon folate metabolism linking the metabolism of formate from the cytosol to mitochondria (Pike et al. 2010).
R-HSA-6801328 (Reactome) Mammalian mitochondria are able to produce formate from one-carbon (1C) donors such as serine, glycine and sarcosine. In mitochondria, the 1C units are oxidised to formate and transported to the cytosol, where the formate is reattached to tetrahydrofolate (THF) for use in de novo purine biosynthesis. The mitochondrial bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolases D2 and D2L (MTHFD2, MTHFD2L) mediate reversible reactions to convert 5,10-methylene-THF, via 5,10-methenyl-THF, to 10-formyl-THF. These enzymes have filled in missing gaps which existed in the transformation of 5,10-methylene-THF to formate in human mitochondria (Yang & MacKenzie 1993, Bolusani et al. 2011, Shin et al. 2014).
R-HSA-6801342 (Reactome) Cytosolic 5-formyltetrahydrofolate cyclo-ligase (MTHFS) catalyses the irreversible transformation of 5-formyltetrahydrofolate (5-formyl-THF) to 5,10-methenyltetrahydrofolate (5,10-methenyl-THF) (Dayan et al. 1995). MTHFS has higher affinity for the polyglutamate form of 5-formyl-THF (5-formyl-THFPG) (Bertrand et al. 1987). This reaction of tetrahydrofolate metabolism helps regulate carbon flow through the folate-dependent one-carbon metabolic network which is essential for growth and proliferation of cells.
R-HSA-6801456 (Reactome) All C1-tetrahydrofolate (C1-THF) synthases characterised to date are trifunctional, containing the activities of 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase. Mitochondrial monofunctional C1-tetrahydrofolate synthase (MTHFD1L) only possesses 10-formyl-THF synthetase activity and it reversibly ligates formate (HCOOH) to tetrahydrofolate (THF), forming 10-formyltetrahydrofolate (10-formyl-THF) (Prasannan et al. 2003, Walkup & Appling 2005). MTHFD1L is functional as a homodimer and could be a missing reaction in one-carbon folate metabolism linking the metabolism of formate from the cytosol to mitochondria (Pike et al. 2010). Under most conditions, the majority of one-carbon units for cytoplasmic processes are derived from mitochondrial formate.
R-HSA-6801462 (Reactome) Mammalian mitochondria are able to produce formate from one-carbon (1C) donors such as serine, glycine and sarcosine. In mitochondria, the 1C units are oxidised to formate and transported to the cytosol, where the formate is reattached to tetrahydrofolate (THF) for use in de novo purine biosynthesis. The mitochondrial bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolases D2 and D2L (MTHFD2, MTHFD2L) mediate reversible reactions to convert 5,10-methylene-THF, via 5,10-methenyl-THF, to 10-formyl-THF. These enzymes have filled in missing gaps which existed in the transformation of 5,10-methylene-THF to formate in human mitochondria (Yang & MacKenzie 1993, Bolusani et al. 2011, Shin et al. 2014).
R-HSA-6803255 (Reactome) Formate (HCOOH) is transported from the mitochondrial matrix to the cytosol, where it is reattached to tetrahydrofolate (THF). The mechanism of transport is thought to be carrier-mediated but no protein has been discovered yet (Tibbetts & Appling 2010).
R-HSA-6808487 (Reactome) ALDH1L2 (mitochondrial 10-formyltetrahydrofolate dehydrogenase) catalyzes the NADP-dependent dehydrogenation of 10-formyl-THFPG (10-formyltetrahydrofolate polyglutamate) to THFPG (tetrahydrofolate polyglutamate). This reaction has the effect of depleting the pool of folate charged with 1-carbon groups and might thus serve to regulate the size of the pool and the overall pace of mitochondrial biosynthetic reactions dependent on it (Krupenko et al. 2010; Strickland et al. 2011).
R-HSA-6808496 (Reactome) ALDH1L1 (cytosolic 10-formyltetrahydrofolate dehydrogenase) catalyzes the NADP-dependent dehydrogenation of 10-formyl-THFPG (10-formyltetrahydrofolate polyglutamate) to THFPG (tetrahydrofolate polyglutamate). This reaction has the effect of depleting the pool of folate charged with 1-carbon groups and might thus serve to regulate the size of the pool and the overall pace of cytosolic biosynthetic reactions dependent on it (Krupenko et al. 2010; Strickland et al. 2011).
R-HSA-8940134 (Reactome) The folate receptor beta (FOLR2, FBP) (Ratnam et al. 1989) binds folate (FOLA) and reduced folic acid derivatives and mediates their delivery into cells (Antony et al. 1985). Antifolates are folate analogues that inhibit vitamin B9 (folic acid)-using cellular enzymes are used in the treatment of cancer and inflammatory diseases. Targeting FOLR2 may be a way to investigate novel folate-based drugs in the treatment of these diseases (Wibowo et al. 2013).
R-HSA-8942344 (Reactome) The folate receptor beta (FOLR2, FBP) binds folate (FOLA) and reduced folic acid derivatives and mediates their delivery into cells (Antony et al. 1985). After ligand binding, the resultant complex is endocytosed into the cell where ligand release occurs in the acidic environment of the recycling endosome (Wibowo et al. 2013). For simplicity, the overall transport of FOLA from the extracellular region to the cytosol of a cell is described here.
SHMT1 tetramermim-catalysisR-HSA-200651 (Reactome)
SHMT1 tetramermim-catalysisR-HSA-200735 (Reactome)
SHMT2 tetramermim-catalysisR-HSA-5694137 (Reactome)
SLC19A1mim-catalysisR-HSA-200652 (Reactome)
SLC25A32mim-catalysisR-HSA-200680 (Reactome)
SLC25A32mim-catalysisR-HSA-200720 (Reactome)
SLC46A1mim-catalysisR-HSA-200646 (Reactome)
SLC46A1mim-catalysisR-HSA-200729 (Reactome)
THFArrowR-HSA-197972 (Reactome)
THFArrowR-HSA-200680 (Reactome)
THFArrowR-HSA-200720 (Reactome)
THFArrowR-HSA-5694137 (Reactome)
THFArrowR-HSA-6801456 (Reactome)
THFPGArrowR-HSA-197958 (Reactome)
THFPGArrowR-HSA-200651 (Reactome)
THFPGArrowR-HSA-200682 (Reactome)
THFPGArrowR-HSA-6808487 (Reactome)
THFPGArrowR-HSA-6808496 (Reactome)
THFPGR-HSA-200711 (Reactome)
THFPGR-HSA-200735 (Reactome)
THFR-HSA-197958 (Reactome)
THFR-HSA-200680 (Reactome)
THFR-HSA-200682 (Reactome)
THFR-HSA-200720 (Reactome)
THFR-HSA-5696839 (Reactome)
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