C1-THF synthase

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C1-THF synthase
C1-THF synthase
Ribbon model of C1-THF synthase according to PDB  1A4I
Properties of human protein
Mass / length primary structure 934 amino acids
Identifier
Gene name MTHFD1
External IDs
Enzyme Classifications
EC, category 1.5.1.5 ,  oxidoreductase
Response type (De) hydrogenation
Substrate 5,10-methylene-THF (-PG) + NADP +
Products 5,10-methenyl-THF (-PG) + NADPH
EC, category 3.5.4.9 ,  hydrolase
Response type hydrolysis
Substrate 5,10-methenyl-THF (-PG) + H 2 O
Products 10-formyl-THF (-PG)
EC, category 6.3.4.3 ,  ligase
Response type Addition of a formyl radical
Substrate Tetrahydrofolate (-PG) + formate + ATP
Products 10-formyl-THF (-PG) + ADP + phosphate
Occurrence
Parent taxon Opisthokonta
Orthologue
human House mouse
Entrez 4522 108156
Ensemble ENSG00000100714 ENSMUSG00000021048
UniProt P11586 Q922D8
Refseq (mRNA) NM_005956 NM_138745
Refseq (protein) NP_005947 NP_620084
Gene locus Chr 14: 64.39 - 64.46 Mb Chr 12: 76.26 - 76.32 Mb
PubMed search 4522 108156

C1-THF synthase (more precisely Cytoplasmic C1-tetrahydrofolate synthase ) is called the enzyme in eukaryotes , the three different reactions in the folic acid - metabolism catalyzed . Bacterial enzymes with the same functions only exist as individual proteins. In humans, the enzyme is found in all types of tissue, and there is a paralogous mitochondrial enzyme that only shows ligase activity. Mutations in MTHFD1 - gene may be prepared by reduction of one or more of the three enzyme functions to increased risk of neural tube defects result in the newborn, which can be reduced by folic acid intake during the first weeks of pregnancy.

The risk of placenta abruptions is increased several times in mothers who are homozygous for a certain mutation in the MTHFD1 gene. According to a study of 600 Chinese people, certain variants of C1-THF synthase increase homocysteine ​​levels and the risk of stomach cancer. Individual variants of the enzyme are also held responsible for the pathological events in migraines with aura.

Catalyzed reactions

THF+ ATP + HCOO - + ADP + phosphate
  Formyl-THF

A formyl group is added to tetrahydrofolic acid (THF) to give 10-formyl-THF.

Formyl-THF    Methenyl THF+ H 2 O

10-formyl-THF is converted to 5,10-methenyl-THF.

Methenyl THF+ NADPH   + NADP +  Methylene THF

5,10-methenyl-THF is hydrogenated to 5,10-methylene-THF.

Individual evidence

  1. ↑ UniProt P11586
  2. ↑ PROSITE entry
  3. ↑ Walkup AS, Appling DR: Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase . In: Arch. Biochem. Biophys. . 442, No. 2, October 2005, pp. 196-205. doi : 10.1016 / j.abb.2005.08.007 . PMID 16171773 .
  4. ↑ Parle-McDermott A, Mills JL, Kirke PN, et al : MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae . In: Am. J. Med. Genet. A . 132, No. 4, February 2005, pp. 365-8. doi : 10.1002 / ajmg.a.30354 . PMID 15633187 .
  5. ↑ Wang L, Ke Q, Chen W, et al : Polymorphisms of MTHFD, plasma homocysteine ​​levels, and risk of gastric cancer in a high-risk Chinese population . In: Clin. Cancer Res . 13, No. 8, April 2007, pp. 2526-32. doi : 10.1158 / 1078-0432.CCR-06-2293 . PMID 17438114 .
  6. ↑ Oterino A, Valle N, Pascual J, et al : Thymidylate synthase promoter tandem repeat and MTHFD1 R653Q polymorphisms modulate the risk for migraine conferred by the MTHFR T677 allele . In: Brain Res Mol Brain Res... . 139, No. 1, September 2005, pp. 163-8. doi : 10.1016 / j.molbrainres.2005.05.015 . PMID 15953655 .

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Folate Metabolism  - Learning and Teaching Materials