UniProt functional annotation for P00374



	UniProt functional annotation for P00374

UniProt code: P00374.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2. {ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:21876188}.

Catalytic activity: Reaction=(6S)-5,6,7,8-tetrahydrofolate + NADP(+) = 7,8-dihydrofolate + H(+) + NADPH; Xref=Rhea:RHEA:15009, ChEBI:CHEBI:15378, ChEBI:CHEBI:57451, ChEBI:CHEBI:57453, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.5.1.3; Evidence={ECO:0000255|PROSITE- ProRule:PRU00660, ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:15039552, ECO:0000269|PubMed:17569517, ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:19478082, ECO:0000269|PubMed:21876184, ECO:0000269|PubMed:9719595};

Biophysicochemical properties: Kinetic parameters: KM=2.7 uM for dihydrofolate {ECO:0000269|PubMed:15039552, ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:21876184}; KM=4.0 uM for NADPH {ECO:0000269|PubMed:15039552, ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:21876184};

Pathway: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8- tetrahydrofolate from 7,8-dihydrofolate: step 1/1.

Subunit: Homodimer. {ECO:0000269|PubMed:12657784, ECO:0000269|PubMed:12925791, ECO:0000269|PubMed:15039552, ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082, ECO:0000269|PubMed:2248959, ECO:0000269|PubMed:3383852}.

Subcellular location: Mitochondrion {ECO:0000250|UniProtKB:P00375}. Cytoplasm {ECO:0000250|UniProtKB:P00375}.

Tissue specificity: Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain. {ECO:0000269|PubMed:21310276}.

Disease: Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]: An inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms. {ECO:0000269|PubMed:21310276, ECO:0000269|PubMed:21310277}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the dihydrofolate reductase family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2. {ECO:0000269\|PubMed:12096917, ECO:0000269\|PubMed:21876188}.


Catalytic activity:		Reaction=(6S)-5,6,7,8-tetrahydrofolate + NADP(+) = 7,8-dihydrofolate + H(+) + NADPH; Xref=Rhea:RHEA:15009, ChEBI:CHEBI:15378, ChEBI:CHEBI:57451, ChEBI:CHEBI:57453, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.5.1.3; Evidence={ECO:0000255\|PROSITE- ProRule:PRU00660, ECO:0000269\|PubMed:12096917, ECO:0000269\|PubMed:15039552, ECO:0000269\|PubMed:17569517, ECO:0000269\|PubMed:19196009, ECO:0000269\|PubMed:19478082, ECO:0000269\|PubMed:21876184, ECO:0000269\|PubMed:9719595};
Biophysicochemical properties:		Kinetic parameters: KM=2.7 uM for dihydrofolate {ECO:0000269\|PubMed:15039552, ECO:0000269\|PubMed:19196009, ECO:0000269\|PubMed:21876184}; KM=4.0 uM for NADPH {ECO:0000269\|PubMed:15039552, ECO:0000269\|PubMed:19196009, ECO:0000269\|PubMed:21876184};
Pathway:		Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8- tetrahydrofolate from 7,8-dihydrofolate: step 1/1.
Subunit:		Homodimer. {ECO:0000269\|PubMed:12657784, ECO:0000269\|PubMed:12925791, ECO:0000269\|PubMed:15039552, ECO:0000269\|PubMed:16222560, ECO:0000269\|PubMed:19478082, ECO:0000269\|PubMed:2248959, ECO:0000269\|PubMed:3383852}.
Subcellular location:		Mitochondrion {ECO:0000250\|UniProtKB:P00375}. Cytoplasm {ECO:0000250\|UniProtKB:P00375}.
Tissue specificity:		Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain. {ECO:0000269\|PubMed:21310276}.
Disease:		Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]: An inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms. {ECO:0000269\|PubMed:21310276, ECO:0000269\|PubMed:21310277}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the dihydrofolate reductase family. {ECO:0000305}.