Disease relevance of Fthfd

• Rat liver 10-FTHFDH was expressed in a baculovirus system, and site-directed mutagenesis has been used to study the role of cysteine 707 in the activity of 10-FTHFDH [1].
• Thus, two mechanisms may be operative in explaining low formate oxidation in species susceptible to methanol toxicity, low hepatic H4folate levels and reduced hepatic 10-formyltetrahydrofolate dehydrogenase activity [2].
• Overexpression of functional hydrolase domain of rat liver 10-formyltetrahydrofolate dehydrogenase in Escherichia coli [3].

High impact information on Fthfd

• 10-Formyltetrahydrofolate dehydrogenase (FDH) converts 10-formyltetrahydrofolate, a precursor for nucleotide biosynthesis, to tetrahydrofolate [4].
• The crystal structure of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase: mechanism of hydrolysis and its interplay with the dehydrogenase domain [4].
• In a previous study, this protein arginine methyltransferase activity was identified as an additional activity of 10-formyltetrahydrofolate dehydrogenase (FDH) protein [5].
• Aspartate 142 is involved in both hydrolase and dehydrogenase catalytic centers of 10-formyltetrahydrofolate dehydrogenase [6].
• The purified rat liver methylase had approximately 33% of the 10-formyltetrahydrofolate dehydrogenase and 36% of the aldehyde dehydrogenase activity as compared with the recombinant dehydrogenase, which also had protein methylase I activity [7].

Chemical compound and disease context of Fthfd

• Folate and 10-formyltetrahydrofolate dehydrogenase in human and rat retina: relation to methanol toxicity [8].
• Presumably, rats are not normally susceptible to formate toxicity because they possess high hepatic H4folate and 10-FTHFDH levels [9].

Biological context of Fthfd

• We conclude that cysteine 707 is directly involved in the active site of 10-FTHFDH responsible for dehydrogenase activity, and there is a separate site for the hydrolase activity [1].
• The amino acid sequence of 10-formyltetrahydrofolate dehydrogenase has three putative domains [10].

Anatomical context of Fthfd

• We have isolated and characterized cDNA clones encoding rat liver cytosol 10-formyltetrahydrofolate dehydrogenase (EC 1.5.1.6) [10].
• We measured folate concentrations and examined cellular 10-FTHFDH expression in regions of the adult rat central nervous system (CNS), to study components of CNS oxidative formate metabolism [11].
• 10-FTHFDH was mostly expressed by glia, especially astrocytes and ventricular ependyma [11].
• Postmitochondrial levels of 10-FTHFDH in rat retina, optic nerve and whole brain were 0.2, 1.3, and 2.1 ng/micrograms protein; mitochondrial values in retina and brain were 0.2 and 1.5 ng/micrograms protein, respectively [9].
• Despite the absence of a leader peptide the recombinant 10-FTHFDH was released from the cells to the culture medium during production in both Sf9 and High five cell lines [12].

Associations of Fthfd with chemical compounds

• 10-Formyltetrahydrofolate dehydrogenase (EC 1.5.1.6) catalyzes the NADP-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 [13].
• The enzyme, 10-formyltetrahydrofolate dehydrogenase (10-FTHFDH) (EC 1.5.1.6) catalyzes both the NADP(+)-dependent oxidation of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 and the NADP(+)-independent hydrolysis of 10-formyltetrahydrofolate to tetrahydrofolate and formate [1].
• The COOH-terminal domain of the 10-FTHFDH (residues 417-902) shows a 46% identity with a series of NAD(+)-dependent aldehyde dehydrogenases (EC 1.2.1.3) [1].
• Cysteine 707 is involved in the dehydrogenase activity site of rat 10-formyltetrahydrofolate dehydrogenase [1].
• 10-FTHFDH with alanine substituted for cysteine at position 707 had no dehydrogenase activity, while hydrolase activity and binding of NADP+ were unchanged [1].

Other interactions of Fthfd

• Identification of protein-arginine N-methyltransferase as 10-formyltetrahydrofolate dehydrogenase [7].
• Furthermore, the enzymatic activity of 10-formyltetrahydrofolate dehydrogenase, the terminal enzyme in the catabolism of the ring-2-carbon of histidine to CO2, was diminished by 32% in methotrexate-treated animals [14].
• Numerical, but not significantly different increases were found in total abundance of lamin A (NCBI Accession No. 1346413) in the liver, and of 10-formyltetrahydrofolate dehydrogenase (10-FTHF DH, #1346044) and glutathione-S-transferase (GST; #2393724) in the kidneys of vapor-exposed subjects [15].
• 10-Formyltetrahydrofolate dehydrogenase (EC 1.5.1.6) was previously identified as a folate-binding protein in rat liver cytosol (R.J. Cook and C. Wagner, Biochemistry 21, 4427-4434, 1982) by virtue of the tetrahydrofolate polyglutamate tightly bound to the partially purified enzyme [16].
• As expected, the hepatic activities of a number of enzymes involved in the catabolism of histidine to CO2 were markedly decreased in hyperthyroid (histidase, 69%; urocanase, 30%; 10-formyltetrahydrofolate dehydrogenase, 65%) and folate-restricted (10-formyltetrahydrofolate dehydrogenase, 44%) rats [17].

Analytical, diagnostic and therapeutic context of Fthfd

• 10-FTHFDH levels were determined using Western blot analysis of mitochondrial and postmitochondrial preparations from these tissues [9].

References