Disease relevance of ALDH1L1

• Characterization of this protein deficiency has identified these liver proteins as forms of the enzyme 10-formyltetrahydrofolate dehydrogenase (10-formyl-THF DH; 10-formyltetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.6) [1].

High impact information on ALDH1L1

• Identification of a heritable deficiency of the folate-dependent enzyme 10-formyltetrahydrofolate dehydrogenase in mice [1].
• 10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to CO(2) and tetrahydrofolate (THF) and is an abundant high affinity folate-binding protein [2].
• The amino-terminal domain (residue 1-310) bears 10-formyltetrahydrofolate hydrolase activity, the carboxyl-terminal domain (residue 420-902) bears an aldehyde dehydrogenase activity, and the full-length FDH produces 10-formyltetrahydrofolate dehydrogenase activity [3].
• Deletion of either the entire putative helix or the central part of the helix or replacement of the six residues within the central part with alanines resulted in total loss of the 10-formyltetrahydrofolate dehydrogenase activity, whereas the full hydrolase and aldehyde dehydrogenase activities were retained [3].
• The intermediate linker (residues 311-419) connecting the two catalytic domains does not contribute directly to the enzyme catalytic centers but is crucial for 10-formyltetrahydrofolate dehydrogenase activity [3].

Biological context of ALDH1L1

• Ectopic expression of 10-formyltetrahydrofolate dehydrogenase in A549 cells induces G1 cell cycle arrest and apoptosis [4].
• A cDNA clone encoding 10-formyltetrahydrofolate dehydrogenase (10-FTHFDH) was isolated from a human fetal liver cDNA library [5].
• We have recently shown that transient expression of 10-formyltetrahydrofolate dehydrogenase (FDH) strongly inhibits proliferation of several cancer cell lines and ultimately results in cell death [4].
• A noncatalytic tetrahydrofolate tight binding site is on the small domain of 10-formyltetrahydrofolate dehydrogenase [6].
• 10-Formyltetrahydrofolate dehydrogenase has previously been identified as a tight binding protein of the polyglutamate forms of tetrahydrofolate (R. J. Cook and C. Wagner, Biochemistry 21, 4427-4434, 1982) [6].

Anatomical context of ALDH1L1

• The 10-FTHFDH transcript with an approximate size of 2.7 kb was mainly expressed in human kidney, skeletal muscle, and liver and rarely expressed in other tissues [5].
• An abundant enzyme of liver cytosol, 10-formyltetrahydrofolate dehydrogenase (FDH), is an interesting example of a multidomain protein [7].

Associations of ALDH1L1 with chemical compounds

• Studies on the mechanism of methanol poisoning: purification and comparison of rat and human liver 10-formyltetrahydrofolate dehydrogenase [8].
• On the role of conserved histidine 106 in 10-formyltetrahydrofolate dehydrogenase catalysis: connection between hydrolase and dehydrogenase mechanisms [9].
• Recombinant 10-formyltetrahydrofolate dehydrogenase catalyses both dehydrogenase and hydrolase reactions utilizing the synthetic substrate 10-formyl-5,8-dideazafolate [10].
• 10-Formyltetrahydrofolate dehydrogenase (EC 1.5.1.6) is a bifunctional enzyme, displaying both NADP(+)-dependent dehydrogenase activity for the formation of tetrahydrofolate and CO2, and NADP(+)-independent hydrolase activity for the formation of tetrahydrofolate and formate [10].
• 10-FTHFDH hydrolase activity was dependent on 2-mercaptoethanol and is probably an artifact of the assay system [11].

Other interactions of ALDH1L1

• Cancer cells activate p53 in response to 10-formyltetrahydrofolate dehydrogenase expression [12].

Analytical, diagnostic and therapeutic context of ALDH1L1

• The distribution of 10-FTHFDH transcript in various human tissues was studied by Northern blot analysis using poly(A+) RNAs from different tissues [5].

References