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Chemical Compound Review

Folacin     (2S)-2-[[4-[(2-amino-4-oxo- 1H-pteridin-6...

Synonyms: Acifolic, Folaemin, Folvite, Folate, Vitamin M, ...
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Disease relevance of folic acid


Psychiatry related information on folic acid


High impact information on folic acid

  • In vitro, the MRPs can collectively confer resistance to natural product drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and, under certain circumstances, alkylating agents [16].
  • However, the current study establishes that a major function of this gene product is proton-coupled folate transport required for folate homeostasis in man, and we have thus amended the name to PCFT/HCP1 [17].
  • We now report the identification of a human proton-coupled, high-affinity folate transporter that recapitulates properties of folate transport and absorption in intestine and in various cell types at low pH [17].
  • To determine whether Folbp1 is involved in maternal-to-fetal folate transport, we inactivated Folbp1 in mice [18].
  • We also produced mice lacking Folbp2, another member of the folate receptor family that is GPI anchored but binds folate poorly [18].

Chemical compound and disease context of folic acid


Biological context of folic acid

  • Using the technology of metaphase chromosome transfer, evidence has been obtained in CHO cells that genes controlling enzymes in a common pathway in folate metabolism are closely linked [23].
  • The importance of an adequate intracellular folate pool for normal embryogenesis has long been recognized in humans and experimental animals [18].
  • Folate-sensitive fragile sites are due to expansion of p(CCG)n trinucleotide repeats; however, the relationship between sequence composition and the chemistry of induction of fragile sites is unclear [24].
  • To facilitate studies of folate metabolism and chemotherapy the sole dhfr-ts copy in a heterozygous deletion line was replaced, yielding lines that were functionally DHFR-TS-. Although most genes are diploid in trypanosomatids, methods exploiting the high frequency of homologous recombination should permit complete replacement of any parasite gene [25].
  • Especially subjects with the homozygous form of this polymorphism (i.e., 677TT genotype) and a low folate status have elevated tHcy concentrations [26].

Anatomical context of folic acid


Associations of folic acid with other chemical compounds


Gene context of folic acid

  • Three folate-sensitive fragile sites, termed FRAXA, FRAXE and FRAXF, have been identified on the distal end of chromosome Xq [42].
  • The NTDs in Grhl3-/- embryos are also folate resistant, but unlike those in ct/ct mice, they are resistant to inositol [43].
  • These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs [44].
  • Methionine synthase reductase (MTRR) is another enzyme essential for normal folate metabolism [45].
  • The Lrp6 mutation in Cd mice provides evidence for a functional connection between Wnt signaling and folate rescue of neural tube defects [46].
  • Also, CGS processing involves chloroplastic serine-type proteases that are expressed in various plant species subjected to folate starvation [47].
  • Long-term oversupplementation with folate leads to a specific and significant down-regulation in intestinal and renal folate uptake, which is associated with a decrease in message levels of hRFC, PCFT/HCP1, and FR [48].
  • These results along with those of a novel mathematical biomodeling devised here suggest that upon severe short term (i.e. up to 7 days) folate deprivation RFC transport activity becomes detrimental as RFC, but not ATP-driven folate exporters, efficiently extrudes folate monoglutamates out of cells [49].
  • High-performance liquid chromatography analysis demonstrated that mild folate depletion (100 nM) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines [50].

Analytical, diagnostic and therapeutic context of folic acid

  • Previous perfusion studies of the human jejunum suggested that conjugated folate is hydrolyzed on the mucosal surface [30].
  • Using data from a recent case-control study, a woman's risk of having a child with a neural tube defect (NTD) was found to be associated with early pregnancy red cell folate levels in a continuous dose-response relationship [51].
  • DESIGN: Retrospective cohort study with serum folate levels measured from September 1970 to December 1972, with follow-up through 1985 [52].
  • Susceptibility to the breast cancer-enhancing effect of alcohol may also be affected by other dietary factors (such as low folate intake), lifestyle habits (such as use of hormone replacement therapy), or biological characteristics (such as tumor hormone receptor status) [53].
  • The results should not be construed as pointing to a potential way of preventing lung cancer in individuals who continue to smoke or as supporting self-medication with large doses of folate or B12 by smokers [54].


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  15. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Mattson, M.P., Shea, T.B. Trends Neurosci. (2003) [Pubmed]
  16. Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Deeley, R.G., Westlake, C., Cole, S.P. Physiol. Rev. (2006) [Pubmed]
  17. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Qiu, A., Jansen, M., Sakaris, A., Min, S.H., Chattopadhyay, S., Tsai, E., Sandoval, C., Zhao, R., Akabas, M.H., Goldman, I.D. Cell (2006) [Pubmed]
  18. Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Piedrahita, J.A., Oetama, B., Bennett, G.D., van Waes, J., Kamen, B.A., Richardson, J., Lacey, S.W., Anderson, R.G., Finnell, R.H. Nat. Genet. (1999) [Pubmed]
  19. Inositol prevents folate-resistant neural tube defects in the mouse. Greene, N.D., Copp, A.J. Nat. Med. (1997) [Pubmed]
  20. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. Rimm, E.B., Willett, W.C., Hu, F.B., Sampson, L., Colditz, G.A., Manson, J.E., Hennekens, C., Stampfer, M.J. JAMA (1998) [Pubmed]
  21. Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent. Allegra, C.J., Kovacs, J.A., Drake, J.C., Swan, J.C., Chabner, B.A., Masur, H. J. Exp. Med. (1987) [Pubmed]
  22. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. Genestier, L., Paillot, R., Fournel, S., Ferraro, C., Miossec, P., Revillard, J.P. J. Clin. Invest. (1998) [Pubmed]
  23. Linkage of markers controlling consecutive biochemical steps in CHO cells as demonstrated by chromosome transfer. Spandidos, D.A., Siminovitch, L. Cell (1977) [Pubmed]
  24. Human chromosomal fragile site FRA16B is an amplified AT-rich minisatellite repeat. Yu, S., Mangelsdorf, M., Hewett, D., Hobson, L., Baker, E., Eyre, H.J., Lapsys, N., Le Paslier, D., Doggett, N.A., Sutherland, G.R., Richards, R.I. Cell (1997) [Pubmed]
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  27. Folate-induced remission in aplastic anemia with familial defect of cellular folate uptake. Branda, R.F., Moldow, C.F., MacArthur, J.R., Wintrobe, M.M., Anthony, B.K., Jacob, H.S. N. Engl. J. Med. (1978) [Pubmed]
  28. Folate and aplasia of bone marrow. Babior, B.M. N. Engl. J. Med. (1978) [Pubmed]
  29. Binding of a specific ligand inhibits import of a purified precursor protein into mitochondria. Eilers, M., Schatz, G. Nature (1986) [Pubmed]
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  31. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. Jacques, P.F., Selhub, J., Bostom, A.G., Wilson, P.W., Rosenberg, I.H. N. Engl. J. Med. (1999) [Pubmed]
  32. Detection of a milk factor that facilitates folate uptake by intestinal cells. Colman, N., Hettiarachchy, N., Herbert, V. Science (1981) [Pubmed]
  33. Mechanisms of resistance of malaria parasites to antifolates. Gregson, A., Plowe, C.V. Pharmacol. Rev. (2005) [Pubmed]
  34. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. Selhub, J., Jacques, P.F., Wilson, P.W., Rush, D., Rosenberg, I.H. JAMA (1993) [Pubmed]
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  36. Plasma homocysteine, folate, and vitamin B 12 and the risk of hip fracture: the hordaland homocysteine study. Gjesdal, C.G., Vollset, S.E., Ueland, P.M., Refsum, H., Meyer, H.E., Tell, G.S. J. Bone Miner. Res. (2007) [Pubmed]
  37. Cobalamin and folate status in infants and young children in a low-to-middle income community in India. Taneja, S., Bhandari, N., Strand, T.A., Sommerfelt, H., Refsum, H., Ueland, P.M., Schneede, J., Bahl, R., Bhan, M.K. Am. J. Clin. Nutr. (2007) [Pubmed]
  38. Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults. Hoey, L., McNulty, H., Askin, N., Dunne, A., Ward, M., Pentieva, K., Strain, J., Molloy, A.M., Flynn, C.A., Scott, J.M. Am. J. Clin. Nutr. (2007) [Pubmed]
  39. Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation. Baggott, J.E., Morgan, S.L. Arthritis Rheum. (2009) [Pubmed]
  40. Higher liposomal membrane fluidity enhances the in vitro antitumor activity of folate-targeted liposomal mitoxantrone. Kawano, K., Onose, E., Hattori, Y., Maitani, Y. Mol. Pharm. (2009) [Pubmed]
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  42. Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Parrish, J.E., Oostra, B.A., Verkerk, A.J., Richards, C.S., Reynolds, J., Spikes, A.S., Shaffer, L.G., Nelson, D.L. Nat. Genet. (1994) [Pubmed]
  43. Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3. Ting, S.B., Wilanowski, T., Auden, A., Hall, M., Voss, A.K., Thomas, T., Parekh, V., Cunningham, J.M., Jane, S.M. Nat. Med. (2003) [Pubmed]
  44. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? van der Put, N.M., Gabreëls, F., Stevens, E.M., Smeitink, J.A., Trijbels, F.J., Eskes, T.K., van den Heuvel, L.P., Blom, H.J. Am. J. Hum. Genet. (1998) [Pubmed]
  45. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Hobbs, C.A., Sherman, S.L., Yi, P., Hopkins, S.E., Torfs, C.P., Hine, R.J., Pogribna, M., Rozen, R., James, S.J. Am. J. Hum. Genet. (2000) [Pubmed]
  46. Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6. Carter, M., Chen, X., Slowinska, B., Minnerath, S., Glickstein, S., Shi, L., Campagne, F., Weinstein, H., Ross, M.E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  47. Regulation of one-carbon metabolism in Arabidopsis: the N-terminal regulatory domain of cystathionine gamma-synthase is cleaved in response to folate starvation. Loizeau, K., Gambonnet, B., Zhang, G.F., Curien, G., Jabrin, S., Van Der Straeten, D., Lambert, W.E., Rébeillé, F., Ravanel, S. Plant Physiol. (2007) [Pubmed]
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  49. The reduced folate carrier (RFC) is cytotoxic to cells under conditions of severe folate deprivation. RFC as a double edged sword in folate homeostasis. Ifergan, I., Jansen, G., Assaraf, Y.G. J. Biol. Chem. (2008) [Pubmed]
  50. Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells. Bistulfi, G., Vandette, E., Matsui, S., Smiraglia, D.J. BMC Biol. (2010) [Pubmed]
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  52. Serum folate and risk of fatal coronary heart disease. Morrison, H.I., Schaubel, D., Desmeules, M., Wigle, D.T. JAMA (1996) [Pubmed]
  53. Alcohol and breast cancer: review of epidemiologic and experimental evidence and potential mechanisms. Singletary, K.W., Gapstur, S.M. JAMA (2001) [Pubmed]
  54. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial. Heimburger, D.C., Alexander, C.B., Birch, R., Butterworth, C.E., Bailey, W.C., Krumdieck, C.L. JAMA (1988) [Pubmed]
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