Polyglutamate folate

Melse-Boonstra, A., Verhoef, P, Konings, E. J., Van Dusseldorp,M., Matser, A., Hollman, P. C.,Meyboom, S., Kok, F. J., West, C. E. (2002). Influence of processing on total, monoglutamate and polyglutamate folate contents of leeks, cauliflower, and green beans. J. Agric. Food Chem., 50, 3473-3478. 

Both sequential and non-sequential types of oral contraceptives impair the absorption of polyglutamic folate but not that of monoglutamic folate the change can result in megaloblastic anemia in predisposed subjects, for example those with celiac disease or having a deficient diet (182). 

Ralitrexed is a folate analog with greater selectivity. It easily crosses the cell membrane and undergoes polyglutamation. Within tissues, ralitrexed may be stored up to 29 days. It directly inhibits thymidylate synthase, the key enzyme for synthesizing thymidine triphosphate (TTP). The drug has been described to induce apoptosis in tumor cells. Ralitrexed is used for the treatment of colon carcinomas. 

Most of the folates that occur naturally in man are polyglutamates,46 although they are transported as monoglutamates. 4 7... 

The chemical structure of folate (or folic acid) is shown in Figure 5.8. In humans, folate usually occurs as polyglutamate derivatives. The active form of folate is THF, sometimes shown as FH4) is derived from folate via two reductase reactions. THF functions as a carrier of one-carbon groups in varying oxidation states (Table 5.1). 

Fig. 14.1 Cellular pathway of methotrexate. ABCBl, ABCCl-4, ABC transporters ADA, adenosine deaminase ADP, adenosine diphosphate AICAR, aminoimidazole carboxamide ribonucleotide AMP, adenosine monophosphate ATIC, AICAR transformylase ATP, adenosine triphosphate SjlO-CH -THF, 5,10-methylene tetrahydrofolate 5-CHj-THF, 5-methyl tetrahydro-folate DHFR, dihydrofolate reductase dTMP, deoxythymidine monophosphate dUMP, deoxy-uridine monophosphate FAICAR, 10-formyl AICAR FH, dihydrofolate FPGS, folylpolyglutamyl synthase GGH, y-glutamyl hydrolase IMP, inosine monophosphate MTHFR, methylene tetrahydrofolate reductase MTR, methyl tetrahydrofolate reductase MTX-PG, methotrexate polyglutamate RFCl, reduced folate carrier 1 TYMS, thymidylate synthase. Italicized genes have been targets of pharmacogenetic analyses in studies published so far. (Reproduced from ref. 73 by permission of John Wiley and Sons Inc.)...

Dervieux, T., Eurst, D., Lein, D. O., et al. (2004) Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis and Rheumatism. 50, 2766-2774. 

HPLC does not give a good response to long-chain derivatives of folate, therefore, conversion of the natural form of folate, polyglutamates, to mono- or di-glutamate is required. The enzyme used is y-glutamylcarboxypeptidase, extracted from chicken pancreas, hog kidney, or to a lesser extent from... 

Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Dietary folates, however, consist primarily of polyglutamate forms of N 5-methyltetrahydrofolate. Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme -1-glutamyl transferase ("conjugase") within the brush border of the intestinal mucosa. 

However, lack of utilization of exogenous folate may not fully explain the apparently indispensable nature of the synthesis of 7,8-dihydropteroate in plasmodium, toxoplasma, and eimeria. It is known that most of the folate molecules in mammalian cells are linked with polyglutamates in the cytoplasm and are transported across cell membranes with difficulty. It may compound the problem of obtaining 7,8-dihydropteroate or dihydrofolate for the parasite and makes all of the enzymes... 

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