- The total folate content of an average Western diet is ~250 µg daily, but the amount varies widely according to the type of food eaten and the method of cooking. - Folate is easily destroyed by heating, particularly in large volumes of water. - Total-body folate in the adult is ~10 mg, the liver containing the largest store. - Daily adult requirements are ~100 µg, so stores are only sufficient for 3–4 months in normal adults and severe folate deficiency may develop rapidly.. - Folates are absorbed rapidly from the upper small intestine. - The absorption of folate polyglutamates is less efficient than for monoglutamates. - ~50% of food folate is absorbed. - Polyglutamate forms are hydrolysed to the monoglutamate derivatives, either in the lumen of the intestine or within the mucosa. - All dietary folates are converted to 5-methylTHF (5-MTHF) within the small-intestinal mucosa before entering portal plasma. - Pteroylglutamic acid at doses >400 µg is absorbed largely unchanged and converted to natural folates in the liver. - Lower doses are converted to 5-MTHF during absorption through the intestine.. - About 60–90 µg of folate enters the bile each day and is excreted into the small intestine. - Loss of this folate, together with the folate of sloughed intestinal cells, accelerates the speed with which folate deficiency develops in malabsorption conditions.. - Folate is transported in plasma. - folate is largely, if not entirely, 5-MTHF in the monoglutamate form. - Two types of folate-binding protein are involved in entry of MTHF into cells. - A high-affinity folate receptor takes folate into cells by endocytosis, is internalized by clathrin- coated pits or in a vesicle (caveola), which is then acidified, releasing folate.. - Folate is then carried by the membrane folate transporter into the cytoplasm. - The high-affinity receptor is attached to the outer surface of the cell membrane by glycosyl phosphatidylinositol linkages. - It may be involved in transport of oxidized folates and folate breakdown products to the liver for excretion in bile. - An independent low-affinity reduced-folate carrier also mediates uptake of physiologic folates into cells but also of methotrexate.. - Folates (as the intracellular polyglutamate derivatives) act as coenzymes in the transfer of single-carbon units (Fig. - Two of these reactions are involved in purine and one in pyrimidine synthesis necessary for DNA and RNA replication. - Folate is also a coenzyme for methionine synthesis, in which methylcobalamin is also involved and in which THF is regenerated. - THF is the acceptor of single carbon units newly entering the active pool via conversion of serine to glycine. - Methionine, the other product of the methionine synthase reaction, is the precursor for S-adenosylmethionine (SAM), the universal methyl donor involved in >100 methyltransferase reactions (Fig. - The role of folates in DNA synthesis and in formation on S- adenosylmethionine (SAM), which is involved in numerous methylation reactions.. - During thymidylate synthesis, 5,10-methylene-THF is oxidized to DHF (dihydrofolate). - The enzyme DHF reductase converts this to THF. - The drugs methotrexate, pyrimethamine, and (mainly in bacteria) trimethoprim inhibit DHF reductase and so prevent formation of active THF coenzymes from DHF. - fraction of the folate coenzyme is not recycled during thymidylate synthesis but is degraded.
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