| Folic acid derivatives are important in single carbon transfer reactions
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Folic acid (pteroyl glutamic acid) has a number of derivatives known collectively as folates. It participates in single carbon transfer reactions in numerous pathways including the synthesis of choline, serine, glycine , methionine and nucleic acids. Deficiency of folate contributes to hyperhomocysteinemia, which is regarded as a risk factor for cardiovascular disease (see Chapter 17).
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| Folic acid is physiologically inactive until reduced to dihydrofolic acid. Its main forms are tetrahydrofolate, 5-methyl tetrahydrofolate (N5MeTHF) and N10-formyltetrahydrofolate-polyglutamate forms based on 5MeTHF predominate in fresh food. Before polyglutamates can be absorbed, they must be hydrolyzed by glutamyl hydrolase (conjugase) in the small intestine. Main circulating form of folate is the monoglutamate N5-THF.
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| Folic acid is necessary for the synthesis of DNA
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| Rapidly dividing cells have high requirements for this vitamin since its role is in the synthesis of purines and pyrimidine thymine required for DNA synthesis (see Chapter 30). On the basis of selective toxicity in rapidly growing cells, e.g. bacteria and cancer cells, this function of folate has also formed the basis for development of drug such as antibiotics (e.g. trimethoprim) and anticancer agents (methotrexate). Folic acid is present in liver yeast, green leafy vegetables. It is measured by HPLC methods.
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| Folate deficiency causes megaloblastic anemia
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| Failure to synthesize methionine and nucleic acids in deficiency states accounts for the signs and symptoms of megaloblastic anemia, i.e. the presence of enlarged blast cells in the bone marrow. Deficiency of folate is one of the commonest vitamin deficiencies and the hematologic abnormalities associated with this cannot be distinguished from those of vitamin B12 deficiency (see below). The neurologic changes are also similar. The block in synthesis slows down the production of erythrocytes, causing the appearance of macrocytic erythrocytes with fragile membranes and a tendency to hemolyze. A macrocytic anemia thus ensues in association with a megaloblastic bone marrow.
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| There are many causes of folate deficiency, including inadequate intake, impaired absorption, impaired metabolism, and increased demand. The most common examples of increased demand are pregnancy and lactation. Folic acid requirements increase dramatically as the blood volume and number of erythrocytes increase in pregnancy. By the third trimester of pregnancy folic acid requirements double. However, megaloblastic anemias in pregnancy, other than multiple pregnancy, are rare. The common practice is to provide folate supplements during pregnancy. Folate deficiencies are seen in the elderly as a result of poor diet and poor absorption.
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