Folate metabolic functions

Physiologically, distinction from folate deficiency is often clinically and haematologically difficult because vitamin B12, also known as cobalamin, functions as an essential cofactor for folate metabolism in the evenmal synthesis of deoxyribonucleic acid. 

Like folate and vitamin C, vitamin B6 (pyroxidine) is water soluble and like folate has several vitamers. Vitamin B6 may be involved in more bodily functions than any other nutrient (Tambasco-Studart et al., 2005), is a cofactor for many enzymes, especially those involved in protein metabolism, and is also a cofactor for folate metabolism. Vitamin B6 has anticancer activity (Theodoratou et al., 2008), is a strong antioxidant (Denslow et al., 2005), is involved in hemoglobin biosynthesis, lipid and glucose metabolism and immune and nervous system function. Possible consequences of deficiency include anemia, impaired immune function, depression, confusion, and dermatitis (Spinneker et al., 2007). Vitamin B6 deficiency is generally not a problem in the developed world, but there could be as yet poorly defined consequences of suboptimal intake particularly for the elderly. 

The evaluation of folic acid status must often also include evaluation of vilamin B1 because of its effect on folate metabolism. A vilamin Bu-dependenl reaction is necessary for an cit/vmc involved in the catabolism of branchcd-chain amino acids (mclhylmalonyl CoA to succinyl CoA). This reaction may provide the basis for a functional assessment method for vitamin Biz status. See also Hormones and Vitamin. 

Folic acid functions in the transfer of one-carbon fragments in a wide variety of biosynthetic and catabolic reactions it is therefore metaboUcaUy closely related to vitamin B12, which also functions in one-carbon transfer. Deficiency of either vitamin has similar clinical effects, and it seems likely that the main effects of vitamin B12 deficiency are exerted by effects on folate metabolism. 

Biochemical Functions. Ascorbic acid has various biochemical fimctions, involving, for example, coUagen synthesis, immune fimction, drug metabohsm, folate metabolism, cholesterol catabolism, iron metabolism, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting directly with nitrites, and consequently may potentially reduce cancer risk. 

The inability to absorb Vitamin B12 occms in pernicious anemia. In pernicious anemia intrinsic factor is missing. The anemia results from impaired DNA synthesis due to a block in purine and thymidine biosynthesis. The block in nucleotide biosynthesis is a consequence of the effect of vitamin B12 on folate metabolism. When vitamin B-12 is deficient essentially all of the folate becomes trapped as the N -methyltetrahydrofolate derivative as a result of the loss of functional methionine synthase. This trapping prevents the synthesis of other tetrahydrofolate derivatives. required for the purine and thymidine nucleotide biosynthesis pathways. 

Folate status may be reliably assessed by direct measurement of serum and erythrocyte or whole blood concentrations, and its metabolic function as coen2yme assessed by metabolite concentrations, such as plasma homocysteine (see Chapters 20 and 26). Serum folate concentrations are considered indicative of recent intake and not of tissue stores, but serial measurements have been used to confirm adequate intake. Whole blood or erythrocyte folate concentrations are more indicative of tissue stores and have been shown to have a moderate correlation with liver folate concentrations taken through a biopsy. Because folate is taken up only by the developing erythrocyte in the bone marrow and not by the mature cell, erythrocyte concentrations reflect folate status over the 120-day lifespan of the ceU. Urine folate excretion is not considered to be a sensitive indicator of folate status. ... 

Several analytes are known to be indicative of folate metabolism. Plasma total homocysteine increases when there is a deficiency of 5-MTHF, such that the methylation of homocysteine to methionine is compromised. However, though plasma homocysteine is considered to be a sensitive functional indicator, it is not specific because its concentration can be influenced by deficiency of other vitamins (Bg and B12) involved in the metabolism of homocysteine. Similarly the methylation of DNA is dependent upon adequate 5-MTHF. A sensitive new method for the rapid detection of abnormal methylation patterns in global DNA patterns has been reported and may have promise as a functional marker, as may the measurement of the degree of uracil incorporation into DNA, 5,10-metliylene THF being required for die conversion of deoxyuridine monophosphate (dUMP) to dTMP by thymidylate synthetase. ... 

Folate (tetrahydropteroylpolyglutamate) functions as the Cj-transfer agent in a variety of important metabolic processes [48]. 

The function of folate binders in folate metabolism remains unclear, except in the case of milk where they have recently been shown to enhance the absorption of folate in breast-fed infants and possibly protect the folate against utilization by intestinal bacteria (C7). The binder may also have a function in sequestering folate from the mother s circulation. It has not been shown to have a role in polyglutamate synthesis nor does it appear to play a part in enabling cells to take up folate on the contrary, Waxman and Schrei-ber (W12) have shown that the binder prevents the uptake of folate by cells in tissue culture. 

METABOLIC FUNCTIONS The active coenzymes methylcobalamin and 5-deoxyadeno-sylcobalamin are essential for cell growth and replication. Methylcobalamin is required for the conversion of homocysteine to methionine and its derivative, SAM. In addition, when concentrations of vitamin Bj are inadequate, folate becomes trapped as methyltetrahydrofolate, causing a functional deficiency of other required intracellular forms of folic acid (see Figures 53-6 and 53-7 and discussion above). The hematological abnormalities in vitamin Bj -deficient patients result from this process. 5-Deoxyadenosylcobalamin is required for the isomerization of L-methylmalonyl CoA to succinyl CoA (Figure 53-6). 

Inborn errors of folate metabolism also shed light on the role of folates and products of folate metabolism in neurological function. Disorders that result in decreased levels of 5-CH3-THF in the central nervous system are frequently associated with development of seizures e.g. MTHFR deficiency, DHFR deficiency, MTHFDl deficiency, and autoimmune or genetic cases of cerebral folate deficiency due to malfunction of folate receptor alpha). Adult onset cases of MTHFR deficiency have in some cases been associated with psychosis. 

Functional SNPs in key genes of folate metabolism are genetic determinants in the folate metabolism balance. 

Prevention of scurvy multiple roles in optimizing health and resistance to infectious diseases numerous functions proposed Folate coenzymes participate in one-carbon transfer reactions in cellular metabolism Prevention of pellagra in humans and black tongue in dogs metabolic functions of nicotinamide coenzymes... 

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