Folate acid

Prescribing perspective is vital so that, if there is any doubt as to whether the macrocytic anaemia is due to shortage of folate acid or vitamin B12, then 1000 mg of the latter must be given by intramuscular injection prior to starting the oral replacement. This will protect the patient from inadvertent precipitation of irreversible damage to the spinal cord known as subacute combined degeneration. 

The CDC suggests 400 meg daily for those two groups of people. The highest meg is found in lentils at 179 meg per half cup and fortified breakfast cereals, which have 146 to 177 meg per half cup. Spinach has 131 meg per half cup, orange juice 109 meg per cup, artichokes 95 meg per cup. Green peas, broccoli, com, and so on are all beneficial. Usually, natural sources are recommended. However, folic acid studies show that supplements are better because they are more easily absorbed the food-based folate acid. 

Biochemical Functions. Ascorbic acid has various biochemical functions, involving, for example, coUagen synthesis, immune function, dmg metabohsm, folate metaboHsm, cholesterol cataboHsm, iron metaboHsm, 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 direcdy with nitrites, and consequently may potentially reduce cancer risk. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

En2ymatic reduction of folic acid leads to the 7,8-dihydrofolic acid (H2 folate) (2), a key substance in biosynthesis. Further reduction, cataly2ed by the en2yme dihydrofohc acid reductase, provides (65)-5,6,7,8-tetrahydrofohc acid (H folate) (3). The folate (3) is the key biological intermediate for the formation of other folates (4—8) (Table 2). 

Radiolabeled folate provides a powerful tool for folate bioavaHabiUty studies in animals and for diagnostic procedures in humans. Deuteration at the 3- and 5-positions of the central benzene ring of foHc acid (31) was accompHshed by catalytic debromination (47,48) or acid-cataly2ed exchange reaction (49). Alternatively, deuterium-labeled fohc acid (32) was prepared by condensing pteroic acid with commercially available labeled glutamic acid (50). 

The metabohcahy active folate cofactors (see Table 2) are prepared synthetically as follows. 7,8-Dihydrofohc acid (2) and 5,6,7,8-tetrahydrofohc acid (3) are prepared via catalytic hydrogenation of fohc acid under controUed reaction conditions (51,52). Optical rotation of (63, R)-H4 folate (3) is [oc] = +14.9° (0.1 NNaOH) and the natural (63)-H folate (3) is [oi] = —16.9° (0.1 NNaOH). 

Methyltetrahydrofohc acid folate) (4) is involved in methionine biosynthesis. Condensation of formaldehyde with folate (3),... 

Methylenetetrahydrofohc acid (5,10-CH2-H4 folate) (5) is a coen2yme in thymidylate biosynthesis the natural (6R)-stereoisomer is prepared by en2ymatic reduction of H2 folate (2), foUowed by condensation with formaldehyde (54). 

Formylation of folate (3) or hydrolysis of 5,10 — CH+ — folate (9) gives (6R,3)-5-formyltetrahydrofohc acid (6) (5-HCO-H folate) (55). On the other hand, (63)-5-HCO-H4 folate is obtained by selective crystaUi2ation in the form of its calcium salt from the diastereomeric mixture of (63, R)-5-HC0-H4 folate (56). 10-Formyltetrahydrofohc acid (7) is a coen2yme in purine synthesis which is synthesi2ed by hydrolysis of 5,10 — CH+ — folate (9) or by hydrogenation of lO-CHO-folate (57). 

Fohc acid is a precursor of several important enzyme cofactors required for the synthesis of nucleic acids (qv) and the metaboHsm of certain amino acids. Fohc acid deficiency results in an inabiUty to produce deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and certain proteins (qv). Megaloblastic anemia is a common symptom of folate deficiency owing to rapid red blood cell turnover and the high metaboHc requirement of hematopoietic tissue. One of the clinical signs of acute folate deficiency includes a red and painhil tongue. Vitamin B 2 folate share a common metaboHc pathway, the methionine synthase reaction. Therefore a differential diagnosis is required to measure foHc acid deficiency because both foHc acid and vitamin B 2 deficiency cause... 

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

The amount of foHc acid required for daily iatake is estimated based oa the minimum amouat required to maintain a certaia level of semm folate. The recommeaded dietary allowance (RDA) for foHc acid accounts for daily losses and makes allowances for variation ia iadividual aeeds and bioavailabiUty from food sources (85). The U.S. recommended daily allowance for adults is 400 p.g and for pregnant women is 800 ]1 (Table 4). 

Three forms of folate appear to be transported ia the blood foHc acid, folate loosely bouad to low affinity binder semm proteins (such as albumin, a-macroglobulin, and transferrin), and folate bound to high affinity protein binders. Approximately 5% of total semm folate is being transported by high... 

The chiralities at C-6 of natural 5,6,7,8-tetrahydrofolic acid and related folates, e.g. 5,10-methylene-, 5-methyl- and 5-formyl-5,6,7,8-tetrahydrofolic acid, from various biological systems are the same and possess the absolute configuration (S) at C-6 as deduced from an X-ray study of the ion (51) (79JA6114). 

Folic acid derivatives (folates) are acceptors and donors of one-carbon units for all oxidation levels of carbon except that of CO2 (where biotin is the relevant carrier). The active coenzyme form of folic acid is tetrahydrofolate (THF). THF is formed via two successive reductions of folate by dihydrofolate reductase (Figure 18.35). One-carbon units in three different oxidation states may be bound to tetrahydrofolate at the and/or nitrogens (Table 18.6). These one-carbon units... 

FIGURE 18.35 Formation of THF from folic acid by the dihydrofolate reductase reaction. The R group on these folate molecules symbolizes the one to seven (or more) glutamate units that folates characteristically contain. All of these glutamates are bound in y-carboxyl amide linkages (as in the folic acid structure shown in the box A Deeper Look Folic Acid, Pterins, and Insect VFingis). The one-carbon units carried by THF are bound at N, or at or as a single carbon attached to both... 

Methotrexate (MTX, chemical structure shown in Fig. 1.) competitively inhibits the dehyrofolate reductase, an enzyme that plays an essential role in purine synthesis. The dehydrofolate reductase regenerates reduced folates when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates cells are unable to synthesize thymine. Administration of N-5 tetrahydrofolate or N-5 formyl-tetrahydrofolate (folinic acid) can bypass this block and rescue cells from methotrexate activity by serving as antidote. 

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