Folic acid reduction

Folic acid Reduction in plasma homocy steine levels SWISS Heart Study (51) Reduced TLR... 

In the human, dietary folic acid must be reduced metaboli-cally to THFA to exert its vital biochemical actions. This reaction, which proceeds through the intermediate dihydro-folic acid, is catalyzed by a reductase. This reductase enzyme system has been implicated as the catalyst in both reaction steps—folic acid reduction and dihydrofolic acid reduction. The coenzyme THFA is converted to other cofactors by formulation of the N-IO and/or N-5 nitrogen. 

The Schiff base obtained is converted in good yield (60 to 80%) to amines by the action of Raney Ni (209). This reductive condensation provides a good synthetic method and was used to prepare thiazole analogs (62) of folic acid (Scheme 43) (210). These Schiff bases under... 

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). 

Catalytic reduction of folic acid to 5,6,7,8-tetrahydrofolic acid (225) proceeds fast in trifluoroacetic acid (66HCA875), but a modified method using chemical reductants leads with sodium dithionite to 7,8-dihydrofolic acid (224). Further treatment with sodium borohydride gives (225) which has been converted into 5-formyl-(6i ,S)-5,6,7,8-tetrahydro-L-folic acid (leucovorin) (226) by reaction with methyl formate (equation 70) (80HCA2554). 

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... 

Anemias, reductions in the number of red blood cells or of hemoglobin in the blood, can reflect impaired synthesis of hemoglobin (eg, in iron deficiency Chapter 51) or impaired production of erythrocytes (eg, in folic acid or vitamin Bjj deficiency Chapter 45). Diagnosis of anemias begins with spectroscopic measurement of blood hemoglobin levels. 

The classic example is that of Prontosil (Figure 2.12) in which the compound is active against bacterial infection in animals though inactive against the bacteria in pure culture. The toxicity in animals is the result of reduction to the sulfanilamide (4-aminobenzenesulfonamide) that competitively blocks the incorporation of 4-aminobenzoate into the vitamin folic acid. 

Possibly the most significant discovery in the metabolism of aromatic azo compounds had implications that heralded the age of modem chemotherapy. It was shown that the bactericidal effect of the azo dye Prontosil in vivo was in fact due to the action of its transformation product, sulfanilamide, which is an antagonist of 4-aminobenzoate that is required for the synthesis of the vitamin folic acid. Indeed, this reduction is the typical reaction involved in the first stage of the biodegradation of aromatic azo compounds. 

Elevated homocysteine concentrations have been associated with an increased risk for cardiovascular disease in both epidemiologic and clinical studies.43 Several studies have evaluated the benefit of lowering homocysteine levels with folic acid supplementation. One study reported a reduction in major cardiac events with the combination of folic acid, vitamin B12, and vitamin B6 following PCI.44 However, a more recent study found an increased risk of instent restenosis and the need for target-vessel revascularization with folate supplementation following coronary stent placement.45 The role of folate in the management of IHD is currently unclear. 

Folic acid antagonist inhibits dihydrofolate reductase (DHFR) blocks reduction of folate to tetrahydrofolate inhibits de novo purine synthesis results in arrest of DNA, RNA, and protein synthesis... 

REDUCTION LEVEL NAME TYPICAL STRUCTURES FOLIC ACID EQUIVALENT2... 

Prognosis is more favorable in the pyridoxine-respon-sive patients. Patients who respond to large doses of vitamin B6 (250-500 mg/day for several weeks) have the best prognosis. Efficacy of treatment usually is reflected in a reduction of blood homocystine and methionine to normal or near-normal levels. Since supplementation with pyridoxine can cause a deficiency of folic acid, the latter should be given (2-5 mg daily) at the same time. Any patient receiving pyridoxine should be monitored carefully for any signs of hepatotoxicity and for a peripheral neuropathy (see Ch. 36). 

In living systems, folinic acid can be synthesized ultimately from folic acid by reduction to tetrahydrofolic acid followed by addition of a 1-carbon fragment to the molecule (N5.N1°-methylenetetrahydrofolate, V). After a 2-step oxidation, the formyl group resides either at the N5 or N10 position or as an equilibrium mixture. The essential reactions are summarized below 32... 

Chemical methods for folic acid detection are not useful for unfractionated biologic materials (H16). Reduction of folic acid in acid yields a methylpteridine and N-(p-aminobenzoyl) glutamic acid. The latter is estimated by a method for aromatic amines (B33). Another assay method of historical interest is the growth of chicks as a measure of the folic acid content of crude biological mixtures. 

Theory Folic acid (I) undergoes cleavage by reduction with Zn-Hg in acidic medium to yield p-aminobenzoylglutamic acid (II). The primary aromatic amino group present in the latter is subsequently diazotized in the usual manner and coupled in acidic solution with N-(l-naphthyl)-ethylenediamine hydrochloride in the absence of light (caution). The colour thus produced has a maximum absorption at 550 nm and the extinction (E) is consequently compared with a calibration curve obtained from / -aminobcnzoic acid (PABA) that has been duly diazotized and coupled exactly in the same fashion as the/ -aminobcnzoylglutamic acid. 

Folic acid becomes sequentially reduced in the body by the enzyme dihydrofolate reductase to give dihydrofolic acid (FH2) and then tetrahydrofolic acid (FFi4). Reduction occurs in the pyrazine ring portion. 

Folate, the anion of folic acid, is made up of three different components—a pteridine derivative, 4-aminobenzoate, and one or more glutamate residues. After reduction to tetrahydrofolate (THF), folate serves as a coenzyme in the Q metabolism (see p. 418). Folate deficiency is relatively common, and leads to disturbances in nucleotide biosynthesis and thus cell proliferation. As the precursors for blood cells divide particularly rapidly, disturbances of the blood picture can occur, with increased amounts of abnormal precursors for megalocytes megaloblastic anemia). Later, general damage ensues as phospholipid... 

Dihydrofolate reductase acts as an auxiliary enzyme for thymidylate synthase. It is involved in the regeneration of the coenzyme N, N -methylene-THF, initially reducing DHF to THF with NADPH as the reductant (see p. 418). The folic acid analogue methotrexate, a frequently used cytostatic agent, is an extremely effective competitive inhibitor of dihydrofolate reductase. It leads to the depletion of N, N -methylene-THF in the cells and thus to cessation of DNA synthesis. 

The biologically active relatives of folic acid and biopterin are the tetrahydro compounds with a reduced pyrazine ring. Reduction to this level occurs rapidly in vivo. The corresponding electrochemical process is well illustrated by reduction of the N-methylated analogue 28 [95], Reduction to the 5,8-dihydro stage is a reversible two-electron and two-proton process. The product rapidly tautomerises to the... 

Electrochemical reduction of folic acid is a convenient route to tefrahydrofolic acid. Reaction is performed in an aqueous buffer of triethylamine bicarbonate [98]. Water and buffer salts can then be removed by freeze-drying. The process generates a new asymmetric centre on the tetrahydropyridazine ring and only one of the... 

Trimetrexate (88) Is an antineoplastic agent related to the well-established folic acid antimeta-bolite methotrexate. It can be synthesized by selective diazotization of the most basic amino group of 2,4,6-triamino-5-methylquinazoline (85) followed by a Sandmeyer displacement with CuCN to give nitrile 86. Careful reduction asing Raney nickel produces the aminomethyl intermediate 87 or, if the reaction is carried out in the presence of 3,4,5-triniethoxyaniline, trimetrexate (88) [24]. One presumes that that outcome is a consequence of amine exchange at the partially reduced imine stage and further reduction. 

Reduced folate Reduction of serum or red cell folate has been reported over long-term administration of cholestyramine. Consider supplementation with folic acid. 

A daily multivitamin supplement may prevent reduction in serum levels of vitamins D, E, K, and folic acid... 

I I 3. The answer is c. (Hardman, pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydrofolate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2), which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

The reduction mechanism of Cd(II)-fer rone complexes accumulated on static mercury electrode was studied using square wave voltammetry (SWV) [92]. The electrochemical behavior of Cd(II) complexes with cysteine and folic acid was investigated. Folic acid forms adducts... 

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