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Folate purine metabolism

Amino acids ate not the only source of ammonium ions produced in the body. Much of the ammonia produced, especially in the brain, arises from the hydrolysis of purines. Adenylate deaminase catalyzes the hydrolysis of AMP, yielding IMP and ammonium ions Cooper and Plum, 1987). IMP is inosine monophosphate (inosinic acid), GMP may also be hydrolyzed in this manner, yielding xanthosine and ammonium ions. Further details on purine metabolism occur at the end of this chapter and under Folate in Chapter 9. [Pg.441]

FEGURE. 11 Conversion of ino< irte monophosphate to adenosine monophosphate and guanos-ine monophosphate. Aspartate donates an amino group in the synthesis of AMP. Cltitaminc donates an amino group in the Synthesis of GMP, Folate is not used in these steps of purine metabolism. [Pg.504]

Methotrexate and aminopterin, a similar compound, are analogs of dihydro folate (DHF) and inhibitors of dihydrofolate reductase, an enzyme that converts DHF to tetrahydro-folate (THF). The thymidylate synthase reaction converts N, N °-methylenetetrahydro-folate to DHF in the process of methylating dUMP to form dTMP In the presence of one of the inhibitors, this reaction functions as a sink that reduces the THF level of the cell by converting THF to DHF. Since THF derivatives are substrates in two reactions of purine metabolism and one of pyrimidine metabolism, both pathways are affected by the inhibitor. [Pg.455]

Antimetabolites interfere with normal metabolic pathways. They can be grouped into folate antagonists and analogues of purine or pyrimidine bases. Their action is limited to the S-phase of the cell cycle and therefore they target a smaller fraction of cells as compared with alkylating agents. [Pg.154]

These one-carbon groups, which are required for the synthesis of purines, thymidine nucleotides and for the interconversion some amino acids, are attached to THF at nitrogen-5 (N5), nitrogen-10 (N10) or both N5and N10. Active forms of folate are derived metabolically from THF so a deficiency of the parent compound will affect a number of pathways which use any form of THF. [Pg.140]

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... [Pg.413]

Correct answer = A. Methotrexate interferes with folate metabolism by acting as a competitive inhibitor of the enzyme dihydrofolate reductase. This starves cells for tetrahydrofolate, and makes them unable to synthesize purines and dTMP This is especially toxic to rapidly-growing cancer cells. Overproduction of dihydrofolate reductase, usually caused by amplification of its gene, can overcome the inhibition of the enzyme at the methotrexate concentrations used for chemotherapy, and can result in resistance of the tumor to treatment by this drug. [Pg.304]

Methotrexate Antiproliferative inhibits folate metabolism, purine synthesis and cell proliferation Porcine coronary artery Local application by balloon catheter Did not prevent neointimal thickening (101)... [Pg.303]

Vitamin B12 is required by only two enzymes in human metabolism methionine synthetase and L-methylmalonyl-CoA mutase. Methionine synthetase has an absolute requirement for methylcobalamin and catalyzes the conversion of homocysteine to methionine (Fig. 28-5). 5-Methyltetrahydrofolate is converted to tetrahydrofolate (THF) in this reaction. This vitamin B12-catalyzed reaction is the only means by which THF can be regenerated from 5-methyltetrahydrofolate in humans. Therefore, in vitamin B12 deficiency, folic acid can become trapped in the 5-methyltetrahydrofolate form, and THF is then unavailable for conversion to other coenzyme forms required for purine, pyrimidine, and amino acid synthesis (Fig. 28-6). All folate-dependent reactions are impaired in vitamin B12 deficiency, resulting in indistinguishable hematological abnormalities in both folate and vitamin B12 deficiencies. [Pg.308]

Two diastereomers of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid, DDATHF, 127, both potent inhibitors of folate metabolism114 and de novo purine synthesis115, have been synthesized116 by catalytic reduction of the unsaturated intermediate diethyl 2-acetyl-5,10-dideaza-9,10-didehydrofolate with Adams catalyst and carrier-free tritium gas in AcOH and 3H20 solution. Each of the separated (6R) and (65) diastereomers had specific activity 11.2 Ci mmol-1 and contained tritium almost exclusively at the metabolically stable positions C(5), C(6), C(7), C(9), C(10) and the phenyl ring of DDATHF. [Pg.1154]

The enzyme dihydrofolic acid (DHF) S5mthase (see below) converts p-aminobenzoic acid (PABA) to DHF which is subsequently converted to tetrahydric folic acid (THF), purines and DNA. The sulphonamides are structurally similar to PABA, successfully compete with it for DHF s)mthase and thus ultimately impair DNA formation. Most bacteria do not use preformed folate, but humans derive DHF from dietary folate which protects their cells from the metabolic effect of sulphonamides. Trimethoprim acts at the subsequent step by inhibiting DHF reductase, which converts DHF to THF. The drug is relatively safe because bacterial DHF reductase is much more sensitive to trimethoprim than is the human form of the enzyme. Both sulphonamides and trimethoprim are bacteriostatic. [Pg.231]

Deficiency of folic acid leads to a megaloblastic anaemia because it is necessary for the production of purines and pyrimidines, which are essential precursors of deoxyribonucleic acid (DNA). The megaloblastic marrow of cobalamin deficiency is due to interference with folic acid utilisation and the morphological changes of cobalamin deficiency can be reversed by folic acid. It is vital to realise that folic acid does not provide adequate treatment for pernicious anaemia. Nor does vitamin 3 2 provide adequate treatment for the megaloblastic anaemia of folic acid deficiency, although a partial response may occur because vitamin plays a role in folate metabolism. [Pg.596]

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. [Pg.43]

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. [Pg.250]

Inhibition of the Reductase affects folate metabolism leading to decreased glycine formation from serine and decreased purine synthesis which requires CH3-THF. To facilitate normal cells folinic acid (Leucovorin) is given along with methotrexate. This acid aids normal cells by its conversion to the coenzyme of Thymidyiate S)mthetase, thus bypassing the block. Since the thymidine nucleotide requirements of rapidly proliferating cells are much greater than for quiescent cells folinic acid cannot meet the demands of the cancer cells. [Pg.385]

A more complete versit>n of folate metabolism is given in Figure 9.5, The cycle of reactions used to regenerate methionine is featured In the center of the diagram. H4folate may be considered the starting and ending point in the cycles depicted. The cycles involve the introduction of a I-carbon unit, derived from serine, into tissue folates. This is followed by use of the 1-carbon unit for the synthesis of methionine, purines, and thymidylate. Conditions that result in a decline in tissue... [Pg.497]

FIGURE 9.5 Simplified version of folate metabolism. Serine is the source of most of the 1-carbon units carried by folates. These 1-carbon units are used in the synthesis of thymidy-late (a pyrimidine nucleotide), purine nucleotides, and methionine. [Pg.498]

Once inside the cell, folates participate in a number of interconnected metabolic pathways involving (1) thymidine and purine biosynthesis necessary for DNA synthesis, (2) methionine synthesis via homocysteine remethylation, (3) methylation reactions involving S-adenosylmethionine (AdoMet), (4) serine and glycine interconversion, and (5) metabolism of histidine and formate (see Figure 8). Via these pathways. [Pg.754]


See other pages where Folate purine metabolism is mentioned: [Pg.148]    [Pg.327]    [Pg.148]    [Pg.387]    [Pg.1819]    [Pg.325]    [Pg.112]    [Pg.298]    [Pg.231]    [Pg.717]    [Pg.204]    [Pg.301]    [Pg.802]    [Pg.1399]    [Pg.1460]    [Pg.325]    [Pg.162]    [Pg.346]    [Pg.745]    [Pg.1291]    [Pg.276]    [Pg.150]    [Pg.292]    [Pg.292]    [Pg.325]    [Pg.499]    [Pg.499]    [Pg.292]   
See also in sourсe #XX -- [ Pg.141 ]




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