Affecting Purine Metabolism

Compounds active in the regulation of oxypurine metabolism can influence the production of purines de novo and the interconversion or 

A number of 2-substituted thiadiazoles (Fig. 7) are unique in that they, among all known drugs, cause an increase in the production of uric acid. The original observation came as a result of the evaluation of 2-ethylamino-l,3,4-thiadiazole (EATDA) as a potential antitumor 

Not only are the effects of thiadiazoles blocked in patients, but the antileukemic action in experimental animals is also reversed by nicotinamide (C3). No direct evidence of interference with NAD synthesis or function has been obtained, but these reversal studies obviously suggest this as a possible explanation of the biochemical actions of these compounds. Ciotti and associates (C3) demonstrated an exchange reaction with NAD in vitro yielding an analog of NAD, but no evidence was obtained that this occurs in vivo. 

Examination of the urine of subjects receiving EATDA showed that several, if not all, of the urinary purines were excreted in increased amounts. There was, furthermore, no change in the mode of excretion of urates or in the proportion disposed of extrarenally (S12). The suggestion has been made (K18) that the fundamental mechanism of action of these compounds is the blocking of the incorporation of newly synthesized adenine into polynucleotides and/or coenzymes, with the production of an undefined deficiency state. This block could stimulate a compensatory increase in purine biosynthesis. The excess purines would not be utilizable and, therefore, would be excreted from the cells, and the normal degradation by enzymes would convert this material to uric acid. 

One of the first studies that indicated the possible interference of ametbopterin and aminopterin with purine synthesis was the demonstration by Skipper et al. (S21) that administration of these compounds to mice inhibited the incorporation of labeled formate into nucleic acid purines. Ametbopterin (4-amino-A -methyl-pteroylglutamic acid) has produced some inhibition of uric acid synthesis during the use of this compound for treatment of leukemia (K15, E24). Another inhibitor of 

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Several disorders affect purine metabolism. They are gout and the syndromes associated with deficiency of HPRT, APRT, adenosine deaminase, nucleoside phosphorylase, myoadenylate deaminase, and xanthine oxidase. 

How Amitrole affects purine metabolism was indirectly investigated by Rabinowitz and Pricer, who demonstrated that Amitrole blocks the enzymatic degradation of 4-aminoimidazole in extracts of Clostridium cylin-... 

Drugs affecting purine metabolism act aberrantly in the Lesch-Nyhan syndrome [127]. Azathioprine and 6-mercapto-purine do not affect purine synthesis allopurinol reduces uric acid production but causes an equivalent increase in oxypurines probenecid increases urinary excretion of uric acid and... 

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

Mutations in the gene for adenylosuccinate lyase (ASL), inherited as an autosomal recessive disorder in purine metabolism, are associated with severe mental retardation and autistic behavior, but apparently not self-mutilation [10, 11]. This enzyme catalyzes two distinct reactions in the de novo biosynthesis of purines the cleavages of adenylosuccinate (S-Ado) and succinylaminoimidazole carboxamide ribotide (SAICAR), both of which accumulate in plasma, urine and cerebrospinal fluid of affected individuals [12]. Measurements of these metabolites in urine... 

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. 

Additionally it should be remembered that nicotine metabolites still retain a pyridyl moiety and this functional group can release nicotinamide from NADPH and generate an analogue of the coenzyme via a glycohydrolase. As these analogues may not be able to participate in the normal oxido/reduction reactions of intermediary metabolism certain pathways may be inhibited leading to accumulation of substrates e.g. glucose-6-phosphate and diminution of availability of products e.g. ribose, and thereby affect purine, pyrimidine and nucleic acid biosynthesis. 

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. 

The cytokinins are extremely potent as little as 5 X 10 M 6-(4-hydroxy-3-methyl-frans-2-butenylamino) purine can be detected by some bioassay systems. They have a wide variety of actions in plants, including promotion of cell division, delay of senescence, and resistance to adverse conditions. They affect plant metabolism, organelle development, and fruit and flower formation. Unfortunately, their basic mechanisms of action are not known. 

The quantitative importance of the salvage pathway in purine metabolism is difficult to estimate [156]. Comparison between uric acid production in normal children and in children affected with a deficiency in hypoxanthine guanine phosphoribosyl transferase has, however, permitted researchers to approximate how much the salvage pathway contributes to purine metabolism. Thus, whereas in normal children uric acid excretion in the urine (per 24 hours and per kilogram of body weight) is of the order of 10 mg, in children affected with the Lesch-Nyhan syndrome, uric acid excretion is around 47 mg. The difference between enzyme-deficient and normal children is believed to reflect the amount of uric acid normally used in the salvage pathway. 

Lesch-Nyhan disease is an X-linked recessive disorder characterized by hyperuricemia, physical and mental retardation, choreo-athetosis, and compulsive self-mutilation. The disease is associated with absence of activity of an enzyme involved in purine metabolism, namely hypoxanthlne guanine phosphoribosyl transferase (HGPRT), and is believed to affect male only. We present here, however, an unusual case of a girl with the Lesch-Nyhan syndrome, whose mother is not heterozygous for a deficiency of the enzyme. 

Despite structural diversity in the superactive enzymes of individual families, studies of PRPP and purine metabolism carried out both vivo and in cells cultured from affected hemizygous males support the idea that a common mechanism accounts for the association of PRPP synthetase superactivity with uric acid overproduction. Increased intracellular PRPP concentrations and rates of PRPP generation as well as increased rates of all PRPP-dependent purine nucleotide synthetic processes are constant accompaniments of enzyme superactivity. These findings suggest a scheme to explain the association of the enzyme defect with uric acid overproduction PRPP synthetase superactivity -> increased intracellular PRPP generation and concentration > increased rate of purine nucleotide synthesis excessive uric acid synthesis. 

Partial deficiency of HGPRT, a salvage enzyme of purine metabolism, has been demonstrated to be the primary abnormality causing purine overproduction in a small proportion of patients with gout (l-4). The quantitative deviation in the activity of this enzyme has been shown by Kelley et al. to be associated with decreased stability to thermal inactivation (2). These authors suggest that in the affected subjects HGPRT is structurally altered. Furthermore, in some of these patients erythrocyte adenine phosphoribosyltransferase (APRT) activity was found to be increased and relatively thermostable (2). 

Purine drugs, especially thiopurines, are potent antineoplastic agents. 6-Thiopurine is also an effective immunosuppressant. Purine drugs are used extensively in treatment of various leukemias. Their activity and toxicity are affected by metabolic redox processes which, despite extensive biochemical studies, are still only partially understood. 

As early as 1981, several different research groups were successful in developing replication-defective avian and murine retroviral vectors (8-10). With the advent of such tools it was now possible to test an important proof of concept—correcting genetic defects through the transduction of normal genes into affected cells. One of the first important experiments involved the use of a retroviral vector to correct both the enzyme defect and purine metabolic abnormalities in cells taken from a patient with Lesch-Nyhan syndrome (11). 

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. 

It plays a vital role in various intracellular reactions e.g. conversion of serine to glycine, synthesis of thymidylate, synthesis of purines, histidine metabolism etc. Due to folic acid deficiency these reactions are affected. 

Pernicious anemia. Purine biosynthesis is impaired by vitamin Bj2 deficiency. Why How might fatty acid and amino acid metabolism also be affected by a vitamin Bj2 deficiency ... 

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