Purine Metabolism In Man Research Articles

Analysis of abnormalities in purine metabolism leading to gout and to neurological dysfunctions in man.

A modelling approach is used to analyse diseases associated with purine metabolism in man. The specific focus is on deficiencies in two enzymes, hypoxanthine:guanine phosphoribosyltransferase and adenylosuccinate lyase. These deficiencies can lead to a number of symptoms, including neurological dysfunctions and mental retardation. Although the biochemical mechanisms of dysfunctions associated with adenylosuccinate lyase deficiency are not completely understood, there is at least general agreement in the literature about possible causes. Simulations with our model confirm that accumulation of the two substrates of the enzyme can lead to significant biochemical imbalance. In hypoxanthine:guanine phosphoribosyltransferase deficiency the biochemical mechanisms associated with neurological dysfunctions are less clear. Model analyses support some old hypotheses but also suggest new indicators for possible causes of neurological dysfunctions associated with this deficiency. Hypoxanthine:guanine phosphoribosyltransferase deficiency is known to cause hyperuricaemia and gout. We compare the relative importance of this deficiency with other known causes of gout in humans. The analysis suggests that defects in the excretion of uric acid are more consequential than defects in uric acid synthesis such as hypoxanthine:guanine phosphoribosyltransferase deficiency.

Validation and steady-state analysis of a power-law model of purine metabolism in man.

The paper introduces a model of human purine metabolism in situ. Chosen from among several alternative system descriptions, the model is formulated as a Generalized Mass Action system within Biochemical Systems Theory and validated with analyses of steady-state and dynamic characteristics. Eigenvalue and sensitivity analyses indicate that the model has a stable and robust steady-state. The model quite accurately reproduces numerous biochemical and clinical observations in healthy subjects as well as in patients with disorders of purine metabolism. These results suggest that the model can be used to assess biochemical and clinical aspects of human purine metabolism. It provides a means of exploring effects of enzyme deficiencies and is a potential tool for identifying steps of the pathway that could be the target of therapeutical intervention. Numerous quantitative comparisons with data are given. The model can be used for biomathematical exploration of relationships between enzymic deficiencies and clinically manifested diseases.

Developmental changes in purine nucleotide metabolism in cultured rat astroglia

The present study was conducted in order to clarify the role of the glia in brain purine metabolism. This, in connection with the clarification of the etiology of the neurological manifestations associated with some of the inborn errors of purine metabolism in man. Purine nucleotide content, the capacity for de novo and salvage purine synthesis and the activity of several enzymes of purine nucleotide degradation, were assayed in primary cultures of rat astroglia in relation to culture age. The capacity of the intact cells to produce purine nucleotides de novo exhibited a marked decrease with the culture age, but the activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), catalyzing salvage nucleotide synthesis, increased. Aging was also associated with a marked increase in the activity of the degradation enzymes AMP deaminase, purine nucleoside phosphorylase (PNP) and guanine deaminase (guanase). The activity of adenosine deaminase and of AMP-5′-nucleotidase, increased markedly during the first 17 days in culture, but decreased thereafter.The results indicate that purine nucleotide metabolism in the cultured astroglia is changing with aging to allow the cells to maintain their nucleotide pool by reutilization of preformed hypoxanthine, rather than by de-novo production of new purines. Aging is also associated with increased capacity for operation of the adenine nucleotide cycle, contributing to the homeostasis of adenine nucleotides and to the energy charge of the cells. In principle, the age-related alterations in purine metabolism in the astroglia resemble those occurring in the maturating neurons, except for the capacity to produce purines de novo, which exhibited inverse trends in the two tissues. However, in comparison to the neurons, the cultured astroglia possess the capacity for a more intensive metabolism of purine nucleotides.

The effect of high-intensity training on purine metabolism in man.

The effect of intermittent high-intensity training on the activity of enzymes involved in purine metabolism and on the concentration of plasma purines following acute short-term intense exercise was investigated. Eleven subjects performed sprint training three times per week for 6 weeks. Muscle biopsies for determination of enzyme activities were obtained prior to and 24 h after the training period. After training, the activity of adenosine 5'-phosphate (AMP) deaminase was lower (P < 0.001) whereas the activities of hypoxanthine phosphoribosyl transferase (HPRT) and phosphofructokinase were significantly higher compared with pre-training levels. The higher activity of HPRT with training suggests an improved potential for rephosphorylation of intracellular hypoxanthine to inosine monophosphate (IMP) in the trained muscle. Before and after the training period the subjects performed four independent 2-min tests at intensities from a mean of 106 to 135% of VO2max. Venous blood was drawn prior to and after each test. The accumulation of plasma hypoxanthine following the four tests was lower following training compared with prior to training (P < 0.05). The accumulation of uric acid was significantly lower (46% of pre-training value) after the test performed at 135% of VO2max (P < 0.05). Based on the observed alterations in muscle enzyme activities and plasma purine accumulation, it is suggested that high intensity intermittent training leads to a lower release of purines from muscle to plasma following intense exercise and, thus, a reduced loss of muscle nucleotides.

Towards the physiological function of uric acid

Uric acid, or more correctly (at physiological pH values), its monoanion urate, is traditionally considered to be a metabolically inert end-product of purine metabolism in man, without any physiology value. However, this ubiquitous compound has proven to be selective antioxidant, capable especially of reaction with hydroxyl radicals and hypochlorous acid, itself being converted to innocuous products (allantoin, allantoate, glyoxylate, urea, oxalate). There is now evidence for such processes not only in vitro and in isolated organs, but also in the human lung in vivo. Urate may also serve as an oxidase cosubstrate for the enzyme cyclooxygenase. As shown for the coronary system, a major site of production of urates is the microvascular endothelium, and there is generally a net release of urate from the human myocardium in vivo. In isolated organ preparations, urate protects against reperfusion damage induced by activated granulocytes, cells known to produce a variety of radicals and oxidants. Intriguingly, urate prevents inactivation of endothelial enzymes (cyclooxygenase, angiotensin converting enzyme) and preserves the ability of the endothelium to mediate vascular dilatation in the face of oxidative stress, suggesting a particular relationship between the site of urate formation and the need for a biologically potent radical scavenger and antioxidant.

Action of biologically-relevant oxidizing species upon uric acid. Identification of uric acid oxidation products

Uric acid is an end-product of purine metabolism in Man, and has been suggested to act as an antioxidant in vivo. Products of attack upon uric acid by various oxidants were measured by high performance liquid chromatography. Hypochlorous acid rapidly oxidized uric acid, forming allantoin, oxonic/oxaluric and parabanic acids, as well as several unidentified products. HOCl could oxidize all these products further. Hydrogen peroxide did not oxidize uric acid at detectable rates, although it rapidly oxidized oxonic acid and slowly oxidized allantoin and parabanic acids. Hydroxyl radicals generated by hypoxanthine/xanthine oxidase or Fe 2+-EDTA/H 2O 2 systems also oxidized uric acid to allantoin, oxonic/oxaluric acid and traces of parabanic acid. Addition of ascorbic acid to the Fe 2+-EDTA/H 2O 2 system did not increase formation of oxidation products from uric acid, possibly because ascorbic acid can ‘repair’ the radicals resulting from initial attack of hydroxyl radicals upon uric acid. Mixtures of methaemoglobin or metmyoglobin and H 2O 2 also oxidized uric acid: allantoin was the major product, but some parabanic and oxonic/oxaluric acids were also produced. Caeruloplasmin did not oxidize uric acid under physiological conditions, although simple copper (Cu 2+) ions could, but this was prevented by albumin or histidine. The possibility of using oxidation products of uric acid, such as allantoin, as an index of oxidant generation in vivo in humans is discussed.

Electron transfer mechanisms of some biochemically active purines

Free purines are found in some of the biological Systems. Some types of purines as consti- tuents of large molecules however are found in every living celi. Uric acid is a purine derivative which was discovered över one hundred years ago. It is found in blood, cerebral spinal fluid and milk. Bird excrement, guano contains a significant amount of uric acid. Uric acid as well as other oxypurines are the majör products of purine metabolism in man. Presence of adenine and guanine in nucleic acids is important in transfer of genetic infor- mation. Oxidation and reduction of purine derivatives in human and animal metabolisms have been studied extensively. Electron transfer mechanisms of purines, are therefore important in stud- ying their role in biological Systems. In the present study the electron transfer mechanisms of some biologically active purines are discussed.

Molecular Genetics of Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency in Man

Hypoxanthine - guanine phosphoribosyltransferase (HPRT) is a purine salvage enzyme that plays a key role in the regulation of purine metabolism in man. Interest in this X-linked enzyme stems, in part, from the existence of two clinical syndromes associated with deficiency of HPRT enzyme activity. In 1967, Seegmiller et al 1 described a virtually complete deficiency of HPRT activity in patients with the Lesch-Nyhan syndrome. This syndrome is characterized by an overproduction of uric acid as well as a bizarre constellation of neurologic and behavioral abnormalities, including mental retardation, spasticity, choreoathetosis, and a compulsive form of self-mutilation. A partial deficiency of HPRT was subsequently demonstrated in several male patients who presented with hyperuricemia and a severe form of gout at an early age. 2 This latter group of patients is usually free of the central nervous system manifestations that characterize the Lesch-Nyhan syndrome, although an occasional patient with partial HPRT deficiency

A COMPARATIVE STUDY OF ALLOPURINOL AND PENTOSTAM IN THE TREATMENT OF VISCERAL LEISHMANIASIS: 210

Allopurinol has been shown to inhibit the in vitro growth of leishmaniasis Donovani (1). Recently allopurinol has also been reported effective in the treatment of visceral leishmaniasis with a response rate of 14 out of 16 treated cases (2). The purpose of the present study is to compare the clinical effect of allopurinol versus pentostam at fixed dosages (30 ml/kg and 10 mg/kg daily for 30 days respectively) in the treatment of visceral leishmaniasis. 16 patients were included. 7 patients received allopurinol and 9 pentostam treatment. The clinical effect was monitored using a scoring system. 5 parameters were included each gave 1 point for improvement and 0 point for no improvement. In an average the patients in the allopurinol group scored 1 1/7 point and the pentostam group 3 7/9 point within the first month of treatment. The difference is significant (p < 0.01 Wilcoxon test). Conclusion: Although allopurinol improve the clinical condition of the patients to some extent pentostam treatment was superior in that respect. (1) J.J.Marr: Purine Metabolism in Man - IV, Plenum Press, New York, Editor: C.H.M.M. Bruym, H.A.Simmonds & M.M.Muller 1984, p. 231-237. (2) T.K.Jha: Transaction of the Royal Society of Tropical Medicine and Hygiene. Vol. 77, 204-207, 1983.

IN VIVO INHIBITION OF MOUSE LIVER METHYLTRANSFERASE (MT) ENZYMES FOLLOWING TREATMENT WITH 2'DEOXYCOFORMYCIN (dCf) AND 2'DEOXYADENOSINE (AdR): 171

Treatment of BDF1 mice with AdR/dCf combinations (daily x5) leads to acute hepatic dysfunction with accumulative dose related hepatocellular necrosis (Paine et al Cancer Treat. Rep. 65:281-266, 1971). In vivo inhibition of liver S-adenosyl-homocysteine (SAH) hydrolase by AdR is implicated since liver SAH levels increase dramatically following treatment. S-adenosylmethionine (SAM) levels also increase and the SAM:SAH ratios drop from control values of 15 to <1 (Renshaw & Harrap, in Purine Metabolism in Man, Vol. 165B, Plenum Press, pp 363-366, 1984). Further investigations have revealed that while SAH and SAM levels and their ratios normalise following the first 2 days treatment, recovery does not occur thereafter. These data indicate a correlation between the duration of depression of SAM:SAH ratios and the manifestation of hepatocellular necrosis. In addition we have obtained evidence of in vivo inhibition of MT reactions as a result of reduced SAM:SAH ratios: both plasma and urinary creatinine levels are significantly reduced (eg, 23% control urinary creatinine levels by day 5) reflecting inhibition of liver guanidinioacetate MT. Plasma:urinary creatinine ratios do not alter indicating a lack of kidney toxicity in mice. Treated animals also excrete significantly less pseudouridine (<30% from day 2) which may reflect a biochemical lesion at the level of tRNA post-transcriptional modification.

Purine Metabolism in Man—IV—Clinical and Therapeutic Aspects, Regulatory Mechanisms. (Advances in Experimental Medicine and Biology/Vol. 165 A)

Purine Metabolism in Man—IV—Clinical and Therapeutic Aspects, Regulatory Mechanisms. (Advances in Experimental Medicine and Biology/Vol. 165 A)

Uricostatic effect of allopurinol in the allantoxanamide-treated rat: a new method for evaluating antiuricopathic drugs.

In most mammals, uric acid is converted into allantoin by the enzyme uricase, which does not occur in man and apes. Thus, the urinary end product of purine metabolism in man and apes is uric acid, whereas it is allantoin in most mammals. An attempt to produce an animal model for research into hyperuricemia was made by Johnson1, who blocked the activity of hepatic uricase in rats by a selective enzyme inhibitor, oxonic acid (oxonate). Particularly the amide of oxonic acid (allantoxanamide) has been described as an effective inhibitor of uricase activity in vitro and in vivo. Hropot2 demonstrated that the prolonged duration of action of allantoxanamide as compared to oxonic acid is due to its elimination kinetics. Allantoxanamide was eliminated by the kidneys with a half-life of 25.4 min, which was double that of oxonate during the first 30 min after administration. The purpose of this study was to establish an appropriate screening method for evaluating antiuricopathic drugs in the allantoxanamide-treated rat.

In born errors of purine metabolism in man: development of purine enzyme assays using high performance liquid chromatography

In born errors of purine metabolism in man: development of purine enzyme assays using high performance liquid chromatography

Purine metabolism during strenuous muscular exercise in man

This study was designed to examine the influence of exercise on purine metabolism in man. In 15 men, the plasma uric acid concentration increased from 6.9 to 8.5 mg/dl following a 5000-m race and from 6.2 to 7.9 mg/dl in 11 men following a 42-km marathon. During a progressive exercise test on a cycle ergometer, the plasma uric acid concentration did not change significantly in 11 subjects. However, the plasma oxypurines increased from 19 μ M at rest to 50 μ M at exhaustion and the urinary excretion of oxypurines increased from 140 to 400 μmol/g creatinine. Intracellular ATP decreased from 5.17 to 2.91 μmol/g and ADP and AMP increased from 0.85 to 1.29 and from 0.12 to 0.15 μmol/g wet weight, respectively. These observations suggest that there is an accelerated degradation of purine nucleotides to the precursors of uric acid in skeletal muscle during vigorous exercise.

Reviews

Book reviewed in this article: Human Heredity. By C. O. Carter. Human Genetics. By E. Novitski Genetic Engineering: Threat or Promise? By Laurence E. Karp. Purine Metabolism in Man. 2. Regulation of Pathways and Enzyme Defects. Advances in Experimental Medicine and Biology, Volume 76A. Edited by M. M. Muller, E. Kaiser and J. E. Seegmiller. Superoxide and Superoxide Dismutases. Edited by A. M. Michelson, J. M. McCord and I. Fridovich. Molecular Population Genetics and Evolution. By Masatoshi Nei.

Purine Metabolism in Man II. Advances in Experimental Medicine and Biology. Volume 76A: Regulation of Pathways and Enzyme Defects; Volume 76B: Physiology, Pharmacology, and Clinical Aspects. Prooceedings of the First and Second Halves of the Second International Symposium on Purine Metabolism in Man, Held in Baden, Vienna, Austria, June 20-26, 1976.Mathias M. Muller , Erich Kaiser , J. Edwin Seegmiller

<i>Purine Metabolism in Man II. Advances in Experimental Medicine and Biology. Volume 76A: Regulation of Pathways and Enzyme Defects; Volume 76B: Physiology, Pharmacology, and Clinical Aspects. Prooceedings of the First and Second Halves of the Second International Symposium on Purine Metabolism in Man, Held in Baden, Vienna, Austria, June 20-26, 1976.</i>Mathias M. Muller , Erich Kaiser , J. Edwin Seegmiller

Purine Metabolism in Man--II

Purine Metabolism in Man--II

Purine Metabolism in Man—II. Regulation of Pathways and Enzyme Defects.

of Volume 76 A -- History of Gout. Including Comments from an Illustrious Timeless Gathering -- Metabolic Pathways of Purines -- Mutations Affecting Purine Metabolism in Man -- Immunological Aspects -- Relationship Between Carbohydrate, Lipid and Purine Metabolism -- Methodology -- Author Index.

Ultramicrochemistry: a contribution to the analysis of purine metabolism in man.

Since 1963 a simple general methodology has been developed for ultra-micro enzyme assays of cultured fibroblasts (1,2,3). These techniques permit to isolate from cell cultures grown in a Plastic Film Dish (PFD;2) a small number of visually selected, lyophilised cells.

Complete deficiency of adenine phosphoribosyltransferase: report of a family.

The study of inborn errors of purine metabolism in man has led to a better understanding of the latter. Deficiencies of enzymes involved in the purine reutilization pathways mainly concern the hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the clinical expression being the Lesch-Nyhan syndrome or eventually gout. Partial deficiency of adenine phosphoribosyltransferase (APRT), the enzyme catalyzing the transport of the ribosylphosphate moiety of phosphoribosylpyrophosphate (PRPP) to adenine with formation of AMP, has only rarely been described (2,3,5–9), Complete deficiency of this enzyme was reported in only one patient (2). We report here on two siblings with complete APRT deficiency: in the youngest child the deficiency was detected during an investigation for urolithiasis, in the older brother it was demonstrated on the occasion of the family study.