Uric Acid Biosynthesis Research Articles

Uric acid degradation and biosynthesis of the enzymes uricase, glyoxylate carboligase and urease in Hydrogenomonas H 16

Uric acid degradation and biosynthesis of the enzymes uricase, glyoxylate carboligase and urease in Hydrogenomonas H 16

Excessive production of uric acid in type I glycogen storage disease

An increased de novo production of uric acid has been demonstrated in three hyperuricemic siblings with Type I glycogen storage disease. The hyperuricemia in Type I glycogen storage disease, therefore, appears to result from the previously demonstrated reduced renal clearance of uric acid as well as increased uric acid biosynthesis. Hyperuicemia regularly occurs in patients with Type I glycogen storage disease; gouty arthritis and gouty nephropathy frequently develop into the major clinical problems in these patients as they become adults. Hypoxanthine-guanine phosphoribosyltransferase activity, which is deficient in certain patients with overproduction of uric acid, was normal in the three patients studied.

Clinical pharmacology of drugs which influence uric acid production and excretion.

The hyperuricemia which occurs in primary gout can be demonstrated in a large proportion of cases to be due to overproduction of uric acid, i.e., an increase in rate and amount of de novo biosynthesis. In myeloproliferative diseases there is also consistent overproduction of uric acid, in this case due to an exaggeration of cell “turnover” and degradation of nucleic acid purines. Several compounds are available which can increase the urinary excretion of uric acid with beneficial effects on chronic gout, both primary and secondary. The recent availability of allopurinol, an effective inhibitor of uric acid biosynthesis, provides a highly effective means for controlling hyperuricemia with less risk of toxicity and adverse effects than is present in the use of the uricosuric drugs. Other compounds are discussed which block uric acid excretion or increase uric acid biosynthesis. These are of interest from a pharmacologic standpoint and as models for the study of uric acid metabolism.

Studies of uric acid biosynthesis in the chronic leukemias.

Studies of uric acid biosynthesis in the chronic leukemias.

Increase in uric acid biosynthesis produced by 2-substituted thiadiazoles.

Increase in uric acid biosynthesis produced by 2-substituted thiadiazoles.

Intramolecular distribution of uric acid-N15 after administration of glycine-N15 and ammonium-N15 chloride to goury and non-goury subjects.

Thus far, administration of N'5- or C14-labeled uric acid precursors to patients with primary gout has revealed an unequivocal metabolic aberration (namely, grossly increased total uric acid-N'5 or -C14) only in some cases (3-8), estimated to represent roughly 30 per cent of the gouty population (9). This group of gouty subjects is further characterized by greatly enhanced uric acid excretion while maintaining enlarged uric acid pools-clear evidence of production of uric acid considerably in excess of the normal. In the remaining gouty subjects studied, apparently representative of the majority of cases of primary gout, the available isotope data either reveal lesser increases in utilization of isotope-labeled precursors for uric acid biosynthesis, manifest only when appropriate corrections are made for enlarged uric acid pools and increased uric acid excretion into the gut (10), or fail to disclose any distinct metabolic abnormality whatever. In the isotope studies made to date, measurements have been limited almost exclusively to total uric acid-N15 or -C14; i.e., the mean isotope enrichment of all four nitrogens or all five carbons, collectively, of the uric acid molecule. The present study extends such measurements to analysis of the intramolecular distribution of uric acid-N'5, and explores further the possibility of abnormal distribution of isotope within the uric acid molecule even when the total uric acid isotope abundance approximates that found in nongouty subjects. Dissection of the uric acid molecule in this way can be particularly revealing in gout now that the sequential enzymatic reactions effecting placement of each atom in purine biosynthesis are securely established (11).

Inhibition of uric acid biosynthesis in birds by o-diazoacetyl-L-serine (azaserine) and 6-diazo-5-oxo-L-norleucine (DON).

Uric acid, the principal end product of nitrogen metabolism in birds, was measured in the plasma and urine of birds during intravenous infusion of solutions of glucose, saline and ammonium acetate. Ammonium acetate infusions increased the content of uric acid in plasma and urine. Administration of o-diazoacetyl-l-serine (azaserine) and 6-diazo-5-oxo-l-norleucine (DON) at ld50 doses produced prompt and nearly complete inhibition of uric acid synthesis in chickens, pigeons and cormorants as demonstrated by a parallel fall in plasma and urine uric acid. This inhibition is due to a block in purine biosynthesis. The ability of birds to synthesize uric acid recovers within 12–24 hours in spite of delayed toxicity with 50% of birds dying in 3–5 days. There is a dissociation between the acute, transient effects of azaserine and DON on uric acid production and the slower evolution of a lethal effect.

On the mechanism of overproduction of uric acid in patients with primary gout.

In order to study the rate of generation of uric acid in man, Benedict, Roche, Yu, Bien, Gutman, and Stetten (5-7) administered relatively large doses of glycine-N15 orally to control and gouty subjects and measured the appearance of isotope in urinary uric acid. With this technique, they demonstrated overincorporation of isotope into uric acid only in gouty subjects excreting large quantities of uric acid in urine. Subsequently, however, excessive incorporation of tracer quantities of glycine-1-C14 into uric acid was demonstrated in all of seven subjects studied, regardless of the stage of severity of the disease or of the magnitude of urinary uric acid excretion (8). These results indicated that overproduction of uric acid from glycine and other small molecules was the fundamental defect responsible for hyperuricemia in primary gout. The characteristics of the curves of uric acid enrichment indicated that excessive biosynthesis of uric acid occurred in these gouty subjects without the intermediary intervention of nucleic acids (5, 7, 8). Since the mechanism of overproduction of uric acid in primary gout has not been defined in detail, it was decided to investigate the incorporation of glycine-1-C'4 into various urinary purine bases and to compare enrichment patterns with those of uric acid determined simultaneously. From such comparisons, information was sought regarding purine intermediates involved in normal and abnormal uric acid production. These studies have suggested two types of mechanism resulting in uric acid synthesis in man and have strengthened the present concepts (5, 7, 8-12) that over-

On the biosynthesis of uric acid from glycine-N 15 in primary and secondary polycythemia

1. 1. The rate and magnitude of glycine-N 15 incorporation into urinary uric acid was studied in two cases of polycythemia vera and two cases of polycythemia secondary to congenital heart anomaly. 2. 2. It was demonstrated, by the magnitude of cumulative isotope labeling of urinary uric acid, that the occurrence of hyperuricemia and/or hyperuricosuria in some cases of polycythemia is attributable to overproduction of uric acid, as has long been suspected. 3. 3. The rate curves of glycine-N 15 incorporation into uric acid in polycythemia vera revealed slow, progressive enrichment of isotope, with peak abundance at the end of the second week after glycine-N 15 ingestion. The predominant route of uric acid biosynthesis in polycythemia vera therefore does not involve rapid, “shunt” metabolic pathways. The time relationships, however, are consistent with conversion of glycine into the purine components of intracellular nucleic acids, and subsequent biotransformation into uric acid. Evidence was obtained of diversion of excessive quantities of glycine into these metabolic channels, presumably to meet the excessive requirements of augmented hemopoietic activity. 4. 4. The rate curves of glycine-N 15 incorporation into urinary uric acid in secondary polycythemia were found to differ significantly from those in polycythemia vera, at least in the late phases examined. These differences may be related to the excessive production of cells of the myeloid series associated with the late phases of the myeloproliferative disorders. 5. 5. The sharp contrast between the rapid peak of glycine-N 15 incorporation into uric acid in primary gout and the slow peak in secondary gout indicates that, despite the similarities in clinical manifestations and therapeutic responses, the predominant pathways of uric acid biosynthesis in primary and secondary gout are different, and hence they have a different pathogenesis. 6. 6. It is not possible, from the rate and cumulative curves of glycine-N 15 incorporation into uric acid, to determine whether or not clinically overt gout has developed or will develop. This apparent paradox, which applies to latent and manifest primary and secondary gout, is discussed. 7. 7. The urinary excretion of purine bases other than uric acid was studied in primary and secondary polycythemia. Excessive excretion of 8-hydroxy-7-methylguanine, a newly discovered purine demonstrated by glycine-N 15 incorporation to be an endogenous metabolite, was found in polycythemia vera.

The oxidation of uric acid to oxonic acid (allantoxanic acid) and its application in tracer studies of uric acid biosynthesis

1. 1. Using isotropic tracer methods, the alkaline oxidation of uric acid to oxonic acid (allantoxanic acid) and allantoxaidine has been investigated. These two compounds do not contain the imidazole ring of uric acid, as is generally believed. They are formed from carbon atoms 2, 4 and 8, and nitrogens 3 and 9 of uric acid. The third nitrogen originates 50-50 from positions 1 and 7. In addition, oxonic acid contains the former carbon 5 as a carboxyl group. 2. 2. Symmetrical triazine structures are proposed for oxonic acid, allantoxaidine, and their derivatives to replace the generally accepted imidazolidine formulas. 3. 3. An indirect method is given for the calculation of the complete N- and C-isotope distribution in labelled uric acids. It is based on isotope determinations of uric acid and simple degradation products which are easily obtained in good yield and a very pure state.

A simultaneous study of glycine-N 15 incorporation into uric acid and heme, and of Fe 59 utilization, in a case of gout associated with polycythemia secondary to congenital heart disease

By simultaneous use of glycine-N 15 and Fe 59 as tracers the interrelationships between purine, porphyrin and iron metabolism were studied in a patient with gout associated with polycythemia secondary to congenital heart disease. The time course of glycine-N 15 incorporation into uric acid was unlike that previously observed in normal subjects and in patients with primary gout, in whom peak enrichment of uric acid N 15 occurs within two to four days of administration of the isotope. In the case recorded herein there was progressive increase in the N 15 abundance of the urinary uric acid until the tenth day. The protracted uric acid biosynthesis observed in this instance of secondary gout is presumed to reflect the augmented turnover of red cell precursor nucleic acids associated with increased erythropoiesis characterizing the polycythemic state. The time course of glycine-N 15 incorporation into heme in this case of secondary polycythemia did not deviate significantly from the normal, thus corresponding with the similar findings reported in polycythemia vera. As in other recorded instances of increased crythropoietic activity due to primary and secondary polycythemia, the initial half-time of disappearance of injected Fe 59 from the blood plasma was reduced (in this case to thirty-one minutes), the rate of Fe 59 incorporation into circulating red cells was correspondingly accelerated and the utilization of the Fe 59 for erythrogenesis was increased, by the seventh day, to over 90 per cent of the amount injected. The turnover rate of Fe 59 was accelerated both in the plasma and in the red cells.

Purine and pyrimidine metabolism

ArticlesPurine and Pyrimidine MetabolismAdam A. ChristmanAdam A. ChristmanPublished Online:01 Jul 1952https://doi.org/10.1152/physrev.1952.32.3.303MoreSectionsPDF (8 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByPurines in the Urine of Normal and Schizophrenic Subjects8 February 2018 | Journal of Mental Science, Vol. 106, No. 445On the biosynthesis of uric acid from glycine-N15 in primary and secondary polycythemiaThe American Journal of Medicine, Vol. 21, No. 6Utilization of purine and pyrimidine compounds in nucleic acid synthesis by Escherichia coliBiochimica et Biophysica Acta, Vol. 13 More from this issue > Volume 32Issue 3July 1952Pages 303-348 https://doi.org/10.1152/physrev.1952.32.3.303PubMed12983226History Published online 1 July 1952 Published in print 1 July 1952 Metrics

Uric acid metabolism and gout

Dr. Gutman: Gout is a disorder of purine metabolism characterized by hyperuricemia and recurrent acute arthritis, often eventually associated with urate deposits in the tissues which may be manifest as tophi or as typical roentgenographic changes. The natural history of the disorder is generally divided into two phases: “acute gout,” the period of single or recurring acute attacks of gouty arthritis with complete freedom of symptoms between attacks; and “chronic gouty arthritis,” when the interval between acute attacks no longer is symptom-free but is characterized by progressive disability due to stiffness and deformities of joints, and the appearance of tophi and typical roentgenographic changes. The course of the disease is variable, however, and many patients with acute gout do not, even upon observation for many years, develop the manifestations of chronic gouty arthritis. An important recent development is the realization that uric acid is derived not only from ingested preformed nucleoprotein or puririe but is synthesized within the body at a vigorous rate from the simplest carbon and nitrogen compounds. It has been established by isotope studies that glycine and ammonia contribute nitrogen to the formation of uric acid and that the carbon atoms are derived from formate, glycine and carbon dioxide. Evidently, ingested carbohydrate, fat and proteins, as well as preformed purines, all must be considered to be precursors of uric acid. It has also been shown that incorporation into nucleic acids is not an obligatory step in the biosynthesis of uric acid. Another important advance in elucidation of the mechanisms of gout is the development of a method for estimating the turnover rate and extent of the miscible pool of uric acid. This is accomplished by measuring the rate of dilution of N 15-labeled uric acid after intravenous injection. The method has already revealed that in the normal subject some 700 to 850 mg. of uric acid is formed daily; it has not yet been established whether or not the rate of production of uric acid is excessive in the gouty patient, an important point. It has been demonstrated further that the miscible pool of uric acid is increased in gout, even when uric acid deposits are not clinically or roentgenographically apparent. The method offers a means of measurement of these deposits although a serious limitation derives from the circumstance that the uric acid incorporated into tophi probably does not mix readily with the injected labeled uric acid, hence is not included in the miscible pool. Finally, additional evidence has been provided that uric acid is not degraded to any significant extent in man. With regard to the role of the kidneys in gout, several important advances have been made. A maximum tubular transport capacity, Tm, has been established for uric acid in normal man, indicating an “active” (enzymatic) tubular transporting mechanism of limited capacity. The tubular capacity for reabsorption of urate is large, however, in excess of any load that would be imposed even in gout. Of further significance are recent data indicating that many patients with gout excrete greater than normal amounts of uric acid so long as kidney damage, as measured by the ordinary laboratory criteria, is not appreciable. It is not yet possible to state definitely whether the hyperuricemia of gout is due to increased production of uric acid, decreased destruction of uric acid or impaired renal excretion of uric acid. The available evidence suggests, however, that increased production of uric acid occurs at least in some instances, in which it appears to be a primary factor. Impaired renal excretion of uric acid is an important secondary factor which in many cases contributes significantly to hyperuricemia, particularly in the later phases of gout. In the management of gout the mainstay of treatment of the acute gouty attack is still colchicine, with ACTH and cortisone as additional effective agents. In patients subject to frequent bouts of acute gout colchicine should be taken regularly as an important prophylactic agent. When there are indications of the development of chronic gouty arthritis uricosuric agents should be employed. Of these Benemid appears to be the most promising yet developed. With regard to dietary restriction in gout, the situation still is unsettled. In patients subject to frequent recurrences of acute gout and in those with chronic gouty arthritis it seems prudent to restrict the purine, protein and alcoholic intake.

BIOSYNTHESIS OF URIC ACID LABELED WITH RADIOACTIVE CARBON

Sonne, Buchanan, and Delluva (1,2) have recently identified some of the precursors of the carbon atoms of uric acid in the pigeon. We have had occasion to repeat and extend their experiments during an investigation of the suitability of the pigeon as an agent for the biosynthesis of uric acid labeled in various positions with C14. This paper presents data on the yields of several different kinds of labeled uric acid obtained after injecting suitably labeled precursors and also provides information on the r6le of the methylene carbon of glycine’ in the synthesis of uric acid.