A Further Study of the Utilization of Dietary Glycine Nitrogen for Uric Acid Synthesis in Gout 1

Benedict, Jean D.; Yu, Tzy‐Chyi; Bień, E; Gutman, Alexander B.; Stetten, DeWitt

doi:10.1172/jci102791

Cited by 54 publications

(13 citation statements)

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“…Degradation of the labeled urate suggested that glycine had been incorporated intact and indicated that non-specific labeling of the purine nucleus by secondary reactions was negligible. 4. These results constitute strong evidence that overproduction of uric acid from glycine and other small molecules is the fundamental defect responsible for the hyperuricemia of primary gout.…”

Section: Discussionmentioning

confidence: 81%

“…In an earlier study, Benedict, Yii, Bien, Gutman, and Stetten (4) found that control subjects and gouty subjects excreting normal quantities of uric acid incorporated 0.1 to 0.2 per cent of a test dose of N15, fed as glycine, into uric acid in a nine-day period, whereas two gouty subjects excreting excessive quantities of uric acid incorporated much larger quantities of N'5. In the latter patients, 0.45 and 0.56 per cent, respectively, of the N15 appeared in urinary uric acid in nine days.…”

Section: Discussionmentioning

confidence: 96%

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Overproduction of Uric Acid as the Cause of Hyperuricemia in Primary Gout

Wyngaarden¹

1957

J. Clin. Invest.

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Glycine contributes carbon atoms 4 and 5 and nitrogen atom 7 of the purine ring (1-3). Benedict, Yfi, Bien, Gutman and Stetten (4) have described experiments in which the abundance of N15 in uric acid was measured for several days following an oral test dose of glycine-N'5. In two gouty subjects, three times as much of the administered N15 was recovered in urinary uric acid as in normal subjects. In two others, however, normal quantities of N15 appeared in uric acid. In these studies, there was a rank order correlation between the daily excretion of uric acid in the urine and the per cent of ingested isotope appearing in urinary uric acid. In subjects who exhibited abnormally high basal uric acid excretions, an abnormally rapid and excessive incorporation of dietary glycine into uric acid occurred. In others whose basal excretion was approximately normal, utilization of glycine for uric acid synthesis was normal. Muller and Bauer (5) and Bishop, Rand, and Talbott (6) have each reported an additional gouty patient excreting normal quantities of uric acid who incorporated normal quantities of glycine-N'5 into urinary uric acid. The latter authors also described one gouty patient who incorporated excessive quantities of glycine-N'5 into urinary uric acid on two of three occasions despite a normal urinary urate excretion. These studies, therefore, demonstrated that overproduction of uric acid was present in some gouty subjects, but failed to give a clear indication of the cause of hyperuricemia in another, perhaps predominant group of the gouty population.Recently, we have administered glycine-1-C'4 to control and gouty patients in order to label urinary purines, as part of a study of intermediates in urate synthesis (7). The first two gouty patients both exhibited excessive incorporation of C14 into urinary urate, one despite a normal urate excretion (7,8). It was therefore decided to re-investigate the problem of the rate of generation of uric acid in gout, employing tracer doses of glycine-1-C"4 rather than large doses of glycine-N'5 as were required in previous studies.In the present study, glycine-1-C'4 was administered orally in 2.5 to 25 uc. doses to control and gouty subjects, and the concentration and cumulative incorporation of isotope into urinary uric acid were determined. This paper presents data indicating that overincorporation of glycine-1-C'4 into uric acid is a consistent finding in primary gout, and that the failure of the glycine-N'5 technique to disclose overincorporation in some gouty subjects may have been the result of the large dose of glycine employed. These results have been interpreted as showing that the hyperuricemia of primary gout is due to overproduction of uric acid in the majority if not all gouty subjects. METHODSGlycine-1-C'4, specific activity 1 to 2 mc. per mM, was purchased from Nuclear Instrument and Chemical Company. Uric acid determinations were performed by differential spectrophotometry according to Praetorius (9), employing purified uricase purchased from Worthington Bio...

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 96%

Overproduction of Uric Acid as the Cause of Hyperuricemia in Primary Gout

Wyngaarden¹

1957

J. Clin. Invest.

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“…at pH 4.2 overnight at 4'C, eluted with hot 0.1 N NaOH (31), and repeatedly recrystallized from Li2CO3 solution (32). All uric acid analyses were performed by the differential spectrophotometric 2 Abbreviations used in this paper: CoA-SH, reduced coenzyme A; formyl-GAM, a-formyl glycinamidineribonucleotide; formyl-GAR, a-formyl-GAR; 5-P,5-phosphate; GAR, glycinamideribonucleotide; PP-ribose-P, a-5-phosphoribosyl-1-pyrophosphate; PRA, jp-5-phosphoribosyl-1-amine; PRT, hypoxanthine-guanine phosphoribosyltransferase.…”

Section: Methodsmentioning

confidence: 99%

The Kinetics of Intramolecular Distribution of 15N in Uric Acid after Administration of [15N]Glycine A REAPPRAISAL OF THE SIGNIFICANCE OF PREFERENTIAL LABELING OF N-(3 + 9) OF URIC ACID IN PRIMARY GOUT

Sperling¹,

Wyngaarden²,

Starmer³

1973

J. Clin. Invest.

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A B S T R A C T The concept of an abnormality of glutamine metabolism in primary gout was first proposed on the basis of isotope data: when ["N]glycine was administered to gouty subjects, there was disproportionately great enrichment of N-(3 + 9) of uric acid, which derive from the amide-N of glutamine. An unduly high concentration of "N in glutamine was postulated, and attributed to a hypothetical defect in catabolism of glutamine. Excess glutamine was proposed as the driving force of uric acid overproduction.We have reexamined this proposition in four gouty subjects: one mild overproducer of uric acid with "idiopathic gout," one marked overproducer with high-grade but "partial" hypoxanthine-guanine phosphoribosyltransferase deficiency, and two extraordinary overproducers with superactive phosphoribosylpyrophosphate synthetases. In the last three, the driving force of excessive purine biosynthesis is a known surplus of a-5-phosphoribosyl-l-pyrophosphate. Disproportionately high labeling of N-(3 + 9) was present in all four gouty subjects, most marked in the most flamboyant overproducers. The precursor glycine pool was sampled by periodic administration of benzoic acid and isolation of urinary hippuric acid. Similarly, the precursor glutamine pool was sampled by periodic administration of phenylacetic acid and isolation of the amide-N of urinary phenylacetylglutamine. The ment of hippurate differed from that of the amide-N of glutamine. Whereas initial enrichment values of hippurate were very high, those of glutamine-amide-N were low, increasing to a maximum at about 3 h, and then declining less rapidly than those of hippurate. However, enrichment values of hippurate and of phenacetyl glutamine were normal in all of the gouty subjects studied. Thus, preferential enrichment of N-(3 + 9) in gouty overproducers given ["N]glycine does not necessarily reflect a specific abnormality of glutamine metabolism, but rather appears to be a kinetic phenomenon associated with accelerated purine biosynthesis per se.In addition, greater enrichment of N-9 than of N-3 on days 1 and 2 provided suggestive evidence for a second pathway for synthesis of the initial precursor of purine biosynthesis, phosphoribosylamine, perhaps utilizing ammonia rather than the amide-N of glutamine as nitrogen donor. In this limited study, the activity of this potential second pathway did not appear to be selectively increased in gout.

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“…Existing tracer studies on the metabolic defect of primary gout have employed injection of labeled uric acid and measurement of the kinetic behavior of the uric acid pool by classical dilution technics (3,4), or administration of a labeled precursor and measurement of its incorporation into uric acid (5,6,7,8). The dilution studies have shown major increases in the miscible pool of uric acid in almost all gouty subjects studied.…”

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confidence: 99%