Incorporation of glycine-1-C14, glycine-2-C14 and glycine-N15 into uric acid in normal and gouty subjects

Gutman, Alexander B.; Yu, Tzy‐Chyi; Black, Hannah; Yalow, Rosalyn S.; Berson, Solomon A.

doi:10.1016/0002-9343(58)90063-9

Cited by 47 publications

(24 citation statements)

References 14 publications

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“…The area-under-the-curve (AUC) of the extracted ion chromatograms (XIC) for m/z 168 → 124 and 168 → 125 and 169 → 125 represents the amount of 13 C at C 2 , C 8 and both C 2 and C 8 , respectively. The AUC of XIC for m/z 167 → 124 represents uric acid containing only 12 C, 1 H, 14 N and 16 O. The percentage of 13 C at C 2 (% 13 C 2 ) and C 8 (% 13 C 8 ) in total uric acid was estimated using the following formulae: % 13 Similar calculations were made to estimate the % 13 C after a [2-13 C]glycine dose.…”

Section: Measurement Of 13 C Enrichmentmentioning

confidence: 99%

“…In mammals, C 2 and C 8 of purines are not more labile to simple isotope exchange in vivo than the other Cs of purines [12,13]. The peak in labeled urinary uric acid occurs 1 -3 days after a dose of labeled formate or glycine in humans [14][15][16][17][18][19], representing catabolism of newly synthesized purines [14]. We measured the 13 C enrichment independently at C 2 and C 8 of uric acid by expanding the in vivo formate pool with an oral [ 13 C]formate dose using a liquid-chromatography mass spectrometry (LC/MS/MS) method [20].…”

Section: Introductionmentioning

confidence: 99%

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13C enrichment of carbons 2 and 8 of purine by folate-dependent reactions after [13C]formate and [2-13C]glycine dosing in adult humans

2007

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The 10-formyl moiety of 10-formyltetrahydrofolate is the source of carbons at the positions 8 (C 8 ) and 2 (C 2 ) of the purine ring, originating from formate and a few amino acids. Uric acid is the final catabolic product of purines. In adult humans, we independently measured the 13 C enrichment of the C 2 and C 8 positions of urinary uric acid after an oral dose of [ 13 C]sodium formate and that of the C 2 and C 8 plus C 5 positions after [2-13 C]glycine. A liquid-chromatography mass-spectrometric method was used to measure the 13 C enrichment of uric acid in urine which was collected for 3 -4 days. Purine catabolism to uric acid does not alter the positions of carbons in the ring. After the formate dose, the 13 C-enrichment at C 2 was greater that at C 8 , and a circadian rhythm was observed in the enrichment at C 2 . After the glycine dose, the C 8 plus C 5 positions were enriched, whereas no significant enrichment at C 2 was found. These 13 C enrichment patterns are not consistent with previous accepted metabolism. To our knowledge, this is the first study to investigate 13 C enrichment from formate and glycine independently into the C 2 and C 8 positions of purine in the same subjects. Possible mechanisms explaining our findings are discussed. Oral [ 13 C]formate or [2-13 C]glycine dosing and urine collection can be used to study purine biosynthesis in humans.

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Section: Measurement Of 13 C Enrichmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

13C enrichment of carbons 2 and 8 of purine by folate-dependent reactions after [13C]formate and [2-13C]glycine dosing in adult humans

2007

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“…Numerous studies in the past decade have demonstrated that a significant proportion of gouty patients have a metabolic defect characterized by synthesis of abnormally large quantities of uric acid (1)(2)(3)(4). The underlying biochemical mechanism responsible for the overproduction of uric acid has not yet been defined, but several hypotheses have been proposed.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Azathioprine (Imuran) on Purine Synthesis in Clinical Disorders of Purine Metabolism*

Kelley

Rosenbloom²,

Seegmiller³

1967

J. Clin. Invest.

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Abstract. Azathioprine, a purine analogue, significantly suppressed the purine synthesis de novo of two gouty patients manifesting overproduction of uric acid, as well as three of four gouty patients who showed normal uric acid production. This suppression is taken as evidence that phosphoribosylpyrophosphate amidotransferase, the rate-controlling step in purine synthesis de novo, has a normal sensitivity to feedback inhibitors in the patients who responded to the drug.Two children afflicted with the familial disorder of hyperuricemia, choreoathetosis, and self-mutilation described by Lesch and Nyhan showed no reduction in the activity of the biosynthetic pathway in response to azathioprine. This inability to respond to azathioprine can be directly related to the absence in these patients of the enzyme hypoxanthine-guanine phosphoribosyltransferase which is required for conversion of the drug or its metabolites to the biochemically active ribonucleotide form.

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“…It should be recalled that gouty overexcretors regutlarly show enhanced incorporation of labeled precursors into uric acid, whether the precursor is ammonium-Nt 5 (s12), glycine-No5 (5) or C14 (6,7,11,30), formate-C. (8), or 5-amino-4-imidazole-carboxamide-Cgc (38). Thus, an increased activity of purine synthesis de novo is well established in this type of gouty subject.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

Accelerated Turnover of Phosphoribosylpyrophosphate, a Purine Nucleotide Precursor, in Certain Gouty Subjects*

Jones¹,

Ashton²,

Wyngaarden³

1962

J. Clin. Invest.

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Incorporation of glycine-1-C14, glycine-2-C14 and glycine-N15 into uric acid in normal and gouty subjects

Cited by 47 publications

References 14 publications

13C enrichment of carbons 2 and 8 of purine by folate-dependent reactions after [13C]formate and [2-13C]glycine dosing in adult humans

13C enrichment of carbons 2 and 8 of purine by folate-dependent reactions after [13C]formate and [2-13C]glycine dosing in adult humans

The Effects of Azathioprine (Imuran) on Purine Synthesis in Clinical Disorders of Purine Metabolism*

Accelerated Turnover of Phosphoribosylpyrophosphate, a Purine Nucleotide Precursor, in Certain Gouty Subjects*

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