Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency in Gout

Kelley, William N.; Greene, M. Claire; Rosenbloom, Frederick M.; Henderson, J. Frank; Seegmiller, J. Edwin

doi:10.7326/0003-4819-70-1-155

Cited by 418 publications

(130 citation statements)

References 110 publications

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“…(20,29). In previous studies in fibroblasts, results of this method have correlated well with in vivo determinations of rates of purine synthesis de novo (20,27,30). The generation and extraction of labeled FGAR and separation of FGAR from other labeled compounds were carried out as described (27,31).…”

Section: Methodsmentioning

confidence: 92%

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Variant human phosphoribosylpyrophosphate synthetase altered in regulatory and catalytic functions.

Becker¹,

Raivio²,

Bakay³

et al. 1980

J. Clin. Invest.

104

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A B S T R A C T An inherited, structurally abnormal and superactive form of the enzyme 5-phosphoribosyl 1-pyrophosphate (PP-ribose-P) synthetase (EC 2.7.6.1) has been characterized in fibroblasts cultured from a 14-yr-old male (S.M.) with clinical manifestations of uric acid overproduction present since infancy. PPribose-P synthetase from the cells of this child showed four-to fivefold greater than normal resistance to purine nucleotide (ADP and GDP) feedback inhibition ofenzyme activity and hyperbolic rather than sigmoidal inorganic phosphate (Pi) and by an accelerated, age-related decrement in enzyme activity in lysates of erythrocytes separated by specific density. Despite the diminished amount of PP-ribose-P synthetase in the S.M. erythrocyte population, S.M. erythrocytes had increased PPribose-P concentration and increased rates of incorporation of ['4C]adenine and hypoxanthine into acid-soluble nucleotides during incubation at 1 mM Pi. These findings provided further confirmation of the extent to which PP-ribose-P synthesis is modulated in the normal cell at physiological Pi concentration by purine nucleotide inhibition of PP-ribose-P synthetase.The activity and kinetic characteristics of PPribose-P synthetase from fibroblasts of the mother of patient S.M. indicated that this woman was a heterozygous carrier of the enzyme defect expressed in hemizygous manner by her son. INTRODUCTIONThe high-energy sugar phosphate 5-phosphoribosyl I-pyrophosphate (PP-ribose-P)' is an intermediate in the synthesis of purine, pyrimidine and pyridine nucleotides. The synthesis of PP-ribose-P from ATP and ribose-5-phosphate (Rib-5-P) is catalyzed by the enzyme PP-ribose-P synthetase (E.C. 2.7.6.1) in a reaction requiring Mg2+ and inorganic phosphate (Pi). Studies of PP-ribose-P production by intact cells (1, 2) and analyses of the kinetic characteristics of purified microbial (3-5) and mammalian (6-10) PP-ribose-P synthetases indicate that a substantial number of effector compounds including substrates, inhibitors, activators, and products influence enzyme activity.

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Section: Methodsmentioning

confidence: 92%

“…Activities of PP-ribose-P synthetase (measured as described above), hypoxanthine-guanine phosphoribosyltransferase (38), adenine phosphoribosyltransferase (30), and glucose-S-phosphate dehydrogenase (E.C. 1.1.1.49) (39) were determined in dialyzed erythrocyte lysates prepared from freshly drawn heparinized venous blood.…”

Section: Methodsmentioning

confidence: 99%

Variant human phosphoribosylpyrophosphate synthetase altered in regulatory and catalytic functions.

Becker¹,

Raivio²,

Bakay³

et al. 1980

J. Clin. Invest.

104

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“…HPRT is an intracellular enzyme found in many tissues (7). It is normally expressed at very low levels as compared with the more abundant intracellular proteins.…”

Section: Introductionmentioning

confidence: 99%

Human hypoxanthine-guanine phosphoribosyltransferase. Demonstration of structural variants in lymphoblastoid cells derived from patients with a deficiency of the enzyme.

Wilson¹,

Baugher²,

Mattes³

et al. 1982

J. Clin. Invest.

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“…2.4.2.8) (HGPRT) (some authors have used the nomenclature inosine monophosphate (IMP)-pyrophosphate phosphoribosyl transferase [5]) in erythrocyte lysates from three patients and in cultured skin fibroblasts from another patient with this disease, the LeschNyhan syndrome. The enzyme defect was subsequently confirmed in other tissues from many similarly affected patients [30].…”

Section: Introductionmentioning

confidence: 66%