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首页> 美国卫生研究院文献>The Journal of Clinical Investigation >Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts.
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Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts.

机译：突变反馈抗性磷酸核糖焦磷酸合成酶与嘌呤过量生产和痛风有关。培养的成纤维细胞中的磷酸核糖焦磷酸和嘌呤代谢。

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摘要

We have reported previously two siblings with gout and uric acid lithiasis associated with excessive purine production. In the erythrocytes of these patients, phosphoribosylpyrophosphate (PRPP) synthetase exhibited resistance to feedback-inhibition by normal cell constituents such as guanosine-5'-diphosphate (GDP) and adenosine-5'-diphosphate (ADP), resulting in superactivity of the mutant enzyme and consequently in increased PRPP content and availability for nucleotide synthesis. Erythrocyte PRPP content and availability were normal in the propositus' parents, his healthy brother and three sons, and they all had normal serum level and urinary excretion of uric acid, except for the mother who was hyperuricosuric. To further characterize this mutation we studied PRPP and purine metabolism in cultured fibroblasts of the affected family. PRPP synthetase in dialyzed lysates of fibroblasts from the propositus and his mother exhibited increased specific activity, more markedly at low inorganic phosphate concentration, and decreased sensitivity to inhibition by ADP and GDP, PRPP content and availability and the rate of de novo purine nucleotide synthesis were markedly increased in the fibroblasts of the propositus and to a lesser extent in the fibroblasts of his mother but were normal in the fibroblasts of the other family members investigated. The fibroblast studies demonstrate the following sequence of abnormalities: feedback-resistance of PRPP synthetase; superactivity of this enzyme in normal physiological milieu; increased availability of PRPP; and increased de novo synthesis of purine nucleotides. The pattern of inheritance of this disorder is compatible with both an X-linked recessive and autosomal dominant traits.
机译：我们以前曾报道过两个兄弟姐妹，他们患有痛风和尿酸结石，而嘌呤产量过多。在这些患者的红细胞中，磷酸核糖焦磷酸（PRPP）合成酶表现出对正常细胞成分如鸟苷5'-二磷酸（GDP）和腺苷5'-二磷酸（ADP）的反馈抑制的抵抗力，从而导致突变体的超活性酶，因此增加了PRPP含量和核苷酸合成的可用性。泌尿生殖系统的父母，他的健康兄弟和三个儿子的红细胞PRPP含量和可及性均正常，除母亲尿酸尿过多外，他们的血清水平和尿酸均正常。为了进一步表征这种突变，我们在受影响家庭的培养成纤维细胞中研究了PRPP和嘌呤代谢。脯氨酸和他的母亲的成纤维细胞透析的裂解物中的PRPP合成酶表现出增加的比活性，在低无机磷酸盐浓度下表现得更明显，并且对ADP和GDP抑制的敏感性降低，PRPP含量和可用性以及从头嘌呤核苷酸合成的速率降低。垂体的成纤维细胞显着增加，而母亲的成纤维细胞的增幅较小，但其他受调查家庭成员的成纤维细胞则正常。成纤维细胞研究表明以下异常序列：PRPP合成酶的反馈抗性；该酶在正常生理环境中的超活性； PRPP的可用性增加；并增加了嘌呤核苷酸的从头合成。这种疾病的遗传模式与X连锁隐性和常染色体显性性状都兼容。

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