Becker M A
J Clin Invest. 1976 Feb;57(2):308-18. doi: 10.1172/JCI108282.
In the majority of patients with gout and excessive uric acid production, underlying enzyme abnormalities have not been identified. In the present study, measurement of both the rate of generation and concentration of phosphoribosylpyrophosphate (PP-ribose-P) and the concentration of ribose-5-phosphate in cultured cells were undertaken to establish a classification of purine overproducers to direct study of additional enzyme defects. Fibroblasts were cultured from 24 individuals assigned to 4 groups: group 1, 5 normal controls; group 2, 5 patients with gout and normal dialy urinary uric acid excretion (gouty controls); group 3, 7 patients with well-defined enzyme abnormalities and excessive urinary acid excretion (4 with hypoxanthine-guanine phosphoribosyltransferase deficiency and 3 with excessive PP-ribose-P synthetase activity); and group 4, 7 patients with gout and excessive uric acid excretion but without grossly abnormal activities of the above enzymes in erythrocyte lysates. In all 14 fibroblast strains from patients showing excessive production of uric acid (groups 3 and 4), rates of purine synthesis de novo and PP-ribose-P concentrations exceeded values for cells from control groups. Cells from group 3 patients with hypoxanthine-guanine phosphoribosyltransferase deficiency showed normal PP-ribose-P generation, while those with excessive PP-ribose-P synthetase activity demonstrated increased generation of this regulatory substrate. All strains from group 3 patients had normal ribose-5-phosphate concentrations. Five cell strains from group 4 patients showed one of the two patterns of abnormalities in these measurements seen in strains from group 3 patients: two resembled hypoxanthine-guanine phosphoribosyltransferase-deficient cells, and three resembled cells with excessive PP-ribose-P synthetase activity. Analyses of erythrocyte enzyme preparations from two of these patients in group 4 have led to identification of a kinetic variant of each enzyme as predicted from the foregoing patterns. Two additional group 4 cell lines that showed increased ribose-5-phosphate concentrations in addition to increased PP-ribose-P concentrations and generation were classified in a separate subgroup, since in the individuals excessive purine synthesis appeared to result from increases ribose-5-phosphate concentration, leading to increased availability of PP-ribose-P. No abnormality in either hypoxanthine-guanine phosphoribosyltransferase or PP-ribose-P synthetase has been found in erythrocyte preparations from one patient so classified.
在大多数痛风和尿酸生成过多的患者中，尚未发现潜在的酶异常。在本研究中，对培养细胞中磷酸核糖焦磷酸（PP - 核糖 - P）的生成速率和浓度以及5 - 磷酸核糖的浓度进行了测定，以建立嘌呤过度生成者的分类，从而直接研究其他酶缺陷。从24名个体培养成纤维细胞并分为4组：第1组，5名正常对照；第2组，5名痛风且每日尿尿酸排泄正常的患者（痛风对照）；第3组，7名明确有酶异常且尿酸排泄过多的患者（4名次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶缺乏，3名PP - 核糖 - P合成酶活性过高）；第4组，7名痛风且尿酸排泄过多但红细胞裂解物中上述酶无明显异常活性的患者。在所有14株来自尿酸生成过多患者（第3组和第4组）的成纤维细胞中，嘌呤从头合成速率和PP - 核糖 - P浓度超过了对照组细胞的值。第3组次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶缺乏患者的细胞显示PP - 核糖 - P生成正常，而PP - 核糖 - P合成酶活性过高的患者细胞则显示该调节底物生成增加。第3组患者的所有菌株5 - 磷酸核糖浓度正常。第4组患者的5株细胞在这些测量中显示出第3组患者菌株中所见的两种异常模式之一：2株类似于次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶缺乏的细胞，3株类似于PP - 核糖 - P合成酶活性过高的细胞。对第4组中两名患者的红细胞酶制剂进行分析，已如上述模式所预测的那样鉴定出每种酶的一种动力学变异体。另外2株第4组细胞系除了PP - 核糖 - P浓度和生成增加外，5 - 磷酸核糖浓度也增加，被归为一个单独的亚组，因为在这些个体中嘌呤过度合成似乎是由于5 - 磷酸核糖浓度增加，导致PP - 核糖 - P可用性增加。在如此分类的一名患者的红细胞制剂中，未发现次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶或PP - 核糖 - P合成酶有异常。
