Gruber H E, Jansen I, Willis R C, Seegmiller J E
Biochim Biophys Acta. 1985 Jul 30;846(1):135-44. doi: 10.1016/0167-4889(85)90119-3.
The specific activities of the three enzymes of the inosinate branchpoint are independently regulated when lymphoblasts are grown under various tissue culture conditions. In comparison to rapidly dividing cells, lymphoblasts at high cell density with no cellular division have decreased activity of the enzymes which commit inosinate to adenylate or guanylate, while cytoplasmic 5'-nucleotidase is relatively preserved. A linear relationship between inosinate dehydrogenase activity and growth rate (r = 0.92) exists in lymphoblasts with slowed growth rates. In contrast, in dividing cells adenylosuccinate synthetase and 5'-nucleotidase do not vary with growth rate. Adenylosuccinate synthetase and inosinate dehydrogenase activities appear to be related to the presence or rate of cellular division, as opposed to the presence or degree of neoplastic transformation. Lymphoblast lines with alterations of specific purine metabolic enzymes have characteristic alteration of the inosinate utilizing enzymes. Deficiencies of purine nucleoside phosphorylase or hypoxanthine phosphoribosyltransferase, abnormalities which render the cell unable to salvage purine effectively, are associated with depressed inosinate dehydrogenase activity. Insertion of the hypoxanthine phosphoribosyltransferase gene into hypoxanthine phosphoribosyltransferase-deficient cells normalizes inosinate dehydrogenase activity, while a hypoxanthine phosphoribosyltransferase-deficient mutant selected from a hypoxanthine phosphoribosyltransferase-containing line has depressed inosinate dehydrogenase activity. In contrast, overactivity of phosphoribosylpyrophosphate synthetase, with enhanced excretion of purines due to excessive production, is associated with elevated inosinate dehydrogenase activity. Inosinate dehydrogenase appears to be regulated according to the availability of purine nucleotides. Patients who overproduce uric acid and potentially have undescribed purine metabolic defects are now being screened for abnormalities in the inosinate branchpoint enzymes.
当淋巴母细胞在各种组织培养条件下生长时，次黄苷酸分支点的三种酶的比活性受到独立调节。与快速分裂的细胞相比，处于高细胞密度且无细胞分裂的淋巴母细胞中，将次黄苷酸转化为腺苷酸或鸟苷酸的酶活性降低，而细胞质5'-核苷酸酶的活性相对保持不变。在生长速率减慢的淋巴母细胞中，次黄苷酸脱氢酶活性与生长速率之间存在线性关系（r = 0.92）。相比之下，在分裂细胞中，腺苷酸琥珀酸合成酶和5'-核苷酸酶的活性不随生长速率变化。腺苷酸琥珀酸合成酶和次黄苷酸脱氢酶的活性似乎与细胞分裂的存在或速率有关，而与肿瘤转化的存在或程度无关。具有特定嘌呤代谢酶改变的淋巴母细胞系具有利用次黄苷酸的酶的特征性改变。嘌呤核苷磷酸化酶或次黄嘌呤磷酸核糖转移酶的缺乏，这些异常使细胞无法有效地挽救嘌呤，与次黄苷酸脱氢酶活性降低有关。将次黄嘌呤磷酸核糖转移酶基因插入次黄嘌呤磷酸核糖转移酶缺陷细胞中可使次黄苷酸脱氢酶活性正常化，而从含次黄嘌呤磷酸核糖转移酶的细胞系中选择的次黄嘌呤磷酸核糖转移酶缺陷突变体具有降低的次黄苷酸脱氢酶活性。相比之下，磷酸核糖焦磷酸合成酶活性过高，由于过量产生导致嘌呤排泄增加，与次黄苷酸脱氢酶活性升高有关。次黄苷酸脱氢酶似乎根据嘌呤核苷酸的可用性进行调节。现在正在对尿酸产生过多且可能存在未描述的嘌呤代谢缺陷的患者进行次黄苷酸分支点酶异常的筛查。
