THE PRPP SYNTHETASE SPECTRUM: WHAT DOES IT DEMONSTRATE ABOUT NUCLEOTIDE SYNDROMES?
THE PRPP SYNTHETASE SPECTRUM: WHAT DOES IT DEMONSTRATE ABOUT NUCLEOTIDE SYNDROMES?
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DOI：
10.1080/15257770.2011.591747
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发表时间：
2011-01-01
影响因子：
1.3
通讯作者：
de Brouwer, Arjan P. M.
中科院分区：
文献类型：
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作者：
Duley, John A.;Christodoulou, John;de Brouwer, Arjan P. M.
X连锁磷酸核糖焦磷酸合成酶1（PRPS1）的缺陷表现如下：（1）PRS-I酶“超活性”（影响变构区域的功能获得突变）； (2) PRS-I过表达（可能与miRNA突变有关）； (3)严重的PRS-I缺陷/Arts综合征（错义突变导致功能丧失）； (4) 中度 PRS-I 缺陷/腓骨肌萎缩症 5（不太严重的功能丧失突变）； (5) 轻度 PRS-1 缺陷/Deafness-2（突变产生轻微不稳定）。与 Lesch-Nyhan 病类似，PRPS1 相关疾病是由磷酸核糖焦磷酸 (PRPP) 依赖性嘌呤核苷酸（例如 ATP、GTP）的核苷酸“耗尽”引起的。 S-腺苷甲硫氨酸 (SAMe) 似乎可以通过不依赖于 PRPP 的途径部分缓解嘌呤消耗。嘧啶核苷酸的合成依赖于 PRPP，尿苷单磷酸合酶缺乏会导致嘧啶核苷酸耗尽。但从尿苷中回收嘧啶不需要 PRPP，并且这种核苷可以自由转运至嘧啶耗尽的组织。烟酰胺核苷酸的调节不太清楚；从吡啶核碱基的合成依赖于 PRPP。核苷酸“耗尽”与核苷酸“毒性”形成对比，例如嘌呤紊乱腺苷脱氨酶（ADA）和嘌呤核苷磷酸化酶（PNP）缺陷或嘧啶核苷酸酶缺陷。这些的特征是一种或多种异常核苷酸的积累，例如琥珀酰核苷酸或脱氧核苷酸或其代谢物，它们会中断其他核苷酸或相关途径或对特定细胞类型有毒。理论上，SAMe 疗法不会改善嘌呤中毒病症，这一点在一名腺苷琥珀酸裂合酶缺陷儿童身上得到证实。核苷酸缺陷也可能被视为线粒体疾病的一个方面，基于 SAMe 的线粒体疗法可能值得进一步研究。
Defects in X-linked phosphoribosylpyrophosphate synthetase 1 (PRPS1) manifest as follows: (1) PRS-I enzyme "superactivity" (gain-of-function mutations affecting allosteric regions); (2) PRS-I overexpression (which may be linked to miRNA mutation); (3) severe PRS-I deficiency/Arts syndrome (missense mutations producing loss-of-function); (4) moderate PRS-I deficiency/Charcot-Marie-Tooth disease-5 (less severe loss-of-function mutations); and (5) mild PRS-I deficiency/Deafness-2 (mutations producing slight destabilization). Similar to Lesch-Nyhan disease, PRPS1-related disorders arise from phosphoribosyl-pyrophosphate (PRPP)-dependent nucleotide "depletion" of purine nucleotides (e. g., ATP, GTP). S-adenosylmethionine (SAMe) appears to partially alleviate purine depletion via a PRPP-independent path. Synthesis of pyrimidine nucleotides is PRPP dependent, with uridine monophosphate synthase deficiency producing pyrimidine nucleotide depletion. But pyrimidine salvage from uridine does not require PRPP, and this nucleoside is transported freely to pyrimidine-depleted tissues. Regulation of nicotinamide nucleotides is less clear; synthesis from pyridine nucleobases is PRPP dependent. Nucleotide "depletion" contrasts with nucleotide "toxicity," exemplified by the purine disorders adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiencies or by pyrimidine nucleotidase deficiency. These are characterized by the accumulation of one or more abnormal nucleotides such as succinyl-or deoxy-nucleotides or their metabolites, which interrupt other nucleotide or related pathways or are toxic to specific cell types. Theoretically, purine toxicity disorders would not be ameliorated by SAMe therapy, and this was confirmed for one adenylosuccinate lyase-deficient child. Nucleotide defects may also be seen as an aspect of mitochondrial disease, with SAMe-based mitochondrial therapy perhaps meriting further investigation.