Creatine metabolism in urea cycle defects
Creatine metabolism in urea cycle defects
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DOI：
10.1007/s10545-012-9494-x
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发表时间：
2012-07-01
影响因子：
4.2
通讯作者：
Dionisi-Vici, Carlo
中科院分区：
文献类型：
--
作者：
Boenzi, Sara;Pastore, Anna;Dionisi-Vici, Carlo
肌酸（Cr）和磷酸肌酸在能量储存和传递中起着至关重要的作用。肌酸池的维持由日粮和以精氨酸、甘氨酸和s-腺苷蛋氨酸为底物的从头合成提供。主要存在三种Cr缺乏：精氨酸、甘氨酸氨基转移酶缺乏、胍苷乙酸甲基转移酶缺乏和Cr转运体SLC6A8缺陷。继发性铬缺乏是鸟氨酸-转氨酶缺乏的特征，而尿素循环缺陷（UCDs）患者中有不均匀铬异常的报道，这是一种与精氨酸代谢相关的疾病，由于饮食摄入低，铬必须通过重新合成获得。为了评估尿变性与Cr合成之间的关系，我们系统地测量了大量UCD患者（即OTC、ASS、ASL缺乏、HHH综合征和赖氨酸尿酸蛋白不耐受）的血浆Cr。ucd患者血浆Cr浓度有两种不同的趋势：OTC和ASS缺乏和HHH综合征患者血浆Cr水平显著降低，而ASL缺乏和赖氨酸尿酸蛋白不耐受患者血浆Cr水平显著升高（23.5 vs. 82.6 mu mol/L, p < 0.0001）。这种趋势分布似乎受到细胞精氨酸可用性的调节，突出了它在尿素生成和Cr合成中的关键作用。虽然Cr降低有助于原发性Cr缺乏患者的神经系统症状，但Cr代谢的改变是否也可能参与ucd患者的中枢神经系统功能障碍仍有待探讨。由于精氨酸在大多数ucd中成为半必需氨基酸，测量血浆Cr浓度可能有助于优化精氨酸替代的剂量。
Creatine (Cr) and phosphocreatine play an essential role in energy storage and transmission. Maintenance of creatine pool is provided by the diet and by de novo synthesis, which utilizes arginine, glycine and s-adenosylmethionine as substrates. Three primary Cr deficiencies exists: arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase deficiency and the defect of Cr transporter SLC6A8. Secondary Cr deficiency is characteristic of ornithine-aminotransferase deficiency, whereas non-uniform Cr abnormalities have anecdotally been reported in patients with urea cycle defects (UCDs), a disease category related to arginine metabolism in which Cr must be acquired by de novo synthesis because of low dietary intake. To evaluate the relationships between ureagenesis and Cr synthesis, we systematically measured plasma Cr in a large series of UCD patients (i.e., OTC, ASS, ASL deficiencies, HHH syndrome and lysinuric protein intolerance). Plasma Cr concentrations in UCDs followed two different trends: patients with OTC and ASS deficiencies and HHH syndrome presented a significant Cr decrease, whereas in ASL deficiency and lysinuric protein intolerance Cr levels were significantly increased (23.5 vs. 82.6 mu mol/L; p < 0.0001). This trend distribution appears to be regulated upon cellular arginine availability, highlighting its crucial role for both ureagenesis and Cr synthesis. Although decreased Cr contributes to the neurological symptoms in primary Cr deficiencies, still remains to be explored if an altered Cr metabolism may participate to CNS dysfunction also in patients with UCDs. Since arginine in most UCDs becomes a semi-essential aminoacid, measuring plasma Cr concentrations might be of help to optimize the dose of arginine substitution.