机制的维生素B12-responsiveness cblC methylmalonic酸尿高胱氨酸尿。

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森林DS,张J,希利年代,砾石RA

机制的维生素B12-responsiveness cblC methylmalonic酸尿高胱氨酸尿。

摩尔麝猫金属底座。2009年12月,98 (4):338 - 43。doi: 10.1016 / j.ymgme.2009.07.014。Epub 2009年8月3。

PubMed ID

19700356 (在PubMed

]

文摘

患者cblC维生素B(12)(维生素b12, cbl)障碍有缺陷的细胞内合成adenosylcobalamin和methylcobalamin,结合高胱氨酸尿和methylmalonic酸尿。而其他维生素B(12)疾病是可治的高剂量维生素b12 (CNCbl)或羟钴胺素(OHCbl) cblC病人反应良好OHCbl但不要CNCbl。病人突变引入重组MMACHC (cblC)蛋白质和绑定CNCbl OHCbl检查。三个突变进行了分析:G147D,与早发性有关,维生素B(12)反应迟钝的疾病;R161Q与晚发型疾病有关,OHCbl高度敏感;H122A,选择测试假设H122是中央提出的维生素B(12)绑定MMACHC主题。我们报告在这里野生型MMACHC结合OHCbl和CNCbl相似,紧密关联(K (d) = 5.7 microM)。我们也报告,MMACHC结合CNCbl基地的形式,与dimethylbenzimidazole (DMB)与钴基氰钴胺素流离失所的协调。这种形式,野生型MMACHC能够意向性还原性decyanate CNCbl,棒子(II)就只需要NADPH和时尚。我们证明MMACHC G147D突变无法绑定CNCbl或者OHCbl,提供一个直接的解释缺乏维生素的形式回应。 However, we show that MMACHC containing the R161Q mutation binds OHCbl with wild-type affinity, but is disturbed in binding CNCbl and has impaired decyanation. Finally, we show that H122A has reduced binding, but like R161Q, it binds OHCbl more tightly than CNCbl, suggesting that this histidine is not absolutely required for binding. These studies suggest that the ability of mutant MMACHC to respond to vitamin therapy depends on its ability to bind the vitamin with significant affinity, and for CNCbl, also on its ability to bind in the base-off form to facilitate reductive decyanation. These studies emphasize the continued use of OHCbl with cblC patients for maximum therapeutic effect.

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药物靶点

药物	目标	类	生物	药理作用	行动
维生素b12	Methylmalonic酸尿蛋白类型,线粒体	蛋白质	人类	未知的	粘结剂	细节