Phenylbutyrate therapy for maple syrup urine disease
Phenylbutyrate therapy for maple syrup urine disease
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DOI：
10.1093/hmg/ddq507
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发表时间：
2011-02-15
影响因子：
3.5
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Brunetti-Pierri, Nicola;Lanpher, Brendan;Lee, Brendan
尿素循环紊乱患者用苯乙酸钠/苯甲酸钠或苯丁酸钠治疗与支链氨基酸（BCAA）选择性减少相关，尽管饮食中摄入了足够的蛋白质。基于这一临床观察，我们研究了苯基丁酸治疗降低典型和变异性迟发性枫糖浆尿病（MSUD）患者BCAA及其相应的α -酮酸（BCKA）的潜力。我们还进行了体外和体内实验来阐明这种作用的机制。我们发现，对照组和迟发性中度MSUD患者在苯丁酸治疗后BCAA和BCKA均显著降低。在体外用对照成纤维细胞和淋巴细胞的苯基丁酸盐处理导致残留酶活性增加，而MSUD细胞的处理导致可变反应，不能简单地预测患者的生化反应。在体内，苯基丁酸增加了活性肝酶和未磷酸化形式的比例，超过了支链a-酮酸脱氢酶复合物（BCKDC）的E1 α亚基的无活性磷酸化形式。利用重组酶，我们发现苯基丁酸盐通过抑制BCKDC激酶来抑制E1 α的磷酸化，从而激活BCKDC的整体活性，这为苯基丁酸盐对一部分MSUD患者的作用提供了分子解释。苯基丁酸治疗可能是一种有价值的治疗方法，可以降低一部分MSUD患者血浆中神经毒性BCAA及其相应的BCKA水平，并表明其长期疗效的研究。
Therapy with sodium phenylacetate/benzoate or sodium phenylbutyrate in urea cycle disorder patients has been associated with a selective reduction in branched-chain amino acids (BCAA) in spite of adequate dietary protein intake. Based on this clinical observation, we investigated the potential of phenylbutyrate treatment to lower BCAA and their corresponding alpha-keto acids (BCKA) in patients with classic and variant late-onset forms of maple syrup urine disease (MSUD). We also performed in vitro and in vivo experiments to elucidate the mechanism for this effect. We found that BCAA and BCKA are both significantly reduced following phenylbutyrate therapy in control subjects and in patients with late-onset, intermediate MSUD. In vitro treatment with phenylbutyrate of control fibroblasts and lymphoblasts resulted in an increase in the residual enzyme activity, while treatment of MSUD cells resulted in the variable response which did not simply predict the biochemical response in the patients. In vivo phenylbutyrate increases the proportion of active hepatic enzyme and unphosphorylated form over the inactive phosphorylated form of the E1 alpha subunit of the branched-chain a-keto acid dehydrogenase complex (BCKDC). Using recombinant enzymes, we show that phenylbutyrate prevents phosphorylation of E1 alpha by inhibition of the BCKDC kinase to activate BCKDC overall activity, providing a molecular explanation for the effect of phenylbutyrate in a subset of MSUD patients. Phenylbutyrate treatment may be a valuable treatment for reducing the plasma levels of neurotoxic BCAA and their corresponding BCKA in a subset of MSUD patients and studies of its long-term efficacy are indicated.