Overview of the molecular and biochemical basis of branched-chain amino acid catabolism
Overview of the molecular and biochemical basis of branched-chain amino acid catabolism
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DOI：
10.1093/jn/135.6.1527s
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发表时间：
2005-06-01
影响因子：
4.2
通讯作者：
Obayashi, M
中科院分区：
文献类型：
--
作者：
Harris, RA;Joshi, M;Obayashi, M
支链氨基酸是蛋白质合成和神经递质合成所必需的。支链α-酮酸脱氢酶复合体(BCKDC)是支链氨基酸分解代谢途径中最重要的调节酶。该复合体的活性是通过共价修饰来控制的，其支链α-酮酸脱氢酶亚单位被特定的激酶[支链激酶(BDK)]磷酸化，导致失活，而通过特定的磷酸酶[支链磷酸酶(BDP)]去磷酸化导致激活。严格控制BCKDC的活性对于保存和处置支链氨基酸很重要。当需要保存支链氨基酸用于蛋白质合成时，复合体发生磷酸化；当支链氨基酸过多时，去磷酸化发生。BDK和BDP的相对活性决定了BCKDC的活性状态。BDK活性受α-酮基异己酸抑制和表达水平改变的调节。人们对BDP知之甚少，但最近发现了一种新的线粒体磷酸酶，可能与BCKDC的调控有关。氧化支链氨基酸的能力降低，就像枫树糖浆尿液疾病一样，会导致血液中支链氨基酸过多，并导致严重的神经功能障碍和脑损伤。相反，失去对支链氨基酸氧化的控制会导致生长障碍和癫痫样发作。这些发现强调了控制支链氨基酸分解代谢对正常神经功能的重要性。建议用支链氨基酸耐受性试验和钳制方案来确定支链氨基酸的安全摄入量上限。
The branched-chain amino acids (BCAAs) are required for protein synthesis and neurotransmitter synthesis. The branched-chain a-ketoacid dehydrogenase complex (BCKDC) is the most important regulatory enzyme in the catabolic pathways of the BCAAs. Activity of the complex is controlled by covalent modification with phosphorylation of its branched-chain a-ketoacid dehydrogenase subunits by a specific kinase [branched-chain kinase (BDK)] causing inactivation and dephosphorylation by a specific phosphatase [branched-chain phosphatase (BDP)] causing activation. Tight control of BCKDC activity is important for conserving as well as disposing of BCAAs. Phosphorylation of the complex occurs when there is a need to conserve BCAAs for protein synthesis; dephosphorylation occurs when BCAAs are present in excess. The relative activities of BDK and BDP set the activity state of BCKDC. BDK activity is regulated by a-ketoisocaproate inhibition and altered level of expression. Less is known about BDP but a novel mitochondrial phosphatase was identified recently that may contribute to the regulation of BCKDC. Reduced capacity to oxidize BCAAs, as in maple syrup urine disease, results in excess BCAAs in the blood and profound neurological dysfunction and brain damage. In contrast, loss of control of BCAA oxidation results in growth impairment and epileptic-like seizures. These findings emphasize the importance of control of BCAA catabolism for normal neurological function. It is proposed that the safe upper limit of dietary BCAA intake could be established with a BCAA tolerance test and clamp protocol.