Harris Robert A, Joshi Mandar, Jeoung Nam Ho
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA.
Biochem Biophys Res Commun. 2004 Jan 9;313(2):391-6. doi: 10.1016/j.bbrc.2003.11.007.
The branched-chain amino acids (BCAAs) are essential amino acids and therefore must be continuously available for protein synthesis. However, BCAAs are toxic at high concentrations as evidenced by maple syrup urine disease (MSUD), which explains why animals have such an efficient oxidative mechanism for their disposal. Nevertheless, it is clear that leucine is special among the BCAAs. Leucine promotes global protein synthesis by signaling an increase in translation, promotes insulin release, and inhibits autophagic protein degradation. However, leucine's effects are self-limiting because leucine promotes its own disposal by an oxidative pathway, thereby terminating its positive effects on body protein accretion. A strong case can therefore be made that the proper leucine concentration in the various compartments of the body is critically important for maintaining body protein levels beyond simply the need of this essential amino acid for protein synthesis. The goal of the work of this laboratory is to establish the importance of regulation of the branched chain alpha-ketoacid dehydrogenase complex (BCKDC) to growth and maintenance of body protein. We hypothesize that proper regulation of the activity state of BCKDC by way of its kinase (BDK) and its phosphatase (BDP) is critically important for body growth, tissue repair, and maintenance of body protein. We believe that growth and protection of body protein during illness and stress will be improved by therapeutic control of BCKDC activity. We also believe that it is possible that the negative effects of some drugs (PPAR alpha ligands) and dietary supplements (medium chain fatty acids) on growth and body protein maintenance can be countered by therapeutic control of BCDKC activity.
支链氨基酸（BCAAs）是必需氨基酸，因此必须持续供应以进行蛋白质合成。然而，高浓度的BCAAs具有毒性，枫糖尿症（MSUD）就是证明，这也解释了为什么动物具有如此高效的氧化机制来处理它们。尽管如此，很明显亮氨酸在BCAAs中是特殊的。亮氨酸通过发出翻译增加的信号来促进整体蛋白质合成，促进胰岛素释放，并抑制自噬性蛋白质降解。然而，亮氨酸的作用是自我限制的，因为亮氨酸通过氧化途径促进自身的代谢，从而终止其对机体蛋白质积累的积极作用。因此，可以有力地证明，身体各个部位适当的亮氨酸浓度对于维持身体蛋白质水平至关重要，这不仅仅是因为这种必需氨基酸用于蛋白质合成的需求。本实验室工作的目标是确定调节支链α-酮酸脱氢酶复合体（BCKDC）对身体生长和维持身体蛋白质的重要性。我们假设通过其激酶（BDK）和磷酸酶（BDP）对BCKDC活性状态进行适当调节对于身体生长、组织修复和维持身体蛋白质至关重要。我们相信，通过治疗性控制BCKDC活性，可以改善疾病和应激期间身体蛋白质的生长和保护。我们还认为，通过治疗性控制BCDKC活性，有可能抵消某些药物（PPARα配体）和膳食补充剂（中链脂肪酸）对生长和身体蛋白质维持的负面影响。
