Metabolite control of transcription

越来越清楚的是，基因组中编码的许多蛋白质的转录是由小的代谢物控制的，这些代谢物的浓度取决于环境条件。因此，消耗富含碳水化合物的饮食导致编码形成前体乙酰辅酶A所需的糖酵解的主要酶以及产生脂肪合成所需的NADPH的己糖单磷酸途径的酶的基因的转录。这种转录因子被称为ChREBP，对饮食中的碳水化合物有反应。结合SREBP（由Brown和Goldstein描述的固醇响应性结合蛋白）的作用以及对胰岛素的响应，这两种转录因子在肥胖症、II型糖尿病和血管疾病中具有重要意义。ChREBP的这种优雅的协调控制是由简单的己糖单磷酸途径代谢产物木酮糖5-P发挥作用的。吡啶核苷酸的氧化还原状态的变化是代谢状态变化的标志，并且已知通过酒精摄入而深刻改变。现在已知许多转录因子受吡啶核苷酸的氧化还原状态控制。其中包括：NPAS 2，所谓的负责昼夜节律的时钟基因CtBP，在发育和转化中起作用的转录辅抑制因子，Oct-1，调节核组蛋白表达的转录因子，H2 B，Sir 2，被认为在酵母热量限制的寿命延长特性中起核心作用的基因沉默物，C. elegans线虫，and in mammals哺乳动物cells细胞as well.在最近的工作中，我们与NIH等其他小组合作完成，我们已经表明成肌细胞中SIR 2的活性受游离胞质[NAD+]/[NADH]的变化控制。目前认为，这种酶的活性是由烟酰胺的抑制作用控制的，Ki超过150微摩尔。我们将继续研究这种转录因子的动力学。目前尚不清楚控制如何与[NAD+]/[NADH]比率的变化相关。不言而喻，[NAD+]/[NADH]的变化是酒精摄入和酮症的特征，因此预计会改变上述转录因子的活性。

It is becoming increasingly clear that transcription of many of the proteins encoded in the genome is controlled by small metabolites whose concentrations vary depending upon environmental conditions. Thus consuming a diet rich in carbohydrate leads to the transcription of the genes encoding the major enzymes of glycolysis required to form the precursor acetyl CoA as well as the enzymes of the hexose monophosphate pathway producing the NADPH required for fat synthesis. The transcription factor is called ChREBP and responds to dietary carbohydrate. Combined with the effects of SREBP, the sterol responsive binding protein described by Brown and Goldstein, and responsive to insulin, these two transcription factors are of major importance in obesity, type II diabetes and vascular diseases. This elegant co-ordinate control of ChREBP is exerted by the simple hexose monophosphate pathway metabolite, xylulose 5-P. This work done by Prof Kosaku Uyeda was described in PNAS in 2003. Changes in the redox state of the pyridine nucleotides are the hallmark of changes in metabolic status and is known to be profoundly altered by alcohol ingestion. A number of transcription factors are now known to be controlled by the redox state of the pyridine nucleotides. These include: NPAS2, the so-called clock gene responsible for circadian rhythm CtBP, the transcriptional co-repressor playing a role in development and transformation, Oct-1, the transcription factor regulating expression of nuclear histones, H2B, Sir2, the gene silencer thought to play a central role in the life extending properties of caloric restriction in yeast, C. elegans, and in mammalian cells as well. In recent work, done in colaboration with other groups as NIH, we have shown that the activity of SIR2 in myoblasts is controled by changes in the free cytosolic [NAD+]/[NADH]. Currently it is thought that the activity of this enzyme is controlled by inhibition by nicotinamide with a Ki of over 150 micromolar. We will continue to examine the kinetics of this transcription factor. It is not now clear how control is related to change in the [NAD+]/[NADH] ratio. It goes without saying that changes in [NAD+]/[NADH] are characteristic of both alcohol ingestion and ketosis and would therefore be expected to alter the activity of the above listed transcription factors.