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，摄入富含碳水化合物的饮食会导致编码糖酵解主要酶的基因转录，形成前体乙酰辅酶A所需的基因，以及产生脂肪合成所需的NADPH的己糖单磷酸途径的酶。这种转录因子被称为ChREBP，它对饮食中的碳水化合物做出反应。结合由Brown和Goldstein描述的固醇反应结合蛋白SREBP的作用以及对胰岛素的反应，这两个转录因子在肥胖、II型糖尿病和血管疾病中起着重要的作用。ChREBP的这种优雅的协调控制是由简单的己糖单磷酸途径的代谢物木果糖5-P实施的。内田康作教授所做的这项工作已在2003年发表在《美国国家科学院院刊》上。吡啶核苷酸氧化还原状态的变化是新陈代谢状态变化的标志，众所周知，酒精摄入会极大地改变这种状态。目前已知许多转录因子受吡啶核苷酸的氧化还原状态控制。这些基因包括：NPAS2，负责昼夜节律的所谓时钟基因CtBP，在发育和转化中发挥作用的转录辅助抑制因子，OCT-1，调节核组蛋白表达的转录因子，H2B，Sir2，被认为在酵母、线虫和哺乳动物细胞的热量限制延长寿命特性中发挥核心作用的基因沉默因子。在最近的工作中，我们与NIH等其他研究小组合作，表明成肌细胞中Sir2的活性受胞浆[NAD+]/[NADH]变化的控制。目前认为该酶的活性受烟酰胺抑制，KI大于150微摩尔。我们将继续研究该转录因子的动力学。目前尚不清楚控制与[NAD+]/[NADH]比率的变化有何关系。不用说，[NAD+]/[NADH]的变化既是酒精摄入的特征，也是酮症的特征，因此有望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.