Metabolite control of transcription

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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.