Trends in Biochemical Sciences
ReviewSeries: Superlative SequelsMetabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription
Section snippets
Moonlighting Metabolic Enzymes and Adaptive Cellular Metabolism Homeostasis
Moonlighting proteins perform multiple autonomous and often unrelated functions, increasing functional options for the cell, without increasing the number of genes that need to be replicated and transcribed. The first example of a moonlighting protein was described by Hendriks et al. who showed that ɛ-crystallin, a structural protein of the duck lens, was actually the metabolic enzyme lactate dehydrogenase (LDH) [1]. Since then, multiple moonlighting proteins have been described in many species
Glycolytic Enzymes in the Nucleus
The first reports of glycolytic enzymes present in the nucleus date to the late 1950s 8, 9, 10, but all essential glycolytic enzymes have now been observed in the nucleus [11] (Figure 1). Glycolysis produces pyruvate from glucose using the oxidative potential of NAD+ which is converted to NADH. In the absence of oxygen or healthy mitochondria, lactate dehydrogenase (LDH) converts pyruvate into lactic acid and uses NADH to regenerate NAD+. Otherwise, PDC converts pyruvate into acetyl-CoA in the
Mitochondrial Krebs Cycle Enzymes in the Nucleus
Unlike the enzymes of glycolysis that are all present in the nucleus, only some of the mitochondrial enzymes that support the Krebs cycle have been found in the nucleus (Figure 1 and Table 1).
Acetyl-CoA-Producing Enzymes (ACPEs) and Histone Acetylation in the Nucleus
Acetylation and phosphorylation are the two most common protein post-translational modifications. Acetylation of lysine residues can alter the function or cellular localization of many proteins, including metabolic enzymes, and plays a crucial role in epigenetic regulation through the acetylation of histones. As many as 4600 total acetylation [68] and over 60 histone acetylation [69] sites have now been described. The acetylation of histones promotes gene transcription through neutralization of
Methylation in the Nucleus
DNA and histone methylation/demethylation occur in the nucleus through the metabolite SAM (the sole methyl group donor for all methylation reactions), methyltransferases, and demethylases. As with acetylation, there is also evidence that methylation can occur at specific sub-nuclear domains. For example, methionine adenosyl-transferase IIa (MATIIa) is recruited to specific MafK sites and synthesizes SAM locally [76], which can then be used for localized histone methylation through interactions
Nuclear Metabolic Enzymes and Major Cell Decisions
That nuclear methylation and acetylation are reciprocally regulated [84] suggests a very complex network, partially regulated by the translocation and choreography of specific metabolic enzyme groups in the nucleus. It is intriguing to speculate that this choreography of nuclear metabolic enzymes is a part of a comprehensive mechanism to drive gene transcription toward specific cell decisions, particularly those relating to or driven by the supply/demand of fuels and nutrients, including
Metabolic Enzyme Trafficking
The nuclear translocation mechanism of metabolic enzymes remains largely unknown, and many of them lack nuclear localization sequences. One can provocatively hypothesize that groups of these enzymes can translocate together as a ‘package’, following a common stimulus, as part of a program linked to a specific cell decision. For example, direct acetylation of the glycolytic enzymes GAPDH 99, 100 and PKM2 [101] by the acetyltransferase p300 promotes their nuclear translocation and their
Concluding Remarks: Translational Implications
The nuclear translocation of metabolic enzymes is exploited by cancer cells, and thus may also be explored therapeutically (see Outstanding Questions). (i) There is a rapidly growing interest in targeting many metabolic enzymes in cancer. Metabolic modulators of several enzymes are being studied as potential cancer therapies (Box 2). Such drugs can have epigenetic effects, altering the levels of many gene products, thereby amplifying their effect beyond what would be predicted from their
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