Over the past few years, there has been a growing interest in the interconnection between translation and metabolism. Important oncogenic pathways, like those elicited by c-Myc transcription factor and mTOR kinase, couple the activation of the translational machinery with glycolysis and fatty acid synthesis. Eukaryotic initiation factor 6 (eIF6) is a factor necessary for 60S ribosome maturation. eIF6 acts also as a cytoplasmic translation initiation factor, downstream of growth factor stimulation. eIF6 is up-regulated in several tumor types. Data on mice models have demonstrated that eIF6 cytoplasmic activity is rate-limiting for Myc-induced lymphomagenesis. In spite of this, eIF6 is neither transcriptionally regulated by Myc, nor post-transcriptionally regulated by mTOR. eIF6 stimulates a glycolytic and fatty acid synthesis program necessary for tumor growth. eIF6 increases the translation of transcription factors necessary for lipogenesis, such as CEBP/β, ATF4 and CEBP/δ. Insulin stimulation leads to an increase in translation and fat synthesis blunted by eIF6 deficiency. Paradoxycally, long-term inhibition of eIF6 activity increases insulin sensitivity, suggesting that the translational activation observed upon insulin and growth factors stimulation acts as a feed-forward mechanism regulating lipid synthesis. The data on the role that eIF6 plays in cancer and in insulin sensitivity make it a tempting pharmacological target for cancers and metabolic diseases. We speculate that eIF6 inhibition will be particularly effective especially when mTOR sensitivity to rapamycin is abrogated by RAS mutations.

Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.

Natural killer (NK) cells have key roles in anti-viral and anti-tumour immune responses. Recent research demonstrates that cellular metabolism is an important determinant for the function of pro-inflammatory immune cells, including activated NK cells. The mammalian target of rapamcyin (mTOR) complex 1 (mTORC1) has been identified as a key metabolic regulator that promotes glycolytic metabolism in multiple immune cell subsets. Glycolysis is integrally linked to pro-inflammatory immune responses such that activated NK cells and effector T-cell subsets are reliant on sufficient glucose availability for maximal effector function. This article will discuss the regulation of cellular metabolism in NK cells as compared with that of T lymphocytes and discuss the implications for NK cell responses to viral infection and cancer.

Macrophages are present in a large variety of locations, playing distinct functions that are determined by its developmental origin and by the nature of the activators of the microenvironment. Macrophage activation can be classified as pro-inflammatory (M1 polarization) or anti-inflammatory-pro-resolution-deactivation (M2), these profiles coexisting in the course of the immune response and playing a relevant functional role in the onset of inflammation (Figure 1). Several groups have analysed the metabolic aspects associated with macrophage activation to answer the question about what changes in the regulation of energy metabolism and biosynthesis of anabolic precursors accompany the different types of polarization and to what extent they are necessary for the expression of the activation phenotypes. The interest of these studies is to regulate macrophage function by altering their metabolic activity in a ‘therapeutic way’.

Glycolysis is an ancient biochemical pathway that breaks down glucose into pyruvate to produce ATP. The structural and catalytic properties of glycolytic enzymes are well-characterized. However, there is growing appreciation that these enzymes participate in numerous moonlighting functions that are unrelated to glycolysis. Recently, chemical genetics has been used to discover novel moonlighting functions in glycolytic enzymes. In the present mini-review, we introduce chemical genetics and discuss how it can be applied to the discovery of protein moonlighting. Specifically, we describe the application of chemical genetics to uncover moonlighting in two glycolytic enzymes, enolase and glyceraldehyde dehydrogenase. This led to the discovery of moonlighting roles in glucose homoeostasis, cancer progression and diabetes-related complications. Finally, we also provide a brief overview of the latest progress in unravelling the myriad moonlighting roles for these enzymes.

An RNA world has been placed centre stage for explaining the origin of life. Indeed, RNA is the most plausible molecule able to form both a (self)-replicator and to inherit information, necessities for initiating genetics. However, in parallel with self-replication, the proto-organism had to obtain the ability to catalyse supply of its chemical constituents, including the ribonucleotide metabolites required to replicate RNA. Although the possibility of an RNA-catalysed metabolic network has been considered, it is to be questioned whether RNA molecules, at least on their own, possess the required catalytic capacities. An alternative scenario for the origin of metabolism involves chemical reactions that are based on environmental catalysts. Recently, we described a non-enzymatic glycolysis and pentose phosphate pathway-like reactions catalysed by metal ions [mainly Fe(II)] and phosphate, simple inorganic molecules abundantly found in Archaean sediments. While the RNA world can serve to explain the origin of genetics, the origin of the metabolic network might thus date back to constraints of environmental chemistry. Interestingly, considering a metal-catalysed origin of metabolism gives rise to an attractive hypothesis about how the first enzymes could have formed: simple RNA or (poly)peptide molecules could have bound the metal ions, and thus increased their solubility, concentration and accessibility. In a second step, this would have allowed substrate specificity to evolve.

On 27–29 November 2013, researchers gathered at the University of Warwick, Coventry, U.K., to celebrate the centennial of the discovery of the glyoxalase pathway. The glyoxalase system was discovered and reported in papers by Carl Neuberg and by Henry Drysdale Dakin and Harold Ward Dudley in 1913. All three were leading extraordinary investigators in the pioneering years of biochemistry. Neuberg proposed glyoxalase as the pathway of mainstream glycolysis and Gustav Embden correctly discounted this, later confirmed by Otto Meyerhof. Albert Szent-Györgyi proposed glyoxalase I as the regulator of cell growth and others discounted this. In the meantime, molecular, structural and mechanistic properties of the enzymatic components of the system, glyoxalase I and glyoxalase II, have been characterized. The physiological function of the glyoxalase pathway of enzymatic defence against dicarbonyl glycation, particularly by endogenous methylglyoxal, now seems secure. We are now in an era of investigation of the regulation of the glyoxalase system where a role in aging and disease, physiological stress and drug resistance and development of healthier foods and new pharmaceuticals is emerging. The history of glyoxalase research illustrates the scientific process of hypothesis proposal, testing and rejection or acceptance with further investigation, standing testament to the need for intuition guided by experience and expertise, as well as indefatigable experimentation.

The main function of glycolysis and oxidative phosphorylation is to produce cellular energy in the form of ATP. In the present paper we propose a link between both of these energy-regulatory processes in the form of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and CytOx (cytochrome c oxidase). GAPDH is the sixth enzyme of glycolysis, whereas CytOx is the fourth complex of the mitochondrial oxidative phosphorylation system. In MS analysis, GAPDH was found to be associated with a BN-PAGE (blue native PAGE)-isolated complex of CytOx from bovine heart tissue homogenates. Both GAPDH and CytOx are highly regulated under normal energy metabolic conditions, but both of these enzymes are highly deregulated in the presence of oxidative stress. The interaction of GAPDH with CytOx could be the point of interest as it has already been shown that GAPDH protein damage results in a marked decrease in cellular ATP levels. On the other hand, decreasing the ATP/ADP ratio may ultimately result in switching off the allosteric ATP inhibition of CytOx leading to increased ROS (reactive oxygen species), cytochrome c release and apoptosis. Moreover, we have previously reported that allosteric ATP inhibition of CytOx is responsible for keeping the membrane potential at low healthy values, thus avoiding the production of ROS and this allosteric ATP inhibition is switched on at a high ATP/ADP ratio. So, in the present paper, we propose a scheme that could prove to be a link between these two enzymes and their role in the prevalence of diseases.

Given that inflammatory T-cells have a highly glycolytic metabolism, whereas regulatory T-cells rely more on oxidative glucose metabolism, there is growing interest in understanding how T-cell metabolism relates to T-cell function. The mTORC1 (mammalian target of rapamycin complex 1) has a crucial role to determine the balance between effector and regulatory T-cell differentiation, but is also described as a key regulator of metabolism in non-immune cell systems. The present review explores the relationship between these diverse functions of mTORC1 with regard to T-cell function. In many cell systems, mTORC1 couples PI3K (phosphoinositide 3-kinase) and PKB (protein kinase B), also known as Akt, with the control of glucose uptake and glycolysis. However, this is not the case in activated CD8 + CTLs (cytotoxic T-lymphocytes) where PI3K/PKB signalling is dispensable for the elevated levels of glycolysis that is characteristic of activated T-cells. Nevertheless, mTORC1 is still essential for glycolytic metabolism in CD8 + T-cells, and this reflects the fact that mTORC1 does not lie downstream of PI3K/PKB signalling in CD8 + T-cells, as is the case in many other cell systems. mTORC1 regulates glucose metabolism in CTLs through regulating the expression of the transcription factor HIF1α (hypoxia-inducible factor 1α). Strikingly, HIF1α functions to couple mTORC1 with a diverse transcriptional programme that extends beyond the control of glucose metabolism to the regulation of multiple key T-cell functions. The present review discusses the idea that mTORC1/HIF1α signalling integrates the control of T-cell metabolism and T-cell function.

A key characteristic of cancer cells is the ability to switch from a predominantly oxidative metabolism to glycolysis and the production of lactate even when oxygen is plentiful. This metabolic switch, known as the Warburg effect, was first described in the 1920s, and has fascinated and puzzled researchers ever since. However, a dramatic increase in glycolysis in the presence of oxygen is one of the hallmarks of the development of the early mammalian embryo; a metabolic switch with many parallels to the Warburg effect of cancers. The present review provides a brief overview of this and other similarities between the metabolism in tumours and early embryos and proposes whether knowledge of early embryo metabolism can help us to understand metabolic regulation in cancer cells.

Within the SulfoSYS ( Sulfolobus Systems Biology) project, the effect of temperature on a metabolic network is investigated at the systems level. Sulfolobus solfataricus utilizes an unusual branched ED (Entner–Doudoroff) pathway for sugar degradation that is promiscuous for glucose and galactose. In the course of metabolic pathway reconstruction, a glucose dehydrogenase isoenzyme (GDH-2, SSO3204) was identified. GDH-2 exhibits high similarity to the previously characterized GDH-1 (SSO3003, 61% amino acid identity), but possesses different enzymatic properties, particularly regarding substrate specificity and catalytic efficiency. In contrast with GDH-1, which exhibits broad substrate specificity for C 5 and C 6 sugars, GDH-2 is absolutely specific for glucose. The comparison of kinetic parameters suggests that GDH-2 might represent the major player in glucose catabolism via the branched ED pathway, whereas GDH-1 might have a dominant role in galactose degradation via the same pathway as well as in different sugar-degradation pathways.

The Myc oncogenes are dysregulated in 70% of human cancers. They encode transcription factors that bind to E-box sequences in DNA, driving the expression of a vast amount of target genes. The biological outcome is enhanced proliferation (which is counteracted by apoptosis), angiogenesis and cancer. Based on the biological effects of Myc overexpression it was originally assumed that the important Myc target genes are those encoding components of the cell cycle machinery. Recent work has challenged this notion and indicates that Myc target genes encoding metabolic enzymes deserve attention, as they may be critical arbiters of Myc in cancer. Thus targeting metabolic enzymes encoded by Myc-target genes may provide a new means to treat cancer that have arisen in response to deregulated Myc oncogenes.

A circadian clock optimizes many aspects of plant biology relative to the light/dark cycle. One example is the circadian control of primary metabolism and CO 2 fixation in plants that carry out a metabolic adaptation of photosynthesis called CAM (crassulacean acid metabolism). These plants perform primary CO 2 fixation at night using the enzyme phosphoenolpyruvate carboxylase and exhibit a robust rhythm of CO 2 fixation under constant conditions. Transcriptomic analysis has revealed that many genes encoding enzymes in primary metabolic pathways such as glycolysis and starch metabolism are under the control of the circadian clock in CAM plants. These transcript changes are accompanied by changes in metabolite levels associated with flux through these pathways. The molecular basis for the circadian control of CAM remains to be elucidated. Current research is focusing on the identity of the CAM central oscillator and the output pathway that links the central oscillator to the control of plant metabolism.

FBPA (fructose-1,6-bisphosphate aldolase) catalyses the reversible aldol condensation of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate to form fructose 1,6-bisphosphate. Two classes of FBPA, which rely on different reaction mechanisms, have so far been discovered, class I mainly found in Eucarya and class II mainly in Bacteria. Only recently were genes encoding proteins with FBPA activity identified in Archaea. Archaeal FBPAs do not share any significant overall sequence identity with members of the traditional classes of FBPAs, raising the interesting question of whether they have evolved independently by convergent evolution or diverged from a common ancestor. Biochemical characterization of FBPAs of the two hyperthermophilic Archaea Thermoproteus tenax and Pyrococcus furiosus showed that the enzymes use a Schiff-base mechanism and thus belong to the class I aldolases. The crystal structure of the archaeal FBPA from T. tenax revealed that the protein fold, as for the classical FBPA I and II, is that of a parallel (βα) 8 barrel. A substrate-bound crystal structure allowed detailed active-site comparisons which showed the conservation of six important catalytic and substrate-binding residues between the archaeal and the classical FBPA I. This observation provides further evidence that the two sequence families of proteins share a common evolutionary origin. Furthermore, structure and sequence analysis indicate that the class I FBPA shares a common evolutionary origin with several other enzyme superfamilies of the (βα) 8 barrel fold.

During the last two decades the concept of the MLSS (maximal lactate steady state) has been established. The MLSS detects the highest level of the BLC (blood lactate concentration) and the corresponding workload (MLSS workload) that can be maintained over time without continual BLC accumulation. In spite of a lack of experimental and/or theoretical foundation, it has been speculated that the level of the MLSS may decrease with increasing performance capacity. The potential inter-relationship between performance capacity and BLC response to prolonged constant workload will be analysed based on a recent study, which provided evidence that the MLSS is independent of performance whereas MLSS workload increases with performance capacity, and by a computer-aided simulation. The simulated model modifies and combines previous theories put forward to explain the response of BLC to exercise and incorporates a theory about limiting factors of oxygen transport to the muscle cell. Simulations consider the BLC response to selected prolonged constant workloads while paying special respect to changes in body structure and substrate utilization, which are generally accepted as limiting factors of performance capacity. This complex modulation of appearance and disappearance of lactate during constant prolonged exercise seems to support the experimental results, which indicated independence between MLSS and performance capacity.

The discovery of the AMP-activated protein kinase (AMPK) more than a decade ago has shed much light on the cellular response to stresses characterized by a fall in the concentration of ATP and an increase in the AMP/ATP ratio. All conditions known to increase this ratio activate AMPK, whose major role is to act as an emergency signal to conserve ATP. It does so by inhibiting anabolic processes and by activating pathways producing ATP. In recent years, our laboratory has discovered new targets of AMPK. The purpose of this short review is to summarize our contribution to this field.

Glucose 6-phosphate is an intermediate of pathways of glucose utilization and production as well as a regulator of enzyme activity and gene expression. Studies on the latter functions are in part based on measurement of the glucose 6-phosphate content in a whole-cell extract. Several studies have suggested that there are multiple subcellular pools of glucose 6-phosphate. It is proposed that this data can be interpreted in terms of channelling of metabolic intermediates through multiple pathways of glucose metabolism with leakage of glucose 6-phosphate from the channels into a single free pool. It is also proposed that measurement of total tissue content of glucose 6-phosphate approximates the free pool.