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BackgroundEfficient and selective utilization of metabolic substrates is one of the key strategies in high-altitude animals to cope with hypoxia and hypothermia. Previous findings have shown that the energy substrate utilization of highland animals varies with evolutionary history and phylogeny. The heart is a proxy for the cardiopulmonary system, and the metabolic substrate utilization in the myocardium is also under the strong selective pressure of chronically hypoxic and hypothermic environments. However, little information is available on the physiological adjustments in relation to metabolic substrate utilization in the myocardium for coping with high-altitude environments.MethodsWe compared the metabolic enzyme activities, including hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), citrate synthase (CS), carnitine palmitoyl transferase 1 (CPT-1), lactic dehydrogenase (LDH), and creatine kinase (CK), and metabolic substrate contents including glucose (Glu), triglyceride (TG), and free fatty acid (FFA) in the myocardium of a typical human commensal species, Eurasian Tree Sparrows (Passermontanus) between the Qinghai-Tibet Plateau (the QTP, 3230 m) and low altitude population (Shijiazhuang, 80 m), and between sexes.ResultsAmong the seven metabolic enzymes and three substrates investigated, we identified no significant differences in PK, CPT-1, HK, CS, LDH, and CK activities and TG content of the myocardium between high and low altitude populations. However, the QTP sparrows had significantly lower Glu content and PFK activities but higher FFA content relative to their lowland counterparts. In addition, male sparrows had higher myocardial HK and CS activities relative to females, independent of altitude.ConclusionsOur results showed that the QTP sparrows elevated fatty acid utilization rather than glucose preference in the myocardium relative to lowland counterpart, which contributes to uncovering both the physiological adjustments for adapting to the extreme conditions of the QTP, intraspecifically.

The Indian butter catfish, Ompok bimaculatus (Bloch, 1794), is a high-value catfish that has gained immense consumer preference in South-East Asia. However, information on the nutritional requirements of this species is scanty. Hence, an experiment was conducted to evaluate the effects of varying dietary lipid levels on growth, body composition, and activities of digestive and metabolic enzymes in larvae. Three isonitrogenous (40% crude protein) diets were formulated by supplementing fish and vegetable oil (1:1) at 4.5% (D1), 7% (D2), and 9.5% (D3) levels (containing crude lipid 5.7%, 8.0%, and 10.45%, respectively in diets D1–D3) to a fish meal- and oilcake-based formulated diet. Experimental diets were fed to butter catfish larvae (0.15 ± 0.01 g) in triplicate groups for a period of 42 days. Proximate compositions of the experimental diets, as well as fish carcass, were analyzed using standard procedures (AOAC 2005). Digestive and metabolic enzyme activities were analyzed at the completion of the experiment by standard methodology. Butter catfish larvae fed the diet D2 (8% crude lipid) resulted in the best performance in terms of weight gain (final weight 1.40 ± 0.07 g), net weight gain (1.31 ± 0.06 g), specific growth rate (5.50 ± 0.05% · day−1), and protein efficiency ratio (2.39 ± 0.17). The highest lipid deposition (2.90 ± 0.12%) in the carcass was also recorded in fish reared on diet D2. The final weight, net weight gain, protein efficiency ratio, and specific growth rate were significantly (P < 0.05) higher in D2 having 8% lipid. Moisture and lipid contents of the whole body were significantly (P < 0.05) higher in larvae fed diet D2. Amylase activity in fish significantly (P < 0.05) decreased with increasing dietary lipid levels. The maximum alkaline protease, pepsin, and lipase activities were noticed in the larvae fed diet D2. Progressive decrease in liver glucose-6-phosphate dehydrogenase activities and significant increase (P < 0.05) in the activities of neoglucogenic enzymes (glucose-6-phosphatase and fructose-1,6-bis phosphatase) were noticed with an increase in dietary lipid levels. Significantly lower (P < 0.05) activities of LDH, ALT, and AST were recorded in the group fed diet D2. Results of the study indicated that 8% crude lipid in the diet could assure optimum growth and survival of butter catfish larvae during early development. An appraisal on growth, body composition, and digestive as well as metabolic function in the butter catfish larvae recorded in the study might provide some important information to consider application of formulated diets for the larviculture of Ompok bimaculatus.

Ovarian cancer is one of the most malignant gynecological cancers around the world. In spite of multiple treatment options, the five-year survival rate is still very low. Several metabolism alterations are described as a hallmark in cancers, but alterations of lipid metabolism in ovarian cancer have been paid less attention. To explore new markers/targets for accurate diagnosis, prognosis, and therapeutic treatments based on metabolic enzyme inhibitors, here, we reviewed available literature and summarized several key metabolic enzymes in lipid metabolism of ovarian cancer. In this review, the rate limiting enzymes associated with fatty acid synthesis (FASN, ACC, ACLY, SCD), the lipid degradation related enzymes (MAGL, CPT, 5-LO, COX2), and the receptors related to lipid uptake (FABP4, CD36, LDLR), which promote the development of ovarian cancer, were analyzed and evaluated. We also focused on the review of application of current metabolic enzyme inhibitors for the treatment of ovarian cancer through which the potential therapeutic agents may be developed for ovarian cancer therapy.

The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed.

Cannabis is one of the earliest cultivated plants, of which Cannabis sativa and Cannabis indica are the most widespread and best characterized species. Their extracts contain (phyto)cannabinoids (pCBs) of therapeutic interest, such as Δ9-tetrahydrocannabinol and cannabidiol, along with many other compounds, so that there is no “one cannabis” but several mixtures even from the same plant. This complexity is mirrored, or even exceeded, by the complexity of the molecular targets that pCBs find in our body, most of which belong to the so-called “endocannabinoid (eCB) system”. Here, we describe the major pCBs and the main components of the eCB system to appreciate their differences and mutual interactions, as well as the potential of using pCB/eCB-based drugs as novel therapeutics to treat human diseases, both in the central nervous system and at the periphery. Moreover, we address the question of the evolution of pCBs and eCBs, showing that the latter compounds were the first to appear in nature, and that the former substances took a few million years to mimic the three-dimensional structures of the latter, and hence their biological activity in our body. Graphic abstract

Cyanobacteria possess an atypical tricarboxylic acid (TCA) cycle with various bypasses. Previous studies have suggested that a cyclic flow through the TCA cycle is not essential for cyanobacteria under normal growth conditions. The cyanobacterial TCA cycle is, thus, different from that in other bacteria, and the biochemical properties of enzymes in this TCA cycle are less understood. In this study, we reveal the biochemical characteristics of malate dehydrogenase (MDH) from Synechocystis sp. PCC 6803 MDH (SyMDH). The optimal temperature of SyMDH activity was 45–50°C and SyMDH was more thermostable than MDHs from other mesophilic microorganisms. The optimal pH of SyMDH varied with the direction of the reaction: pH 8.0 for the oxidative reaction and pH 6.5 for the reductive reaction. The reductive reaction catalysed by SyMDH was activated by magnesium ions and fumarate, indicating that SyMDH is regulated by a positive feedback mechanism. The Km-value of SyMDH for malate was approximately 210-fold higher than that for oxaloacetate and the Km-value for NAD+ was approximately 19-fold higher than that for NADH. The catalytic efficiency of SyMDH for the reductive reaction, deduced from kcat-values, was also higher than that for the oxidative reaction. These results indicate that SyMDH is more efficient in the reductive reaction in the TCA cycle, and it plays key roles in determining the direction of the TCA cycle in this cyanobacterium.

It is important for the success of the masu salmon, Oncorhynchus masou , stock enhancement program in Hokkaido (northern Japan) to demonstrate physiological problems in hatchery-reared (hatchery) smolt for artificial release. The present study examined changes in liver and gill metabolic parameters in wild and hatchery masu salmon during smoltification and elucidated differences in hepatic and gill metabolism between wild and hatchery fish. As reference to freshwater-adapted wild and hatchery smolt in this study, metabolic parameters of coastal smolt were studied. Yearling wild and hatchery smolting fish were collected from the Ken-ichi River and the Donan Research Branch, which used Ken-ichi river water for fish culture, at the same time every month from March through May 2008. Coastal smolts were caught from Nemuro Bay of Hokkaido in June. Decreased hepatic glycogen content during smoltification, which was observed in wild fish and revealed activation of glycogenolysis, was not found in hatchery fish. Hatchery fish demonstrated a positive change in hepatic ATP content during smoltification, while wild fish showed negative change in the content, which reflected activated consumption of hepatic ATP stores during smoltification. Increases in gill pyruvate kinase activity during smoltification, which were found in wild fish and indicated activation of glycolysis, were not detected in hatchery fish. There was a difference in increased timing of hepatic citrate synthase activity during smoltification between hatchery and wild fish. Increased gill citrate synthase activity during smoltification, which was observed in wild fish and reflected enhancement of the citric acid cycle, was not found in hatchery fish. Hatchery smolt revealed lower liver cytochrome c oxidase activity and transcript levels of some respiratory chain enzymes compared to wild smolt in May, which suggested lower respiratory chain capacity in hatchery fish at mid-smolt stage. On the other hand, there were no remarkable differences in hepatic and gill 3-hydroxyacyl-coenzyme A dehydrogenase related to lipolysis and creatine kinase activities, which operate in resolution of creatine phosphate, during smoltification between hatchery and wild fish. These results suggested hatchery masu salmon had some metabolic problems with carbohydrate metabolism, the citric acid cycle, and the respiratory chain. Our study will give valuable information to improve physiological quality of hatchery smolt for artificial release.

Background The Danning tablets (DNts) is commonly prescribed in China as a cholagogic formula. Our previous studies showed that DNts exerted the protective effect on α-naphthylisothiocyanate (ANIT)-induced liver injury with cholestasis in a dose-dependent mannar. However, the detailed molecular mechanisms of DNts against ANIT-induced cholestasis are still not fully explored. Methods Danning tablet (3 g/kg body weight/day) was administered orally to experimental rats for seven days before they were treated with ANIT (60 mg/kg daily via gastrogavage) which caused cholestasis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (T-Bil), direct bilirubin (D-Bil) and total bile acid (TBA) were measured to evaluate the protective effect of Danning tablet at 12, 24 and 48h after ANIT treatment. Meanwhile, total bilirubin or total bile acid in the bile, urine and liver were also measured at 48h after ANIT treatment. Furthermore, the hepatic or renal mRNA and protein levels of metabolic enzymes and transports were investigated to elucidate the protective mechanisms of Danning tablet against ANIT-induced cholestasis. Results In this study, we found that DNts significantly attenuated translocation of multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane into an intracellular and up-regulated the hepatic mRNA and protein expressions of metabolic enzymes including cytochrome P450 2b1(Cyp2b1) and uridine diphosphate-5¢- glucuronosyltransferase (Ugt1a1)) and transporters including bile salt export pump (Bsep) and multidrug resistance protein 2 (Mdr2)) as well as renal organic solute transporter beta (Ostβ), accompanied by further increase in urinary and biliary excretion of bile acid and bilirubin. Conclusions DNts might promote bile acid and bilirubin elimination by regulating the expressions of hepatic and renal transporters as well as hepatic metabolic enzymes.

One of the key questions in biology is how the metabolism of a cell responds to changes in the environment. In budding yeast, starvation causes a drop in intracellular pH, but the functional role of this pH change is not well understood. Here, we show that the enzyme glutamine synthetase (Gln1) forms filaments at low pH and that filament formation leads to enzymatic inactivation. Filament formation by Gln1 is a highly cooperative process, strongly dependent on macromolecular crowding, and involves back-to-back stacking of cylindrical homo-decamers into filaments that associate laterally to form higher order fibrils. Other metabolic enzymes also assemble into filaments at low pH. Hence, we propose that filament formation is a general mechanism to inactivate and store key metabolic enzymes during a state of advanced cellular starvation. These findings have broad implications for understanding the interplay between nutritional stress, the metabolism and the physical organization of a cell. DOI: http://dx.doi.org/10.7554/eLife.02409.001, eLife digest Life is based on a series of chemical reactions that control how cells live, grow, and divide. Various metabolic enzymes allow cells to control the rate at which these reactions occur. Recently, researchers have noticed that metabolic enzymes can form filaments in cells, usually when the cells are deprived of energy or nutrients. Petrovska, Nüske et al. now reveal more about how and why an enzyme called glutamine synthetase (Gln1) forms filaments in yeast cells. Gln1 has a cylindrical shape. This shape means that stacking the enzymes end-to-end under the right conditions is enough to make them bond into a long filament. In addition, a zip-like mechanism enables neighboring filaments to fuse to create thicker fibres. These filaments are more likely to form if there are high concentrations of large background molecules around—a condition known as macromolecular crowding. Petrovska, Nüske et al. also found evidence that the filaments are part of a strategy to help cells survive starvation. Enzymes were more likely to construct filaments when the cell division cycle had stopped, which commonly occurs due to a lack of nutrients. In addition, Gln1 filaments only form if the cytoplasm of the cell becomes acidic—which is a response to the cell starving. This has been seen for other metabolic enzymes as well, suggesting that acidification is a signal to reprogram the metabolism of a cell. The Gln1 enzymes in a filament are inactivated, but become active again after the filament breaks up. In addition, preventing Gln1 filament formation makes it harder for cells to recover from a period of starvation. Petrovska, Nüske et al. therefore suggest that the filaments act as a storage depot for the enzymes during starvation. Further experiments are now needed to uncover exactly how these manage to help the starving cell to survive and recover. DOI: http://dx.doi.org/10.7554/eLife.02409.002

Acetylation of protein lysine residues is a reversible and dynamic process that is controlled by histone acetyltransferases (HATs) and deacetylases (HDACs and SIRTs). Recent studies have revealed that acetylation modulates not only nuclear proteins but also cytoplasmic or mitochondrial proteins, including many metabolic enzymes. In tumors, cellular metabolism is reprogrammed to provide intermediates for biosynthesis such as nucleotides, fatty acids, and amino acids, and thereby favor the rapid proliferation of cancer cells and tumor development. An increasing number of investigations have indicated that acetylation plays an important role in tumor metabolism. Here, we summarize the substrates that are modified by acetylation, especially oncogenes, tumor suppressor genes, and enzymes that are implicated in tumor metabolism.