Cell-Specific Expression of Enzymes for Serine Biosynthesis and Glutaminolysis in Farm Animals.
TL;DR: In this paper, cell-specific expression of enzymes required for serine biosynthesis, one-carbon metabolism and glutaminolysis at the uterine-placental interface of sheep and pigs is described.
Abstract: During the peri-implantation period, conceptuses [embryo and placental membranes, particularly the trophectoderm (Tr)] of farm animals (e.g., sheep and pigs) rapidly elongate from spherical to tubular to filamentous forms. In concert with Tr outgrowth during conceptus elongation, the Tr of sheep and pig conceptuses attaches to the endometrial luminal epithelium (LE) to initiate placentation. In sheep, binucleate cells (BNCs) begin to differentiate from the mononuclear trophectoderm cells and migrate to the endometrial LE to form syncytial plaques. These events require Tr cells to expend significant amounts of energy to undergo timely and extensive proliferation, migration and fusion. It is likely essential that conceptuses optimally utilize multiple biosynthetic pathways to convert molecules such as glucose, fructose, and glutamine (components of histotroph transport by sheep and pig endometria into the uterine lumen), into ATP, amino acids, ribose, hexosamines and nucleotides required to support early conceptus development and survival. Elongating and proliferating conceptus Tr cells potentially act, in a manner similar to cancer cells, to direct carbon generated from glucose and fructose away from the TCA cycle for utilization in branching pathways of glycolysis, including the pentose phosphate pathway, one-carbon metabolism, and hexosamine biosynthesis. The result is a limited availability of pyruvate for maintaining the TCA cycle within mitochondria, and Tr cells replenish TCA cycle metabolites via a process known as anaplerosis, primarily through glutaminolysis to convert glutamine into TCA cycle intermediates. Here we describe the cell-specific expression of enzymes required for serine biosynthesis, one-carbon metabolism and glutaminolysis at the uterine-placental interface of sheep and pigs, and propose that these biosynthetic pathways are essential to support early placental development including Tr elongation, cell migration, cell fusion and implantation by ovine and porcine conceptuses.
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TL;DR: In this article, the authors discuss how to mitigate antimicrobial resistance and develop prebiotic and probiotic alternatives to in-feed antibiotics in animal production, while helping reduce greenhouse gas emissions, minimize the urinary and fecal excretion of nitrogenous and other wastes to the environment, and sustain animal agriculture (including aquaculture).
Abstract: Consumption of high-quality animal protein plays an important role in improving human nutrition, growth, development, and health. With an exponential growth of the global population, demands for animal-sourced protein are expected to increase by 60% between 2021 and 2050. In addition to the production of food protein and fiber (wool), animals are useful models for biomedical research to prevent and treat human diseases and serve as bioreactors to produce therapeutic proteins. For a high efficiency to transform low-quality feedstuffs and forages into high-quality protein and highly bioavailable essential minerals in diets of humans, farm animals have dietary requirements for energy, amino acids, lipids, carbohydrates, minerals, vitamins, and water in their life cycles. All nutrients interact with each other to influence the growth, development, and health of mammals, birds, fish, and crustaceans, and adequate nutrition is crucial for preventing and treating their metabolic disorders (including metabolic diseases) and infectious diseases. At the organ level, the small intestine is not only the terminal site for nutrient digestion and absorption, but also intimately interacts with a diverse community of intestinal antigens and bacteria to influence gut and whole-body health. Understanding the species and metabolism of intestinal microbes, as well as their interactions with the intestinal immune systems and the host intestinal epithelium can help to mitigate antimicrobial resistance and develop prebiotic and probiotic alternatives to in-feed antibiotics in animal production. As abundant sources of amino acids, bioactive peptides, energy, and highly bioavailable minerals and vitamins, animal by-product feedstuffs are effective for improving the growth, development, health, feed efficiency, and survival of livestock and poultry, as well as companion and aquatic animals. The new knowledge covered in this and related volumes of Adv Exp Med Biol is essential to ensure sufficient provision of animal protein for humans, while helping reduce greenhouse gas emissions, minimize the urinary and fecal excretion of nitrogenous and other wastes to the environment, and sustain animal agriculture (including aquaculture).
32Â citations
TL;DR: Amino acids (AAs) are the building blocks of proteins that have both structural and metabolic functions in humans and other animals as mentioned in this paper, and proteinogenic AAs are alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine and lysine, methionine, phenylalanine.
Abstract: Amino acids (AAs) are the building blocks of proteins that have both structural and metabolic functions in humans and other animals. In mammals, birds, fish, and crustaceans, proteinogenic AAs are alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. All animals can synthesize de novo alanine, asparagine, aspartate, glutamate, glutamine, glycine, proline, and serine, whereas most mammals (including humans and pigs) can synthesize de novo arginine. Results of extensive research over the past three decades have shown that humans and other animals have dietary requirements for AAs that are synthesizable de novo in animal cells. Recent advances in analytical methods have allowed us to determine all proteinogenic AAs in foods consumed by humans, livestock, poultry, fish, and crustaceans. Both plant- and animal-sourced foods contain high amounts of glutamate, glutamine, aspartate, asparagine, and branched-chain AAs. Cysteine, glycine, lysine, methionine, proline, threonine, and tryptophan generally occur in low amounts in plant products but are enriched in animal products. In addition, taurine and creatine (essential for the integrity and function of tissues) are absent from plants but are abundant in meat and present in all animal-sourced foods. A combination of plant- and animal products is desirable for the healthy diets of humans and omnivorous animals. Furthermore, animal-sourced feedstuffs can be included in the diets of farm and companion animals to cost-effectively improve their growth performance, feed efficiency, and productivity, while helping to sustain the global animal agriculture (including aquaculture).
25Â citations
TL;DR: In this paper, the pregnancy recognition signal from the conceptus (embryo/fetus and associated membranes) to the mother is interferon tau (IFNT) in ruminants and estradiol, possibly in concert with interferons gamma and delta in pigs.
Abstract: The pregnancy recognition signal from the conceptus (embryo/fetus and associated membranes) to the mother is interferon tau (IFNT) in ruminants and estradiol, possibly in concert with interferons gamma and delta in pigs. Those pregnancy recognition signals silence expression of interferon stimulated genes (ISG) in uterine luminal (LE) and superficial glandular (sGE) epithelia while inducing expression of genes for transport of nutrients, including glucose and amino acids, into the uterine lumen to support growth and development of the conceptus. In sheep and pigs, glucose not utilized immediately by the conceptus is converted to fructose. Glucose, fructose, serine and glycine in uterine histotroph can contribute to one carbon (1C) metabolism that provides one-carbon groups for the synthesis of purines and thymidylate, as well as S-adenosylmethionine for epigenetic methylation reactions. Serine and glycine are transported into the mitochondria of cells and metabolized to formate that is transported into the cytoplasm for the synthesis of purines, thymidine and S-adenosylmethionine. The unique aspects of one-carbon metabolism are discussed in the context of the hypoxic uterine environment, aerobic glycolysis, and similarities in metabolism between cancer cells and cells of the rapidly developing fetal-placental tissues during pregnancy. Further, the evolution of anatomical and functional aspects of the placentae of sheep and pigs versus primates is discussed in the context of mechanisms to efficiently obtain, store and utilize nutrients required for rapid fetal growth in the last one-half of gestation.
19Â citations
TL;DR: In this paper, it has been shown that an adequate amount of supplemental rumen-protected Arg or unencapsulated Cit is necessary to support maximum survival, growth, lactation, reproductive performance, and feed efficiency in all ruminants.
Abstract: L-Arginine (Arg) plays a central role in the nitrogen metabolism (e.g., syntheses of protein, nitric oxide, polyamines, and creatine), blood flow, nutrient utilization, and health of ruminants. This amino acid is produced by ruminal bacteria and is also synthesized from L-glutamine, L-glutamate, and L-proline via the formation of L-citrulline (Cit) in the enterocytes of young and adult ruminants. In pre-weaning ruminants, most of the Cit formed de novo by the enterocytes is used locally for Arg production. In post-weaning ruminants, the small intestine-derived Cit is converted into Arg primarily in the kidneys and, to a lesser extent, in endothelial cells, macrophages, and other cell types. Under normal feeding conditions, Arg synthesis contributes 65% and 68% of total Arg requirements for nonpregnant and late pregnany ewes fed a diet with ~12% crude protein, respectively, whereas creatine production requires 40% and 36% of Arg utilized by nonpregnant and late pregnant ewes, respectively. Arg has not traditionally been considered a limiting nutrient in diets for post-weaning, gestating, or lactating ruminants because it has been assumed that these animals can synthesize sufficient Arg to meet their nutritional and physiological needs. This lack of a full understanding of Arg nutrition and metabolism has contributed to suboptimal efficiencies for milk production, reproductive performance, and growth in ruminants. There is now considerable evidence that dietary supplementation with rumen-protected Arg (e.g., 0.25-0.5% of dietary dry matter) can improve all these production indices without adverse effects on metabolism or health. Because extracellular Cit is not degraded by microbes in the rumen due to the lack of uptake, Cit can be used without any encapsulation as an effective dietary source for the synthesis of Arg in ruminants, including dairy and beef cows, as well as sheep and goats. Thus, an adequate amount of supplemental rumen-protected Arg or unencapsulated Cit is necessary to support maximum survival, growth, lactation, reproductive performance, and feed efficiency, as well as optimum health and well-being in all ruminants.
10Â citations
TL;DR: In this article, it was shown that AAs contribute to about 80% of ATP production in the liver, proximal intestine, kidney, and skeletal muscle tissue of the fish.
Abstract: Fish are useful animal models for studying effects of nutrients and environmental factors on gene expression (including epigenetics), toxicology, and carcinogenesis. To optimize the response of the animals to substances of interest (including toxins and carcinogens), water pollution, or climate changes, it is imperative to understand their fundamental biochemical processes. One of these processes concerns energy metabolism for growth, development, and survival. We have recently shown that tissues of hybrid striped bass (HSB), zebrafish, and largemouth bass (LMB) use amino acids (AAs; such as glutamate, glutamine, aspartate, alanine, and leucine) as major energy sources. AAs contribute to about 80% of ATP production in the liver, proximal intestine, kidney, and skeletal muscle tissue of the fish. Thus, as for mammals (including humans), AAs are the primary metabolic fuels in the proximal intestine of fish. In contrast, glucose and fatty acids are only minor metabolic fuels in the fish. Fish tissues have high activities of glutamate dehydrogenase, glutamate–oxaloacetate transaminase, and glutamate-pyruvate transaminase, as well as high rates of glutamate uptake. In contrast, the activities of hexokinase, pyruvate dehydrogenase, and carnitine palmitoyltransferase 1 in all the tissues are relatively low. Furthermore, unlike mammals, the skeletal muscle (the largest tissue) of HSB and LMB has a limited uptake of long-chain fatty acids and barely oxidizes fatty acids. Our findings explain differences in the metabolic patterns of AAs, glucose, and lipids among various tissues in fish. These new findings have important implications for understanding metabolic significance of the tissue-specific oxidation of AAs (particularly glutamate and glutamine) in gene expression (including epigenetics), nutrition, and health, as well as carcinogenesis in fish, mammals (including humans), and other animals.
8Â citations
References
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TL;DR: Transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools, and glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.
Abstract: Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used 13C NMR spectroscopy to examine the metabolism of glioblastoma cells exhibiting aerobic glycolysis. In these cells, the tricarboxylic acid (TCA) cycle was active but was characterized by an efflux of substrates for use in biosynthetic pathways, particularly fatty acid synthesis. The success of this synthetic activity depends on activation of pathways to generate reductive power (NADPH) and to restore oxaloacetate for continued TCA cycle function (anaplerosis). Surprisingly, both these needs were met by a high rate of glutamine metabolism. First, conversion of glutamine to lactate (glutaminolysis) was rapid enough to produce sufficient NADPH to support fatty acid synthesis. Second, despite substantial mitochondrial pyruvate metabolism, pyruvate carboxylation was suppressed, and anaplerotic oxaloacetate was derived from glutamine. Glutamine catabolism was accompanied by secretion of alanine and ammonia, such that most of the amino groups from glutamine were lost from the cell rather than incorporated into other molecules. These data demonstrate that transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools. Rather, glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.
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TL;DR: A brief refresher course on six of the major metabolic pathways involved in immunometabolism is provided, giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response.
Abstract: Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
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TL;DR: A conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis will progressively support the development of new strategies to treat human cancer.
Abstract: Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.
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TL;DR: An updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo is provided, and the recent potential applications of basic science discoveries in the clinical setting are explored.
Abstract: The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.
1,285Â citations