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Biochemical Pharmacology Jul 2022The liver controls the systemic exposure of amino acids entering via the gastro-intestinal tract. For most amino acids except branched chain amino acids, hepatic uptake... (Review)
Review
The liver controls the systemic exposure of amino acids entering via the gastro-intestinal tract. For most amino acids except branched chain amino acids, hepatic uptake is very efficient. This implies that the liver orchestrates amino acid metabolism and also controls systemic amino acid exposure. Although many amino acid transporters have been identified, cloned and investigated with respect to substrate specificity, transport mechanism, and zonal distribution, which of these players are involved in hepatocellular amino acid transport remains unclear. Here, we aim to provide a review of current insight into the molecular machinery of hepatic amino acid transport. Furthermore, we place this information in a comprehensive overview of amino acid transport, signalling and metabolism.
Topics: Amino Acids; Amino Acids, Branched-Chain; Biological Transport; Liver; Signal Transduction
PubMed: 35568239
DOI: 10.1016/j.bcp.2022.115074 -
Cell Stem Cell Jul 2022Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated...
Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.
Topics: Amino Acids; Eukaryotic Initiation Factor-2; Hematopoietic Stem Cells; Oxidative Phosphorylation; Phosphorylation; Proteostasis
PubMed: 35803229
DOI: 10.1016/j.stem.2022.06.004 -
Current Opinion in Structural Biology Jun 2022In living systems, the chemical space and functional repertoire of proteins are dramatically expanded through the post-translational modification (PTM) of various amino... (Review)
Review
In living systems, the chemical space and functional repertoire of proteins are dramatically expanded through the post-translational modification (PTM) of various amino acid residues. These modifications frequently trigger unique protein-protein interactions (PPIs) - for example with reader proteins that directly bind the modified amino acid residue - which leads to downstream functional outcomes. The modification of a protein can also perturb its PPI network indirectly, for example, through altering its conformation or subcellular localization. Uncovering the network of unique PTM-triggered PPIs is essential to fully understand the roles of an ever-expanding list of PTMs in our biology. In this review, we discuss established strategies and current challenges associated with this endeavor.
Topics: Amino Acids; Protein Processing, Post-Translational; Proteins
PubMed: 35334254
DOI: 10.1016/j.sbi.2022.102352 -
Cold Spring Harbor Perspectives in... Apr 2021
Review
Topics: Amino Acids; Catecholamines; Energy Metabolism; Epigenesis, Genetic; Melanins; Nitric Oxide; Synaptic Transmission; Urea
PubMed: 33795250
DOI: 10.1101/cshperspect.a040584 -
Blood Sep 2019Tumor cells rewire metabolic pathways to adapt to their increased nutritional demands for energy, reducing equivalents, and cellular biosynthesis. Alternations in amino... (Review)
Review
Tumor cells rewire metabolic pathways to adapt to their increased nutritional demands for energy, reducing equivalents, and cellular biosynthesis. Alternations in amino acid metabolism are 1 modality for satisfying those demands. Amino acids are not only components of proteins but also intermediate metabolites fueling multiple biosynthetic pathways. Amino acid-depletion therapies target amino acid uptake and catabolism using heterologous enzymes or recombinant or engineered human enzymes. Notably, such therapies have minimal effect on normal cells due to their lower demand for amino acids compared with tumor cells and their ability to synthesize the targeted amino acids under conditions of nutrient stress. Here, we review novel aspects of amino acid metabolism in hematologic malignancies and deprivation strategies, focusing on 4 key amino acids: arginine, asparagine, glutamine, and cysteine. We also present the roles of amino acid metabolism in the immunosuppressive tumor microenvironment and in drug resistance. This summary also offers an argument for the reclassification of amino acid-depleting enzymes as targeted therapeutic agents.
Topics: Amino Acids; Animals; Antineoplastic Agents; Arginine; Asparagine; Cysteine; Glutamine; Hematologic Neoplasms; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; Tumor Microenvironment
PubMed: 31416801
DOI: 10.1182/blood.2019001034 -
International Journal of Molecular... Jul 2019Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological... (Review)
Review
Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon's potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.
Topics: Amino Acids; Animals; Biomarkers; Glucagon; Humans; Lipid Metabolism; Receptors, Glucagon; Signal Transduction
PubMed: 31284506
DOI: 10.3390/ijms20133314 -
Journal of Hematology & Oncology Jun 2023Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor... (Review)
Review
Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor microenvironment, dysregulation of amino acid consumption in immune cells is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered amino acid metabolism is tightly linked to tumor outgrowth, metastasis, and therapeutic resistance through governing the fate of various immune cells. During these processes, the concentration of free amino acids, their membrane bound transporters, key metabolic enzymes, and sensors such as mTOR and GCN2 play critical roles in controlling immune cell differentiation and function. As such, anti-cancer immune responses could be enhanced by supplement of specific essential amino acids, or targeting the metabolic enzymes or their sensors, thereby developing novel adjuvant immune therapeutic modalities. To further dissect metabolic regulation of anti-tumor immunity, this review summarizes the regulatory mechanisms governing reprogramming of amino acid metabolism and their effects on the phenotypes and functions of tumor-infiltrating immune cells to propose novel approaches that could be exploited to rewire amino acid metabolism and enhance cancer immunotherapy.
Topics: Humans; Neoplasms; Energy Metabolism; Immunity; Immunotherapy; Amino Acids; Tumor Microenvironment
PubMed: 37277776
DOI: 10.1186/s13045-023-01453-1 -
Nutrients Dec 2020Aging is determined by complex interactions among genetic and environmental factors. Increasing evidence suggests that the gut microbiome lies at the core of many...
Aging is determined by complex interactions among genetic and environmental factors. Increasing evidence suggests that the gut microbiome lies at the core of many age-associated changes, including immune system dysregulation and susceptibility to diseases. The gut microbiota undergoes extensive changes across the lifespan, and age-related processes may influence the gut microbiota and its related metabolic alterations. The aim of this systematic review was to summarize the current literature on aging-associated alterations in diversity, composition, and functional features of the gut microbiota. We identified 27 empirical human studies of normal and successful aging suitable for inclusion. Alpha diversity of microbial taxa, functional pathways, and metabolites was higher in older adults, particularly among the oldest-old adults, compared to younger individuals. Beta diversity distances significantly differed across various developmental stages and were different even between oldest-old and younger-old adults. Differences in taxonomic composition and functional potential varied across studies, but was most consistently reported to be relatively more abundant with aging, whereas , , and were relatively reduced. Older adults have reduced pathways related to carbohydrate metabolism and amino acid synthesis; however, oldest-old adults exhibited functional differences that distinguished their microbiota from that of young-old adults, such as greater potential for short-chain fatty acid production and increased butyrate derivatives. Although a definitive interpretation is limited by the cross-sectional design of published reports, we integrated findings of microbial composition and downstream functional pathways and metabolites, offering possible explanations regarding age-related processes.
Topics: Adult; Aged; Aged, 80 and over; Aging; Amino Acids; Carbohydrate Metabolism; Cross-Sectional Studies; Feces; Female; Gastrointestinal Microbiome; Humans; Longevity; Male; Middle Aged; Protein Biosynthesis; Signal Transduction
PubMed: 33297486
DOI: 10.3390/nu12123759 -
British Journal of Cancer Jan 2020An abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they... (Review)
Review
An abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they can have roles in energy generation, driving the synthesis of nucleosides and maintenance of cellular redox homoeostasis. As cancer cells exist within a complex and often nutrient-poor microenvironment, they sometimes exist as part of a metabolic community, forming relationships that can be both symbiotic and parasitic. Indeed, this is particularly evident in cancers that are auxotrophic for particular amino acids. This review discusses the stromal/cancer cell relationship, by using examples to illustrate a number of different ways in which cancer cells can rely on and contribute to their microenvironment - both as a stable network and in response to therapy. In addition, it examines situations when amino acid synthesis is driven through metabolic coupling to other reactions, and synthesis is in excess of the cancer cell's proliferative demand. Finally, it highlights the understudied area of non-proteinogenic amino acids in cancer metabolism and their potential role.
Topics: Amino Acids; Cell Proliferation; Energy Metabolism; Humans; Neoplasms; Protein Biosynthesis; Tumor Microenvironment
PubMed: 31819187
DOI: 10.1038/s41416-019-0620-5 -
Cell Metabolism Aug 2020Amino acids are fundamental building blocks supporting life. Their role in protein synthesis is well defined, but they contribute to a host of other intracellular... (Review)
Review
Amino acids are fundamental building blocks supporting life. Their role in protein synthesis is well defined, but they contribute to a host of other intracellular metabolic pathways, including ATP generation, nucleotide synthesis, and redox balance, to support cellular and organismal function. Immune cells critically depend on such pathways to acquire energy and biomass and to reprogram their metabolism upon activation to support growth, proliferation, and effector functions. Amino acid metabolism plays a key role in this metabolic rewiring, and it supports various immune cell functions beyond increased protein synthesis. Here, we review the mechanisms by which amino acid metabolism promotes immune cell function, and how these processes could be targeted to improve immunity in pathological conditions.
Topics: Amino Acids; Animals; Glycolysis; Humans; Mitochondria
PubMed: 32649859
DOI: 10.1016/j.cmet.2020.06.010