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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 -
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 -
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 -
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 -
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 -
Nutrients Dec 2020Ingesting protein-containing supplements and foods provides essential amino acids (EAA) necessary to increase muscle and whole-body protein synthesis (WBPS). Large...
Ingesting protein-containing supplements and foods provides essential amino acids (EAA) necessary to increase muscle and whole-body protein synthesis (WBPS). Large variations exist in the EAA composition of supplements and foods, ranging from free-form amino acids to whole protein foods. We sought to investigate how changes in peripheral EAA after ingesting various protein and free amino acid formats altered muscle and whole-body protein synthesis. Data were compiled from four previous studies that used primed, constant infusions of L-(ring-H)-phenylalanine and L-(3,3-H)-tyrosine to determine fractional synthetic rate of muscle protein (FSR), WBPS, and circulating EAA concentrations. Stepwise regression indicated that max EAA concentration (EAAC; R = 0.524, < 0.001), EAAC (R = 0.341, < 0.001), and change in EAA concentration (ΔEAA; R = 0.345, < 0.001) were the strongest predictors for postprandial FSR, Δ (change from post absorptive to postprandial) FSR, and ΔWBPS, respectively. Within our dataset, the stepwise regression equation indicated that a 100% increase in peripheral EAA concentrations increases FSR by ~34%. Further, we observed significant ( < 0.05) positive (R = 0.420-0.724) correlations between the plasma EAA area under the curve above baseline, EAAC, ΔEAA, and rate to EAAC to postprandial FSR, ΔFSR, and ΔWBPS. Taken together our results indicate that across a large variety of EAA/protein-containing formats and food, large increases in peripheral EAA concentrations are required to drive a robust increase in muscle and whole-body protein synthesis.
Topics: Aging; Amino Acids; Amino Acids, Essential; Dietary Supplements; Eating; Food; Humans; Kinetics; Male; Metabolism; Muscle Proteins; Muscle, Skeletal; Phenylalanine; Postprandial Period; Protein Biosynthesis; Whey Proteins
PubMed: 33276485
DOI: 10.3390/nu12123717 -
Experimental & Molecular Medicine Apr 2023Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via... (Review)
Review
Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a source of nitrogen for amino acid and nucleotide synthesis. To date, many studies have explored the role of glutamine metabolism in cancer, thereby providing a scientific rationale for targeting glutamine metabolism for cancer treatment. In this review, we summarize the mechanism(s) involved at each step of glutamine metabolism, from glutamine transporters to redox homeostasis, and highlight areas that can be exploited for clinical cancer treatment. Furthermore, we discuss the mechanisms underlying cancer cell resistance to agents that target glutamine metabolism, as well as strategies for overcoming these mechanisms. Finally, we discuss the effects of glutamine blockade on the tumor microenvironment and explore strategies to maximize the utility of glutamine blockers as a cancer treatment.
Topics: Humans; Glutamine; Neoplasms; Amino Acids; Citric Acid Cycle; Oxidation-Reduction; Tumor Microenvironment
PubMed: 37009798
DOI: 10.1038/s12276-023-00971-9 -
The FEBS Journal May 2017The 20 standard amino acids encoded by the Genetic Code were adopted during the RNA World, around 4 billion years ago. This amino acid set could be regarded as a frozen... (Comparative Study)
Comparative Study Review
The 20 standard amino acids encoded by the Genetic Code were adopted during the RNA World, around 4 billion years ago. This amino acid set could be regarded as a frozen accident, implying that other possible structures could equally well have been chosen to use in proteins. Amino acids were not primarily selected for their ability to support catalysis, as the RNA World already had highly effective cofactors to perform reactions, such as oxidation, reduction and transfer of small molecules. Rather, they were selected to enable the formation of soluble structures with close-packed cores, allowing the presence of ordered binding pockets. Factors to take into account when assessing why a particular amino acid might be used include its component atoms, functional groups, biosynthetic cost, use in a protein core or on the surface, solubility and stability. Applying these criteria to the 20 standard amino acids, and considering some other simple alternatives that are not used, we find that there are excellent reasons for the selection of every amino acid. Rather than being a frozen accident, the set of amino acids selected appears to be near ideal.
Topics: Amino Acids; Animals; Biological Evolution; Energy Metabolism; Genetic Code; Humans; Models, Biological; Protein Biosynthesis; Protein Conformation; Protein Folding; Protein Stability; Solubility
PubMed: 27926995
DOI: 10.1111/febs.13982