The major sources of amino acids derive from the diet or protein breakdown. Nonessential amino acids are synthesized from car bon skeletons using different metabolic pathways. Amino acids conjugated to transfer RNA (tRNA) are used in protein synthesis; however, in excess, they can be used for energy production. In addition, amino acids are necessary for the synthesis of other compounds. For example, tryptophan catabolism constitutes a route for de novo NAD+ synthesis in a pathway that is important in leukocytes for the replenishment of NAD+ levels after oxidative stress. Interestingly, different metabolites derived from tryptophan catabolism via the kynurenine pathway play a role in immune tolerance. Plasma amino acids are transported in cells against a concentration gradient. Amino acid transporters are specific for neutral (small and larger), basic, and acidic amino acids. Depending on the cell type and specific state (growth, hypoxia, fasting, and so on), intracellular amino acids are used in anabolic or catabolic pathways.

Most of the regulation of amino acid metabolism is achieved through substrate fluxes affecting specific enzyme kinetics. However, there are two major regulatory pathways that involve amino acid sensing mechanisms and metabolic control. (1) General control nonrepressed 2 (GCN2) is a protein kinase that senses amino acid deficiency through direct binding to uncharged tRNA. GCN2 controls the transcription factor ATF4, affecting different enzymes of amino acid metabolism. The high asparagine requirement of certain acute lymphoblastic leukemias has resulted in the use of asparaginase to deplete circulating levels of asparagine. Limited amounts of asparagine result in activation of GCN2 in leukemic cells and reduce their proliferation and viability rates. (2) mTOR is a protein kinase activated in response to increased amino acid concentrations (particularly branch chain amino acids). mTOR controls many aspects involved in protein synthesis, inhibition of protein degradation, and amino acid biosynthetic enzymes.

Biosynthesis of Nonessential Amino Acids

 Nonessential amino acids are synthesized by most of the cells, including hematopoietic lineages. Nonessential amino acids are mainly synthesized from glucose (alanine, arginine [from the urea cycle in hepatic cells], asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, and serine), except for tyrosine, which is synthesized from phenylalanine. The rest of the nine amino acids are essential, and the body needs to obtain these from the diet. Serine, glycine, and cysteine are synthesized from glycolytic inter mediates. Serine synthesis has recently been found to be increased and necessary in stem cells. For some hematopoietic cells, the syn thesis of cysteine and glycine is of elevated importance owing to their use in the synthesis of the tripeptide glutathione. Aspartate and asparagines are synthesized by transamination of oxaloacetate by glutamate and amide transfer from glutamine, respectively. Glutamate, glutamine, proline, and arginine are formed from the TCA cycle intermediate α-ketoglutarate.

Amino Acid Catabolism

 Two central reactions in amino acid catabolism are the generation of ammonia through transamination (catalyzed by amino transferases) and oxidative deamination (catalyzed by glutamate dehydrogenase) in which the α-amino group of the different amino acids is transferred to α-ketoglutarate to form glutamate, which undergoes the release of free NH3 . Free ammonium is added to glutamate to generate glutamine, which is then exported into the circulation to the liver, where it then enters the urea cycle. The urea cycle mainly occurs in the liver and has two purposes: (1) to get rid of free ammonium and (2) to supply arginine. Interestingly, one of the enzymes of the urea cycle, arginase (which converts arginine to ornithine), is expressed in immune cells. Myeloid cell arginase depletes arginine and suppresses T-cell immune responses and is an important mechanism of inflammation associated with immunosuppression. Arginase is viewed as a promising strategy in the treatment of cancer and autoimmunity. Arginine is also essential for the differentiation and proliferation of erythrocytes.

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مواضيع ذات صلة

The Chemical Nature of RNA Differs From That of DNA

DNA Provides A Template For Replication & Transcription

DNA Can be Reversibly Denatured & Specifically Renatured, Both in the Test Tube & in Living Cells

DNA Contains Four Distinct Deoxynucleotides

Overproduction of Pyrimidine Catabolites

Disorders of Purine Metabolism

Biochemical Characteristics and Biological Function of Cardiac Natriuretic Peptides

The Deoxyribonucleosides of Uracil & Cytosine are Salvaged

Biosynthesis of Pyrimidine Nucleotides

Hepatic Purine Biosynthesis is Stringently Regulated

Inosine Monophosphate (IMP) is Synthesized From Amphibolic Intermediates

DNA & RNA are Polynucleotides