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September 01, 2016

Amino Acids in Cancer Metabolism and Neuroscience

These Building Blocks Could Be Valuable Tools for Research

Amino Acids in Cancer Metabolism and Neuroscience

Figure 1. Glutamine and the metabolism of other amino acids as targets for cancer therapy. [Int J Mol Sci 2015;16:22830–22855; doi:10.3390/ijms160922830]

  • Amino acids are important building blocks for protein synthesis and are also intermediary metabolites that fuel biosynthetic reactions, thus playing a dual role in cellular metabolism. Accurate quantification of L-amino acids in body fluids or purified samples may provide valuable information for diagnostic and basic research studies.

  • Cellular Roles of Amino Acids in Cancer and Neurobiology

    Cancer cells have altered metabolism and are known for their metabolic abnormalities. One example is the Warburg effect, in which there is increased glycolytic activity even in the presence of oxygen. Cancer cells depend on a high rate of aerobic glycolysis for continued growth and survival.

    Because amino acids are the most highly consumed nutrients by cancer cells and biosynthetic pathways, they are always in demand for different cancer subtypes. A slight alteration is observed in the components that sense amino acid sufficiency in cancer tissues, leading to cells with mechanistic target of rapamycin (mTOR) modulating the protein synthesis and autophagy. These processes alter the metabolism of proliferative cells to support the biochemical pathways for accumulation of biomass, and hence these alterations in tumor cell metabolism are identified as hallmarks of cancer.1

    Researchers have proven that metabolic activities and the levels of metabolites can differentiate tumor tissue from normal tissues. Thus, any information about this differentiation could be carefully used to detect and cure cancer. Increased understanding of altered metabolism in malignant tissues and cells has high potential for synergy with improved medical therapies for this disease. For example, discovery of L-asparaginase therapy for leukemia was identified by elevated levels of the nutrient asparagine in rapidly growing cancer cells. Also, the multiple affinity of glucose uptake in some tumors led to the development of the 18fluoro-2-deoxyglucose imaging agent for positron emission tomography (PET), stimulating many researchers to study tumor glucose metabolism.1

    In neurobiology, it is well known that the brain has high concentrations of amino acids as compared with other body tissues. Neurons respond to amino acid neurotransmitters, which  include glutamate, aspartate, N-acetyl aspartate (excitatory neurotransmitters), gamma-amino butyric acid (GABA), and glycine (major inhibitory neurotransmitters). Glutamatergic neurotransmission is mediated through ionotropic glutamate receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) and N-methyl-D-aspartate (NMDA). With their role in the production of serotonin and dopamine and in maintaining sleep cycles, amino acids such as tryptophan and phenylalanine are extremely important components for a healthy mental state. Recent research shows that deregulation of both arms of these amino acids is one of the most common alterations seen in cancer. 

  • Amino Acid–based Assays

    Click Image To Enlarge +
    Figure 2. (A and B) Commercial glycine detection kit results showing that metabolites and other amino acids do not interfere with glycine detection. (C) Assay used for research demonstrating decrease of glycine in patients suffering depression and schizophrenia and increased concentration of glycine in Alzheimer’s disease patients. Glycine concentration was evaluated using an in vitro commercial glycine assay kit in human serum samples from patients diagnosed with various neuropsychiatric conditions. Control: Control; A: Multiple Sclerosis; B: Parkinson’s Disease; C: Major Depression; D: Schizophrenia; E: Amyotrophic Lateral Sclerosis; F: Alzheimer’s Disease. All patients were male caucasian and age ranges from 53 to 60 years old.

    Assay kits for detection of L-amino acids are valuable tools for obtaining important information in research.

    Glutamine

    Glutamine (Gln) is essential for several biological processes, such as protein synthesis, regulation of acid balance in mammalian kidneys, and cell growth (Figure 1). It is the cell’s main source of nitrogen for the synthesis of nucleotides and hexosamines. Glutamine is also responsible for energy production, redox homeostasis, and cancer signaling. Some cancer cell lines have shown addiction to glutamine. Glutamine-addicted tumors are characterized by oncogenic expression of the Myc gene, which codes for a transcription factor promoting expression of glutamine transporters and metabolic enzymes for biosynthesis; the result is cells that undergo aerobic glycolysis, ensuring a steady influx of glucose. 

    These findings make glutamine detection an attractive target for future diagnostic and therapeutic alternatives for cancer.2 Glutamine plays a significant role in maintaining the activity of TOR kinase and activating mTOR complex 1, thus integrating metabolism by sensing levels of nutrients and regulating the levels of other amino acid production along with lipid biosynthesis.3 A commercial glutamine colorimetric assay kit is available that can detect biologically relevant concentrations of glutamine in various biological fluids and tissues and thus helps in accelerating the discovery process.

    Glycine

    Glycine (Gly) is a significant constituent of proteins in the body that build tissues forming organs, joints, and muscles. It is the second most widespread amino acid found in human enzymes and proteins, with higher concentrations in collagen. It plays a significant role in the central nervous system (CNS) as an inhibitory neurotransmitter, processing motor and sensory information and permitting movement and audition that is mediated by a strychnine-sensitive glycine receptor. At times, glycine is co-released with GABA, the main inhibitory amino acid neurotransmitter. It potentiates the action of glutamate at NMDA receptors, thus modulating the excitatory neurotransmission.4

    Glycine is used in the treatment of schizophrenia, stroke, benign prostatic hyperplasia (BPH), and other conditions. These applications of glycine have not shown any significant observed adverse events yet.5–7

    Measuring endogenous levels of glycine or glycine in in vivo samples is considered somewhat challenging. Currently there is no accurate method for high-throughput screening of glycine concentrations in samples. Standard procedures for quantitation of glycine involve nulcear magnetic resonance (NMR), mass spectrometry (MS), high-performance liquid chromatography (HPLC), and immunoassay techniques. However, these protocols are not ideal for rapid screening of large number of samples or for compound screening. Commercially available glycine detection kits are useful in high-throughput screening for measuring glycine concentrations in different biological samples. They provide simple, sensitive, and reproducible methods of glycine detection that can be applicable for in vitro serum screening of small-molecule inhibitors/activators.

    Such assays have shown a significant decrease of glycine in patients suffering from depression and schizophrenia; a higher concentration of glycine was found in the sample from a patient suffering from Alzheimer’s disease (Figure 2). Similar trends have been shown in recent research.

  • Click Image To Enlarge +
    Figure 3. Tryptophan functions in human body. [Zhang LS, Davies SS via Wikimedia Commons]

    L-Tryptophan

    L-Tryptophan (TRP) is one of the eight essential amino acids and plays important role in the endogenous synthesis of protein, kynurenine, serotonin, tryptamine, melatonin, nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), and niacin, Kynurenic acid formed from kynurenine is a glutamate receptor antagonist.

    Serotonin synthesis is one of the most important tryptophan pathways (Figure 3). Tryptophan decarboxylation leads to the formation of tryptamine, which is an important neuromodulator of serotonin. Melatonin hormone is produced from the tryptophan–serotonin pathway, which regulates biological rhythms, such as diurnal rhythms stabilizing cardiac and hormonal systems. Tryptophan affects other neurotransmitters and CNS molecules, such as dopamine, norepinephrine, and beta-endorphin, thus showing a wide range of neurophysiological effects in human body.

    Chemically, the TRP side chain (indole) confers unique fluorometric properties. TRP is the only amino acid that can be found in blood in two forms—bound and free. Changes in tryptophan concentrations are directly related to a number of physiological and behavioral processes, including sleep, memory, depression, motion sickness, bipolar disorders, and schizophrenia.  Commercially available in vitro detection of TRP provides a simple, sensitive, and high-throughput adaptable assay that detects tryptophan concentration in biological fluids, including free and bound tryptophan in serum. 

  • Conclusion

    Amino acids are essential components of many cellular and structural proteins. These building blocks could be valuable tools for research. 

     

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