Examining Amino Acids in Neuroscience and Cancer Metabolism Research

Amino acids are not just significant building blocks for protein synthesis but also intermediary metabolites fueling biosynthetic reactions, thereby having a dual role to play in cellular metabolism. Quantifying L-amino acids in body fluids or purified samples in an accurate manner might offer useful information for diagnostic and basic research purposes.

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)

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)

Cellular Roles of Amino Acids in Cancer and Neurobiology

The metabolism of cancer cells is modified and they are known for their metabolic abnormalities. One such abnormality is the Warburg effect, which involves increased glycolytic activity even when oxygen is present. The continuous growth and survival of cancer cells are dependent on a high rate of aerobic glycolysis.

Since cancer cells and biosynthetic pathways largely consume amino acids as nutrients, amino acids are always sought after for various cancer subtypes. It can be observed that there is a slight modification in the components sensing amino acid sufficiency in cancer tissues, resulting in cells with mechanistic target of rapamycin (mTOR) regulating the protein synthesis and autophagy. Such processes modify the metabolism of proliferative cells to support the biochemical pathways for biomass accumulation; therefore, these modifications in the metabolism of tumor cells are regarded as the characteristics of cancer.

It has been proven by scientists that tumor tissue can be differentiated from normal tissues through metabolic activities and the levels of metabolites. As a result, any information related to this differentiation could be cautiously used for the detection and treatment of cancer. Gaining better insights into the modified metabolism in malignant tissues and cells has a greater potential for synergy with enhanced medical therapies for this disease. For instance, the L-asparaginase therapy for leukemia was discovered by identifying the increased levels of the nutrient asparagine in fast-growing cancer cells. Moreover, the multiple affinities of glucose uptake in some tumors paved the way for to the development of the 18fluoro-2-deoxyglucose imaging agent for positron emission tomography (PET), motivating many scientists to study tumor glucose metabolism.

It is a known fact in neurobiology that amino acids are present in higher concentrations in the brain than other body tissues. Neurons respond to amino acid neurotransmitters, including N-acetyl aspartate (excitatory neurotransmitters), glutamate, gamma-amino butyric acid (GABA), aspartate, and glycine (major inhibitory neurotransmitters). Ionotropic glutamate receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) and N-methyl-D-aspartate (NMDA) are responsible for mediating glutamatergic neurotransmission. Amino acids such as phenylalanine and tryptophan play a vital role in the synthesis of dopamine and serotonin and in maintaining sleep cycles; hence, they are highly significant components for a healthy mental state. Latest studies have demonstrated that deregulation of both arms of these amino acids is one of the most usual modifications observed in cancer.

Amino Acid-Based Assays

Assay kits for the detection of L-amino acids are useful tools for acquiring vital information in studies.

Glutamine

Glutamine (Gln) is crucial for various biological processes like protein synthesis, cell growth, and acid balance regulation in mammalian kidneys (Figure 1). It is the main source of nitrogen for cells to synthesize hexosamines and nucleotides. It also has a role to play in redox homeostasis, energy production, and cancer signaling. It has been observed that certain cancer cell lines exhibit affinity toward glutamine. Glutamine-addicted tumors tend to present oncogenic expression of the Myc gene, which codes for a transcription factor that promotes expression of metabolic enzymes and glutamine transporters for biosynthesis; the outcome is cells that undergo aerobic glycolysis, guaranteeing a steady influx of glucose.

These facts make the detection of glutamine an attractive target for future diagnostic and therapeutic alternatives for cancer. Glutamine has a vital role in preserving the activity of TOR kinase and activating mTOR complex 1, thereby integrating metabolism by sensing the levels of nutrients and regulating the levels of production of other amino acids together with lipid biosynthesis. A commercial glutamine colorimetric assay kit with the ability to detect biologically relevant concentrations of glutamine in different biological tissues and fluids, which consequently helps in speeding up the discovery process, is now available.

Glycine

Glycine (Gly) is an important component of body proteins that build tissues forming muscles, joints, and organs. It is the second most abundant amino acid present in human enzymes and proteins, with higher concentrations in collagen. It has a vital role to play in the central nervous system (CNS) as an inhibitory neurotransmitter that processes motor and sensory information and allows movement and audition mediated by a strychnine-sensitive glycine receptor. Occasionally, glycine is co-released with GABA — the key inhibitory amino acid neurotransmitter. It strengthens the action of glutamate at NMDA receptors, thereby regulating the excitatory neurotransmission.

Glycine is used in the treatment of benign prostatic hyperplasia (BPH), stroke, schizophrenia, and other conditions. There have been no evident adverse events in these applications of glycine.

It is somewhat difficult to measure the endogenous levels of glycine or glycine in in-vivo samples. At present, no precision technique exists for high-throughput screening of glycine concentrations in samples. High-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), immunoassay techniques, and mass spectrometry (MS) are the standard procedures for the quantitation of glycine. Yet, these protocols are not perfect for fast-paced screening of a huge number of samples or for compound screening. Commercially available glycine detection kits are valuable for high-throughput screening to measure glycine concentrations in various biological samples. They offer reproducible, sensitive, and simple techniques for the detection of glycine, which are applicable for in vitro serum screening of small-molecule inhibitors/activators.

Assays such as these have exhibited a considerable decrease of glycine in patients suffering from schizophrenia and depression; a higher concentration of glycine was observed in the sample collected from a patient suffering from Alzheimer’s disease (Figure 2). Recent studies have shown similar trends.

(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.

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.

L-Tryptophan

L-Tryptophan (TRP) is among the eight amino acids essential to the human body and has a vital role to play in the endogenous synthesis of protein, serotonin, melatonin, kynurenine, nicotinamide adenine dinucleotide phosphate (NADP), tryptamine, niacin, and nicotinamide adenine dinucleotide (NAD). Kynurenic acid synthesized from kynurenine is a glutamate receptor antagonist.

The synthesis of serotonin is among the most significant tryptophan pathways (Figure 3). Tryptophan decarboxylation results in the formation of tryptamine, which is a vital neuromodulator of serotonin. Melatonin hormone is synthesized from the tryptophan–serotonin pathway regulating biological rhythms, like diurnal rhythms that stabilize the cardiac and hormonal systems. Tryptophan has an impact on other neurotransmitters and CNS molecules like norepinephrine, dopamine, and beta-endorphin, thereby exhibiting a broad array of neurophysiological effects in the human body.

The TRP side chain (indole) chemically presents distinctive fluorometric properties. The only amino acid that can be found in blood in dual forms, free and bound, is TRP. Variations in tryptophan concentrations are directly linked to various behavioral and physiological processes, such as sleep, motion sickness, memory, bipolar disorders, depression, and schizophrenia. Commercially available in vitro detection of TRP offers a sensitive, simple, and high-throughput adaptable assay with the ability to detect tryptophan concentration in biological fluids, including bound and free tryptophan in serum.

Tryptophan functions in human body. (Zhang LS, Davies SS via Wikimedia Commons)

Figure 3. Tryptophan functions in human body. (Zhang LS, Davies SS via Wikimedia Commons)

Conclusion

Amino acids are vital constituents of a number of structural and cellular proteins. These building blocks could prove to be valuable tools for research.

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Last updated: Feb 21, 2020 at 9:30 AM

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