Amino Acids in Homeostasis, Health, and Disease
Amino acid molecules that combine in long chains to form proteins, have a profound impact on the function of the human system in health and disease. The following article discusses the role of amino acids in promoting homeostasis.
In the first part of the article, a few examples describing the impact of amino acids on human health are included. This section covers Glutathione (GSH) synthesis that is dependent on Cysteine (Cys), Glutamate (Glu), and Glycine (Gly), the role of GSH homeostasis, disruption, and oxidative stress. Likewise, key aspects of tryptophan (Trp) metabolism in gut-brain homeostasis is summarized.
The second part focuses on alterations in amino acid metabolism in a state of disease — (i) adverse molecular mechanisms of amino acid metabolism in COVID-19-induced hypoxia, (ii) elevated Cysteine (Cys) levels and limited iron availability impairing mitochondrial respiration in aging, and (iii) the supplementation of Leucine (Leu) to modulate lipid metabolism and promote energy homeostasis.
Role of Amino Acids in Maintaining Homeostasis
Glutathione (GSH) Homeostasis, Oxidative Stress, and Disease
Glutathione (GSH), a water-soluble thiol, is an endogenous antioxidant, and in high concentrations protects against tissue degeneration, cellular damage, and disease progression. GSH is synthesized from the amino acids Cysteine (Cys), Glutamate (Glu), and Glycine (Gly), produced in the cytosol. Thereafter, it is transported to the mitochondria, endoplasmic reticulum, nucleus, and other subcellular structures. The reduced form of GSH exists in these locations, and its oxidized form, GSSG, is formed during redox reactions (Gould and Pazdro, 2019). In an environment of oxidative stress, GSH to GSSG conversion accelerates, decreasing the GSH/GSSG ratio and impacting cell signaling, cell proliferation, and thiol disulphide exchange reactions. A number of diseases are linked to disruption in GSH homeostasis from protein energy malnutrition (PEM) including Alzheimer’s, Parkinson’s, cancer, AIDS, HIV, aging, obesity, diabetes mellitus (DM), liver and heart disease.
Gould and Pazdro (2019) evaluated the action of amino acid and micronutrient supplementation on glutathione (GSH) metabolism. GSH has been administered via various routes from intravenous to transdermal, however, the oral route has been considered the most convenient. Supplementing GSH directly has been associated with limited dietary GSH entering circulation. As a result, researchers concluded that amino acids, micronutrients, and diet strategies may influence GSH homeostasis in specific population groups. Interventions may be age-specific, and several other factors may interfere with GSH synthesis in the body, such as liver dysfunction. In spite of the difficulties in measuring and administering GSH, researchers believe that improving GSH status has protective effects against oxidative stress in disease states.
Tryptophan (Trp) Metabolism and Gut-Brain Homeostasis
Tryptophan (Trp), an essential amino acid, is involved in protein synthesis and participates in the gut-brain-axis homeostasis. Trp levels are influenced by physical activity, stress, and dietary practices. Tryptophan acts as a precursor for serotonin, the neurotransmitter involved in hunger, gut activity (motility, secretory activity), sleep, pain, and emotional regulation. Serotonin is converted to melatonin, which is the regulator for circadian rhythms and initiation of sleep. Trp metabolites support the enteric and central nervous system development. Tryptophan catabolites (from kynurenine degradation pathway) modulate neural activity and participate in systemic inflammatory cascades (Roth et al., 2021). Several psychiatric (depression, anxiety, schizophrenia, autism spectrum disorders) and neurologic (Parkinson’s, Alzheimer’s, cerebrovascular disease, multiple sclerosis, TBI, and migraine) disorders are associated with Trp dysregulation. The gut microbiome influences tryptophan metabolism, which in turn, influences behavior and cognition. Gastrointestinal disorders associated with Trp metabolism include inflammatory bowel disease, irritable bowel syndrome, and age-related gastro-intestinal dysfunction.
Cases of Altered Amino Acid Metabolism in Disease
Hypoxia-Induced Adverse Molecular Mechanisms of Amino Acid Metabolism in COVID-19
Researchers examined amino acid metabolism in COVID-19 and the mechanisms that led to altered oxygen homeostasis. Hypoxia plays a key role in the adverse outcomes associated with the condition, and restoring oxygen levels is a common clinical approach. The state of hypoxia is linked to vasodilation, increased respiratory rate, and vascularization, as a means to fulfill energetic requirements. At the molecular level, oxidative phosphorylation in mitochondria is inhibited as a result of hypoxia, affecting adenosine triphosphate (ATP) production, that is critical for protein synthesis and maintaining ionic equilibrium (Páez-Franco et al., 2021). In COVID-19 patients, researchers found that there was a dysregulation in energy production pathways i.e. Warburg effect and Krebs cycle, and catabolism of branched chain amino acids, Glutamine (Gln), Glutamate (Glu), and Threonine (Thr). They traced the results of this metabolomics analysis to adverse effects such as the manifestation of neurological disabilities and diabetes. Researchers concluded that amino acid supplementation has potential relevance as an effective intervention in cases of SARS-CoV-2 infection.
Elevated Cysteine (Cys), Limited Intracellular Iron Availability, and Impaired Mitochondrial Respiration during Aging
Mitochondria are sites of cellular metabolism, and are involved in ATP production, and host amino acid pathways, nucleotide pathways, heme, lipid, and iron-sulphur cluster metabolism. Mitochondria participate in innate immunity, apoptosis, and reactive oxygen species (ROS) signaling. Mitochondrial decline is associated with aging and age-induced disease (Hughes et al., 2020). Researchers pointed at the function of vacuoles (acidic organelle) in metabolic signaling, protein degradation, and metabolite compartmentalization. They identified that mitochondrial health is maintained by vacuole acidification during aging. In yeast models, researchers discovered that lysosome-like vacuoles deteriorated during aging.
In their study, researchers demonstrated that mitochondrial deterioration during aging resulted from “amino-acid dependent limitation” and indicated that vacuoles could be integral to promoting mitochondrial health through subcellular compartmentalization, limiting amino acid toxicity (Hughes et al., 2020). On studying underlying molecular mechanisms from several angles related to Cys, iron, and amino acid metabolism, researchers concluded the possibility of amino acid toxicity in the absence of proper control of intracellular levels. In the present research, Cys was the driving factor for “iron and mitochondrial deficits in aging”. Cys was found to increase reactive oxygen species (ROS), impairing iron homeostasis, although the exact mechanism needs to be still determined. Lysosomal compartmentalization of Cys may be a key mechanism to minimize Cys toxicity.
Leucine (Leu) Supplementation for Lipid Metabolism Modulation and Energy Homeostasis
Energy store and maintainence of normal biological function is mediated by the complex biological process of lipid metabolism. Researchers hypothesized that Leucine (Leu) plays an important role in modulation of lipid metabolism and energy homeostasis. Leucine, an essential and branched-chain amino acid (BCAA) has anabolic effects on muscles, lipid metabolism, glucose tolerance, and insulin sensitivity (Zhang et al., 2020). Leu regulates protein metabolism, supplies oxidative energy (for utilization during hunger, stress, lactation, exercise), participates in lipid metabolism, and regulates immune function. Leu promotes homeostasis through comprehensive mechanisms.
Therefore, it must be noted that homeostasis mechanisms are influenced in numerous ways, in vivo and as a result of environmental factors, and amino acids form a major aspect of homeostasis mechanisms in the human system. Research evidence also indicates that appropriate amino acid supplementation can improve health outcomes. However, the optimal mechanism of administration of amino acids for availability in circulation and measurement needs to be examined further.
References
Gould, R. L., & Pazdro, R. (2019). Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis. Nutrients, 11(5). https://doi.org/10.3390/nu11051056
Hughes, C. E., Coody, T. K., Jeong, M.-Y., Berg, J. A., Winge, D. R., & Hughes, A. L. (2020). Cysteine Toxicity Drives Age-Related Mitochondrial Decline by Altering Iron Homeostasis. Cell, 180(2), 296–310.e18. https://doi.org/10.1016/j.cell.2019.12.035
Páez-Franco, J. C., Torres-Ruiz, J., Sosa-Hernández, V. A., Cervantes-Díaz, R., Romero-Ramírez, S., Pérez-Fragoso, A., Meza-Sánchez, D. E., Germán-Acacio, J. M., Maravillas-Montero, J. L., Mejía-Domínguez, N. R., Ponce-de-León, A., Ulloa-Aguirre, A., Gómez-Martín, D., & Llorente, L. (2021). Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID-19 patients. Scientific Reports, 11(1). https://doi.org/10.1038/s41598-021-85788-0
Roth, W., Zadeh, K., Vekariya, R., Ge, Y., & Mohamadzadeh, M. (2021). Tryptophan Metabolism and Gut-Brain Homeostasis. International Journal of Molecular Sciences, 22(6), 2973. https://doi.org/10.3390/ijms22062973
Zhang, L., Li, F., Guo, Q., Duan, Y., Wang, W., Zhong, Y., Yang, Y., & Yin, Y. (2020). Leucine Supplementation: A Novel Strategy for Modulating Lipid Metabolism and Energy Homeostasis. Nutrients, 12(5), 1299. https://doi.org/10.3390/nu12051299
