Medical Science Essay Sample Paper on Glutathione

Glutathione

Introduction

Glutathione is a peptide component of cells, including strings of amino acids or blocks of proteins found in the body. Glutathione is vital in the human body due to various reasons. It acts as redox buffer as well as a cofactor for antioxidant and electrophile defenses and signal transduction mainly in the brain. Deregulating and deactivation of Glutathione can initiate and enhance spread of neurodegenerative diseases. Glutathione deregulation occurs through a process known as homeostasis. Conversely, deactivation is caused by dependent enzymes found in the Glutathione. Neurodegenerative diseases include Huntington’s, Parkinson’s, and Alzheimer’s diseases as well as Friedreich’s ataxia and Amyotrophic lateral sclerosis. Neurodegeneration is caused by multiple sclerosis often considered to be an autoimmune disease (Danyelle, Kenneth & Haim 2003, p. 146).

This research will therefore focus on Glutathione and its contributions towards biochemistry and cell biology either attributing to or preventing neurodegenerative diseases. Perspectives on Glutathione synthesis, regulation, and transportation mainly across the brain will be discussed thoroughly. Consequently, the functions of Glutathione as a redox buffer, signal transduction agent, and nucleophilic scavenger of electrophilic compounds will be presented. Impairments in Glutathione can also lead to disruption of thiol homeostasis, oxidative stress, and protein misfolding as well as aggregation. Thus, it is vital to discuss Glutathione as a therapeutic and/or biomarker agent (Volodymyr 2012, p. 1).

Components of Glutathione

According to Kelly Dorfman, Glutathione comprises of three amino acids. The amino acids are namely glycine, cysteine, and glutamic acid. Glutathione is grouped as an antioxidant. This is because its primary role involves alleviating stress. Thus, oxidative stress is a chemical compound occurring when body cells are injured either physically or by bacteria and viruses. Body cells can also be damaged from exposure to toxics and normal aging process. As a result, the body requires new body cells as the atoms in the damaged and injured cells loose electrons. Glutathione is an antioxidant due to presence of sulfur in L-cysteine with an electron known as thiol. Glutathione can detoxify mercury, lead, arsenic, and cadmium through provision of thiol binding metals and poisons. The combined components are excreted by the body as a mixture of metal-cysteine (Kelly 2005, p. 2).

Thus, insufficient Glutathione and other antioxidants can lead to storage of the heavy metals and toxins in fat tissues. The fat tissues include the brain, breasts, nervous system, and prostate. Consequently, the tissues become receptacles for environmental poisons. Decrease in autism, prostate and breast cancer incidences can therefore rely on reduction of environmental poisons Thus, components of Glutathione are tasked in preventing pathological conditions and diseases. The redox state of body cells minimizes commencement of oxidative stresses by supplementing with antioxidants such as Glutathione and N-acetyl-cysteine (NAC). Glutathione reduces lipid peroxidation of cellular membranes from oxidative stress while N-acetyl-cysteine (NAC) maintains metabolism. These functions occur from Glutathione synthesis (Kelly 2005, p. 2).

Synthesis of Glutathione

Glutathione is synthesized in cells comprising of intracellular concentrations ranging between 0.2 mM to 10 mM. Glutathione concentrations among major cells in the body are therefore between 1 mM and 2 mM. However, the concentrations in cerebral spinal fluids are higher at approximately 4 μM in order to correspond with the low amounts of intracellular Glutathione cells. Intracellular synthesis is vital as it maintains larger concentrations of Glutathione creating a link between amino moiety of cysteine and gamma-carboxyl moiety of glutamic acids (Koji, Masahiko & Toshio 2008, p. 227).

Rates of synthesizing Glutathione are dependent on two activities. They include enzyme activities with regard to γ-glutamylcysteine synthetase and availability and accessibility of cysteine. An enzymatic synthesis takes place in amino acid components namely cysteine, glycine, and glutamate. The synthesis occurs in sequel actions of double ATP dependent and cystosolic enzymes. A complete synthesis of Glutathione therefore involves a catalyst known as glutathione synthetase (GS). It converts γ-GluCys dipeptide into GSH through gamma carbon refractory of standard proteasis. This process relies on the addition of glycine. The enzymes involved cleave gamma links between glutamyl residues to amino acids mainly cysteine generating. Consequently, cysteinylglycine through an external dipeptidase is cleaved yielding free glycine and cysteine. Conversely, these dipeptidase products reenter body cells through amino acids upon which they are separated. The process is vital in recycling and reducing cysteine to yield glutamate (Dale, Shelly & Henry 2011, p. 6).

Thus, enzymes involved in Glutathione synthesis are controlled by multiple mechanisms either pre or/and post transcriptionally. The mechanisms enhance the importance of Glutathione in body cells. Environmental factors can also influence the synthesis process by regulating it at various levels. However, the processes ought to ensure synthesis of Glutathione involves protective reactions and export of products from body cells. Consequently, broken down components ought to regain entry into body cells through the transporting amino acids. The figure below summarizes synthesis of Glutathione (Koji, Masahiko & Toshio 2008, p. 229).

Synthesis of Glutathione (Dale, Shelly & Henry 2011, p. 19).

Glutathione Metabolism Process for Exogenous and Endogenous Compounds

Exogenous compounds are tasked in balancing oxidation and antioxidation of living systems. Antioxidants in human health are substances present at low concentrations compared to oxidizable compounds tasked in either delaying or preventing oxidative damages. The damages are often caused by presence of ROS/RNS (Jaouad & Torsten 2010, p. 228).  ROS refer to Reactive Oxygen Species while RNS are Reactive Nitrogen Species. They are both molecules with chemical reactive containing oxygen and nitrogen. They are natural by-products formed from a normal metabolism of oxygen with an important role of signaling cells and homeostasis. However, environmental stresses including exposure to heat and ultraviolent sunrays prompt ROS to increase significantly. This can lead to damage of cell structures due to oxidative stress. ROS including peroxides and oxygen ions can also be generated by ionizing radiation from exogenous sources. Thus, high doses of ROS therefore are poisonous as they exhibit path-physiological actions. Conversely, low doses are beneficial and recommended for normal physiological actions (Benoît & Michel 2007, p. 814).

 Exogenous compounds include vitamin C and E as well as polyphenols and carotenoids. Conversely, endogenous antioxidants either enzymatic or non-enzymatic such as catalase (CAT), Glutathione, superoxide dismutase (SOD), and Glutathione Peroxidase (GPx) are found in defense systems among human beings (Anna-Liisa 2000, p. 9). Both endogenous and exogenous compounds interact actively to re-establish and maintain redox homeostasis. This can be experienced in regeneration of vitamin E by Glutathione and/or vitamin C. These regenerated compounds are vital in preventing lipid peroxidation processes that can adversely affect membrane fluidity while damaging membrane proteins. Membrane proteins can be damaged through activation of receptors, ion and enzyme channels, and disruption of membrane integrity leading to death of major body cells. Consuming foods naturally rich in antioxidants and nutrients such as phytochemicals and vitamins is recommended. Human beings lack the ability to synthesize antioxidant compounds. Thus, foods such as onions, tomatoes, plums, potatoes, apples, and broccolis with natural sources of antioxidants can be helpful. However, Glutathione can also react with endogenous and exogenous compounds (Chad & Darryn 2005, p. 38).

Naturally, Glutathione reacts with endogenous and exogenous compounds forming adducts produced as by-products from free radical or high energy irradiation processes. These compounds are mainly cytotoxic and genotixic. Through Glutathione, the human body is detoxified resulting in radical damages, membrane decomposition and attacks on free radicals and other cells including DNA. The Glutathione metabolism process for exogenous and endogenous compounds involving synthesis and biological actions mediating responses from immunological and inflammatory stimuli involves white blood cells. White blood cells comprise monocytes, macrophages, eosinophils, neutrophils, and mast cells located in lungs, heart, brain, and spleen (Jaouad & Torsten 2010, p. 229). 

After the Glutathione metabolism, Leukotrienes are produced and released by body cells. Leukotrienes are derived from a polyunsaturated fatty acid plentiful in biological membranes known as arachidonic acid. Arachidonic acid is released at a position of membrane

Phospholipids due to stimulation of body cells and oxygenation subsequent dehydration of catalyzed 5-lipoxygenase-activating and 5-lipoxygenase proteins.  The Leukotrienes detectable in multiple body fluids are therefore formed after arachidonic acid is converted into unstable epoxide Leukotrienes (Jaouad & Torsten 2010, p. 229). 

Glutathione Role with ROS and RNS

ROS and RNS are Reactive Oxygen and Nitrogen Species respectively. ROS can cause either damaging effects on cell membranes or positive results like inducing host defense. This depends on sudden or chronic overconsumption of oxygen leading to production of free radicals known as ROS. ROS are produced from mitochondrial mechanism through which free radicals escape attacking enzymes while developing errors on the oxidative process. Body cells defend from ROS using enzymes such as superoxide dismutases, lactoperoxidases, alpha-1-microglobulin, catalases, and Glutathione. Vitamin C also known as ascorbic acid and tocopherol or Vitamin E as well as uric acid and Glutathione are also vital in the antioxidant process. They prevent ROS from damaging body cells through the free radicals (Benoît & Michel 2007, p. 813).

With regard to positive effects, ROS induce host defense. They prevent mobilization of ions and genes taking control of cellular functions. For example, platelets repair wounds while blood homeostasis releases ROS in order to gather more platelets incase of injuries in the future. Couple with leukocytes, the immune system consequently adapts.  These positive effects are coupled with Glutathione’s role as an antioxidant.  When Glutathione regulates immune responses, it also regulates prostaglandin metabolism and Leukotrienes. Consequently, the redox state of body cells is maintained. The figure below summarizes thiol redox status and the many roles accompanying presence of Glutathione (Chad & Darryn 2005, p. 40).

                                                                                                Thiol Redox Status

Cardiovascular diseases can be attributed to inflammatory responses from ROS/RNS cellular activities. This can also lead to hearing impairments due to cochlear damages from elevated sound levels. Critically, it can lead to heart attacks and stroke. Thus, ROS/RNS are more harmful than beneficial. They are continuous produced as by-products of either a response to stress or an aerobic metabolism. Very toxic ROS/RNS are rapidly detoxified by cellular enzymatic and non-enzymatic mechanisms. Glutathione synthesis is therefore essential in order to develop reactions and interactions controlling ROS/RNS to prevent biotic and abiotic responses. The responses refer to damages on cells leading to development of degenerative diseases in humans and processes in plants.  As a result, Glutathione undergoes the synthesis process to ensure ROS/RNS are less harmful and damaging. The synthesis process signals ROS/RNS as stress factors (William, Amy & John 2012, p. 1400).

Consequently, molecules effective in inducing molecules preventing cell deaths are rapidly generated by enzymes under metabolic control. Thus, ROS/RNS are restricted to stress responses. However, they can also interfere with growth and development stages among plants. ROS/RNS bioactivities rely on production and detoxification dependent on antioxidant defense. This requires enzymatic activities and antioxidant molecules including Glutathione. Thus, Glutathione, production of ROS/RNS and presence of antioxidant defense are active components in regulating environmental influences on cell and plant development. When ROS/RNS are combined with antioxidant defense, they attribute towards the redox balance for physiological regulations. Thus, effects of ROS/RNS differ among humans and plants. However, they can either be beneficial or harmful. As a result, presence of Glutathione is vital to control and regulate the effects. However, human beings ought to acknowledge environmental and dietary factors interfere with Glutathione levels in body cells. This is because ROS/RNS interfere with the role of Glutathione in plants. Thus, cellular dysfunctions and disruptions in growth and development of plants can be detrimental. It can lead to interference of Glutathione homeostasis. Consequently, environmental and dietary factors modifying enzymes dependent on Glutathione to initiate and progress prevention of neurodegenerative diseases can be deregulated inducing cellular problems (Nicolas, Chiara, Karine, Gilles, Alexandre, Emmanuel, Didier, Pierre & Alain 2006, p. 1771).

The figure below represents cellular effects from presence of ROS/RNS (Anna-Liisa 2000, p. 11).

Reactive Oxygen and Nitrogen Species Cellular Effects

Conclusion

Glutathione helps in maintaining healthy chemical and biological systems among human beings and plants. Through re-established redox homeostasis, high doses of antioxidant compounds are regulated. More so, phytochemicals and nutrients consumed from natural foods by human beings are safer and healthier enabling Glutathione to be a biomarker. This function is based on the role of Glutathione in preventing neurodegenerative diseases impacting multiple lives adversely. Thus, brain damage and biopsy of nerves among other neurodegenerative diseases can be controlled through Glutathione synthesis. These problems can further lead to mitochondrial dysfunctions, disrupted signal pathways, protein aggregation, damages to ROS and RNS and lastly cell death. Thus, Glutathione synthesis should not be interrupted to avoid nerve cell damages. More importantly, it is crucial to discover ways of either preventing or reversing the damages by developing effective therapies addressing neurodegenerative diseases.

References

Anna-Liisa, L 2000, Glutathione: Synthesis during Development and Metabolism in Experimental Hypertension, University of Helsinki.

Benoît, D & Michel, B. T 2007, ROS as Signaling Molecules: Mechanisms that Generate Specificity in ROS Homeostasis, Nature Reviews: Molecular Cell Biology, 8(1), 813-824.

Chad, K & Darryn, W 2005, The Antioxidant Role of Glutathione and N-Acetyl-Cysteine Supplements and Exercise-Induced Oxidative Stress, Journal of the International Society of Sports Nutrition, 2(2), 38-44.

Dale, A. D., Shelly, C. L & Henry, J. F 2011, Gluthione: Synthesis, The Virtue Free Radical School.

Danyelle, M. T., Kenneth, D. T & Haim, T 2003, The Importance of Glutathione in Human Disease, Biomedicine & Pharmacotherapy Review. 57(1), 145–155.

Jaouad, B & Torsten, B 2010, Exogenous Antioxidants—Double-Edged Swords in Cellular Redox State: Health Beneficial Effects at Physiologic Doses versus Deleterious Effects at High Doses, Oxid Med Cell Longev. 3(4), 228-237.

Kelly, D 2005, Understanding Glutathione, New Developments Review, 10(2).

Koji, A., Masahiko, W & Toshio, N 2008, Regulation of Neuronal Glutathione Synthesis, Journal of Pharmacological Sciences, 108(1), 227 – 238.

Nicolas, P., Chiara, P., Karine, M., Gilles, I., Alexandre, J., Emmanuel, B., Didier, H., Pierre, F & Alain, P 2006, Reactive Oxygen and Nitrogen Species and Glutathione: Key Players in the Legume–Rhizobium Symbiosis, Journal of Experimental Botany, (57)8, 1769–1776.

Volodymyr, I. L 2012, Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions, Journal of Amino Acids.

William, M. J., Amy, L. D & John, J. M 2012, Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases, Journal of Nutrients, 4(1), 1399-1440.