Calcium: Ca2+
Calcium ion (Ca2+) is an extremely critical mineral required for a vast array of biochemical processes. Some of the most wide-spread functions for this ion are its requirements for neural signaling, cell proliferation, bone mineralization, cardiac function, muscle contraction, digestive system function, and secretory processes. In the context of Ca2+ in secretion, the ion is required for neurotransmitter release and hormone release from a number of different tissues. In addition, calcium is necessary for proper activity of a number of proteins involved in blood coagulation. Calcium concentrations in the blood are very tightly regulated within a narrow range. Within the blood over half of the Ca2+ is free while the rest is bound to albumin or complexed with other ions such as bicarbonate and phosphate.
Calcium functions both intracellularly and extracellularly. As an intracellular ion, Ca2+ serves the role of a second messenger. The difference between the Ca2+ concentration outside the cell, within the interstitial fluids, is on the order of 12,000 times that of the free intracellular concentration. This difference creates an inwardly directed electrical gradient as well as allowing for dramatic influxes of the ion in response to a variety of cellular stimuli. Within the cell, most calcium is not free in the cytosol but is stored within the endoplasmic reticulum (ER) and other microsomal (membrane) compartments. This calcium is able to be rapidly mobilized to the cytosol via the activation of ligand-gated ion channels. One of the most significant events resulting in intracellular calcium release is the plasma membrane receptor-mediated activation of phospholipase Cβ (PLCβ) in response to ligand (e.g. hormone) binding. Active PLCβ, in turn, hydrolyzes membrane phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 binds to receptors in the ER, activating the inherent calcium channel of the receptor leading to the flooding of the cytosol with free calcium.
Humans express three distinct IP3 receptors encoded by the ITPR1, ITPR2, and ITPR3 genes. The ITPR1 gene is located on chromosome 3p26.1 and is composed of 63 exons that generate three alternatively spliced mRNAs encoding three distinct isoforms of the receptor. ITPR1 isoform 1 is a 2710 amino acid protein, isoform 2 is a 2695 amino acid protein, and isoform 3 is a 2743 amino acid protein. The ITPR2 gene is located on chromosome 12p11.23 and is composed of 62 exons that encode a 2701 amino acid protein. The ITPR3 gene is located on chromosome 6p21.31 and is composed of 60 exons that encode a 2671 amino acid protein. Each of the IP3 receptors possess a cytoplasmic N-terminal ligand-binding domain and is comprised of six membrane-spanning helices that forms the core of the ion pore. Once released, the free calcium interacts with a variety of proteins activating a series of biochemical reactions specific to the particular cell type and the signal initiating the calcium release.
Calcium exerts many of its biochemical effects by binding to Ca2+-binding proteins, several of the most significant are outlined in the following Table. The vast majority of proteins, whose activities are controlled by Ca2+ binding, contain a structural motif referred to as the EF-hand. The EF-hand domain consists of two regions of α-helix linked by a short (usually 12 amino acids) loop region. These EF-hand proteins are found both intracellularly and extracellularly. The superfamily of human EF-hand domain containing proteins consists of 222 proteins with an additional subset of four actinin proteins included in the superfamily. The total number of proteins that bind calcium is beyond the scope of this discussion but several important examples of intracellular Ca2+-binding proteins include the calmodulins, calcineurins, calbindins, and troponins, whereas important extracellular Ca2+-binding proteins include the coagulation factors [II (prothrombin), VII, IX, X, protein C, protein S] and the cell-cell communication/adhesion proteins of the cadherin family.
Chlorine
Chlorine (as chloride ion: Cl–) is a major ion necessary for digestive processes as it is required for the formation of gastric acid (HCl) within the lumen of the stomach. The majority of the chloride ion in the body is found in the extracellular fluid compartment. Chloride ion represents approximately 3% of the total electrolyte composition of the human body. Chloride ion functions along with sodium ion (Na+) and potassium ion (K+) in the maintenance of electrolyte balance. Chloride ion is required for the function of several ligand-gated ion channels. Of particular importance is the role of Cl– in the function of the inhibitory neurotransmitter, GABA (γ-aminobutyric acid). The GABA-A receptor is a Cl– channel that, in response to GABA binding induces an inward flux of Cl– into the neuron.Magnesium
Phosphorous
Phosphorous is the most important systemic electrolyte acting as a significant buffer in the blood in the form of phosphate ion: PO43– as well as the monobasic (HPO42–) and dibasic (H2PO4–) forms. In the context of biological systems, phosphate ion is commonly referred to as inorganic phosphate and written as Pi which is used to designate all phosphate ion forms. In addition to its role as a critical blood buffer, phosphate is required in the biosynthesis of cellular components, such as ATP, nucleic acids, phospholipids, and proteins, and is involved in many metabolic pathways, including energy transfer, protein activation, and carbon and amino acid metabolic processes. Phosphate is also required for bone mineralization, and is necessary for energy utilization. One of the most important metabolic reactions that requires Pi is the phosphorolytic cleavage of glucose from glycogen by the enzyme glycogen phosphorylase.In order to carry out its functions in metabolic processes, serum and intracellular Pi levels are maintained within a narrow range via a complex interplay between intestinal absorption, bone storage, and intracellular exchange. Hormonal control of phosphate levels is exerted primarily via the actions of vitamin D and parathyroid hormone within the proximal tubules of the kidneys.
Potassium: K+
Potassium ion is a key circulating electrolyte as well as being involved in the regulation of ATP-dependent channels along with sodium ion. These channels are referred to as Na+/K+-ATPases and their primary function is in the regulation of electrochemical gradients between the inside of cells and the interstitial spaces particularly in the brain and the kidney tubule. Numerous other forms of potassium channels utilize this ion to regulate action potential propagation in the context of the transmission of nerve impulses in the brain and in the control of cardiac muscle and skeletal muscle activity. Potassium ions represent approximately 5% of the total electrolyte pool in the human body. The majority of potassium ion in the body is found intracellularly. The average intracellular potassium concentration in around 150mM, whereas the concentration of potassium in the blood is only around 3.5mM–5mM.Sodium: Na+
Sodium ion is a key circulating electrolyte and also functions in the regulation of Na+/K+-ATPases with potassium ion. Sodium ions represent approximately 2% of the total electrolyte composition in the human body. Along with chloride ion (Cl–) and potassium ion (K+), sodium ion is required for normal cellular osmolarity, maintenance of normal water distribution and water balance in the body, and maintenance of normal acid-base balance. Sodium ions are also critical to the initiation of action potentials in the context of nerve transmission, cardiac muscle, and skeletal muslce activity. The majority of the total body sodium ion is found in the extracellular fluids. The intracellular Na+ concentration is around 10mM while the concentration in the blood is around 135mM–145mN. The functions of the Na+/K+-ATPases in the body are numerous with primary roles being in the processes of nerve transmission in the central and peripheral nervous systems, in the functioning of muscle cells, in particular cardiac muscle function, and in the regulation of fluid and ionic balance via the kidneys.Sulfur
Sulfur has a primary function in amino acid metabolism (methionine and cysteine) but is also necessary for the modification of complex carbohydrates present in proteins (glycoproteins) and lipids (glycolipids), however, it should be noted that in this latter function the sulfur is donated from the amino acid methionine.Copper
Copper is involved in the formation of red bloods cells, the synthesis of hemoglobin, and the formation of bone. Additional functions of copper are energy production, wound healing, taste sensation, skin and hair color. Copper is also involved in the proper processing of collagen and elastin via the action of the extracellular matrix-associated enzyme, lysyl oxidase. Thus, copper is critical to the proper production of connective tissue.Iodine
Iodine is required for the synthesis of the thyroid hormones and thus plays an important role in the regulation of energy metabolism via thyroid hormone functions.Iron: Fe2+ and Fe3+
Iron is the most abundant trace metal in the human body. Iron (as the ferrous ion, Fe2+) is a critical micronutrient with a major role in the transport of oxygen. Iron is the functional center of the heme moiety found in each of the protein subunit of hemoglobin. The function of Fe2+ is to coordinate the oxygen molecule into heme of hemoglobin so that it can be transported from the lungs to the tissues. Aside from its role in oxygen transport, iron is critical to the overall process of oxidative phosphorylation where it is also found in the heme of cytochromes and in the Fe-S (iron-sulfur) centers of the various complex of oxidative phosphorylation. Iron is the only metal in the human body that is toxic if allowed to remain free in the plasma or the fluid compartments of cells. The toxicity of free iron is related to its ability to rapidly generate the highly toxic hydroxyl free radical (HO⋅) via the Fenton reaction. For this reason there are extremely tight controls on overall iron homeostasis. The regulation of iron homeostasis is discussed in the Porphyrin and Heme Metabolism page.Manganese
Manganese is involved in reactions of protein and fat metabolism, promotes a healthy nervous system, and is necessary for digestive function, bone growth, and immune function. Maintenance of blood glucose levels is controlled in large part via the ability of the liver to produce glucose from precursor carbon atoms in the pathway of gluconeogenesis. Two of the enzymes of gluconeogenesis, pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK) require manganese for their activity. Within the liver, kidneys, and brain manganese is critical in the regulation of ammonium ion (NH4+) levels via its role activating glutamine synthetase. Within the liver, manganese plays an additional role in the regulation of NH4+ levels in the body via its activation of the urea cycle enzyme arginase. Manganese also serves as an important anti-oxidant mineral since it is necessary for the proper function of mitochondrial superoxide dismutase (SOD2) which catalyzes the same reaction as that catalyzed by the cytosolic version, SOD1 (see Table above in Copper discussion).Molybdenum
Molybdenum is primarily involved as a co-factor in oxidase enzymes such as xanthine dehydrogenase/oxidase necessary for purine nucleotide catabolism. Molybdenum is also a necessary cofactor in the detoxification reactions catalyzed by sulfite oxidase. Sulfite oxidase is the terminal enzyme in the pathways of the metabolism of sulfur-containing compounds such as the amino acid cysteine. The product of the sulfite oxidase reaction, sulfate, is then excreted.Selenium
Selenium serves as a modifier of the activity of several enzymes through its incorporation into protein in the form of selenocysteine. The mechanism for selenocysteine incorporation during protein synthesis is described in the Protein Synthesis page. Two critical re-dox enzyme families that require selenocysteine residues are the glutathione peroxidase and thioredoxin reductase families. Glutathione peroxidase is a critical enzyme involved in the protection of red blood cells from reactive oxygen species (ROS). This enzyme is a component of a re-dox system that also involves the enzyme glutathione reductase and NADPH as the terminal electron donor. This system is required for the continued reduction of oxidized glutathione (GSSG) and represents the single most significant system requiring continued glucose metabolism via the Pentose Phosphate Pathway in erythrocytes as the means for the production of the NADPH. Glutathione (GSH) becomes oxidized in the context of reducing various ROS and peroxides and to continue in this capacity the oxidized form needs to be continously reduced. Humans express eight different glutathione peroxidase genes identified as GPX1 through GPX8, with five of these enzymes (GPX1, GPX2, GPX3, GPX4, and GPX6) having been demonstrated to harbor selenocysteine residues. The enzyme encoded by the GPX1 gene (GPx1) is found in the cytosol of nearly all cell types in humans. GPx1 functions almost exclusively to reduce hydrogen peroxide (H2O2) to water. The protein encoded by the GPX3 gene, GPx3, is an extracellular enzyme found primarily in the plasma. The GPX4 encoded enzyme, GPx4, is localized to the intestines and is an extracellular enzyme as well. The GPX1 gene is located on chromsome 3p21.3 and is composed of 2 exons that generate two alternatively spliced mRNAs. The GPX1 coding region contains a polyalanine tract in the N-terminal region of the protein. There are several alleles of this gene that have five, six, or seven alanine repeats. The allele with five alanine repeats has been shown to be highly correlated to increased risk for development of breast cancer. The GPX2 gene is located on chromsome 14q24.1 and is composed of 4 exons. The GPX3 gene is located on chromsome 5q33.1 and is composed of 5 exons. The GPX4 gene is located on chromsome 19p13.3 and is composed of 8 exons. The GPX5 gene is located on chromsome 6p22.1 and is composed of 7 exons. The resultant GPX5 mRNA does not contain the canonical selenocysteine codon (UGA) and thus, the resulting protein does not contain a selenocysteine residue. Expression of the GPX5 gene is regulated by androgens and the gene is expressed exclusively in the epididymis in the male reproductive tract where the expressed protein, GPx5, is involved in protecting spermatazoa membranes from the damaging effects of lipid peroxidation. The GPX6 gene is located on chromsome 6p22.1 and is composed of 5 exons. GPX6 expression is restricted to embryonic tissues and the adult olfactory system. The GPX7 gene is located on chromsome 1p32 and is composed of 3 exons. The GPX8 gene is located on chromsome 5q11.2 and is composed of 3 exons.As the name of the enzyme implies, thioredoxin reductase is involved in the reduction of thioredoxin which itself is principally involved in the reduction of oxidized disulfide bonds in proteins. The reduction of these disulfide bonds results in oxidation of thioredoxin which then is reduced by thioredoxin reductase. The overall process, like the glutathione peroxidase system, requires NADPH as the terminal electron donor for the reduction process. A critically important reaction that is coupled to the thioredoxin system is the formation of deoxynucleotides. Humans contain three thioredoxin reductase genes that encode three distinct enzymes identified as TrxR1, TrxR2, and TrxR3. The TrxR1 enzyme is functional in the cytosol and is primarily involved in the maintenance of the ribonucleotide reductase system. The TrxR2 enzyme is functional in the mitochondria where it is principally involved in the detoxification of reactive oxygen species (ROS) produced in this organelle. TrxR3 is a testes-specific isoform of the enzyme. The TrxR1 enzyme is encoded by the TXNRD1 gene located on chromosome 12q23–q24.1 and is composed of 18 exons that generate several alternatively spliced mRNAs encoding five different isoforms of TrxR1. The TrxR2 enzyme is encoded by the TXNRD2 gene located on chromosome 22q11.21 and is composed of 19 exons that generate two alternatively spliced mRNAs resulting in two different isoforms of TrxR2. The TrxR3 enzyme is encoded by the TXNRD3 gene located on chromosome 3q21.3 and is composed of 16 exons that generate two alternatively spliced mRNAs resulting in two different isoforms of TrxR3.
The enzymes of the deiodinase family are also important selenocysteine-containing enzymes. Clinically relevant enzymes in this family are the thyroid deiodinases that are critical for the maturation and catabolism of the thyroid hormones. Humans express three different thyroid deiodinase genes identified as DIO1, DIO2, and DIO3. The enzyme encoded by the DIO1 gene, thryroxine deiodinase type I (also called iodothyronine deiodinase type I) is involved in the peripheral tissue conversion of thyroxine (T4) to bioactive form of thyroid hormone, tri-iodothyronine (T3). In addition to its role in the generation of T3, thyroxine deiodinase I is involved in the catabolism of thyroid hormones. The enzyme encoded by the DIO2 gene, iodothyronine deiodinase type II, is also involved in the conversion of T4 to T3 but does so within the thyroid gland itself. The activity of iodothyronine deiodinase II has been associated with the thyrotoxicosis of Graves disease. The enzyme encoded by the DIO3 gene is involved only in the inactivation (catabolism) of T3 and T4. Expression of the DIO3 gene is highest the female uterus during pregnancy and in fetal and neonatal tissue suggesting a role for this enzyme in the regulation of thyroid hormone levels and functions during early development. The DIO1 gene is located on chromosome 1p33–p32 and is composed of 4 exons that generate four alternatively spliced mRNAs. The DIO2 gene is located on chromosome 14q24.2–q24.3 and is composed of 6 exons that generate four alternatively spliced mRNAs. The DIO3 gene is located on chromosome 14q32 and is an intronless gene (is a single exon gene) that encodes a protein of 304 amino acids.
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