The role of zinc in health and disease

The role of zinc in health and disease

The Role of Zinc in Health and Disease

Introduction

Zinc is an essential mineral for both animals and plants.It is found in several body tissues,including the brain, muscle, bone, prostate, liver and kidney.It is important for several body functions, including human growth and development,immunity,and mainetenance of glucose levels.This is regulated by its role in enzyme functions and DNA replication.Its deficiency can lead to many disorders.1

Zinc is required by more than 50 different types of enzymes, for their functioning.It has an electronic configuration of [Ar]3d104s2, as shown in Figure 1, making it a moderately reactive metal.

Zinc has 35 neutrons, 30 protons and 30 electrons. It has 3 full shells of electrons and a partially-filled 4th shell.

Its role in the human body is, however, dominated by its +2 oxidation state. This oxidation state is formed by the outer shell s losing its electrons. The resulting zinc ion has an electronic configuration of [Ar]3d,10 as shown in Figure 2. This allows zinc to become much more reactive , through the formation of four covalent bonds.

The zinc cation has the same number of protons and neurons as zinc, but has 28 electrons. The electrons of the 4th shell have been removed, leaving it with 3 full shells of electrons.8

The stereochemistry of structures containing the zinc ion is therefore tetrahedral. Zinc is also able to forms stable structures with common macromolecules, especially those containing sulphur and nitrogen atoms;its complexes contain 4 or 6 coordinate bonds, the most common one being [Zn(H2O)6]2+ in aqueous solution,as shown in Figure 3.

The zinc ion has formed 6 coordinate bonds with 6 water molecules. The different shapes of the bonds represent a different 3D plane of the molecule.

Role in Enzyme Action

Zinc occurs in the active of several metallo-enzymes, in the form of the cation Zn2+.1 It is present in all six enzymes classes, as established by the International Union of Biochemistry.7 It is able to function at a biological pH, as it is an aqua ion with a modest affinity for OH-, which increases its acidity. This increase in acidity is important as studies have shown that replacement of Zn2+ with the less acidic cadmium ion, Cd2+, produces enzymes that do function, but only at a higher pH.

There are two unique properties of zinc that makes it essential for so many biochemical systems.7 Firstly, its homoeostatic mechanisms efficiently maintain its levels in various tssues and cells (leading to less danger of toxicity), as opposed to several others metals. Secondly, its general stability with macromolecules and its flexibility regarding coordination bonds makes it very adaptable to the various and differing functions of enzymes.

Carbonic anhydrase

Carbonic anhydrase is a metallo-enzymethat is present in red blood cells, parietal cells and renal tubular epithelia cells.3 It catalyzes the reaction between carbon dioxide and water to form bicarbonate ions and protons, and increases its rate about 5000-fold,as shown in Figure 4.

CO2 + H2O ↔ HCO3− + H+

Figure 4. Equation of Carbon Dioxide and Water.

Carbonic anhydrase catalyzes this reaction.

Carbonic anhydrase has a secondary structure consisting mostly of a 10-stranded β-sheet.15 The zinc ion is part of the active site.13 It is coordinated to three histidyl residues and a solvent molecule (usually a hydroxide molecule) 15 as shown in Figure 5.

The mode of action of carbonic anhydrase involves an attack on a CO2 molecule (loosely bound in a hydrophobic pocket) by a zinc-bound OH- ion. This results in a HCO3− ion coordinated to zinc, and is displaced from the metal ion by H2O. 15

Figure 5. Active site of Carbonic Anhydrase.

The active site of carbonic anhydrase: the purple molecule is the zinc ion being coordinated by three histidine residues (in pink) and a hydroxide group (red and white).

Zinc-finger motif

Zinc-finger motif is one of the three unique motifs (the other two are ‘helix-turn-helix' and ‘leucine-zipper') involved in the control of transcription,3 by regulating gene transcription using hormonal signals. Zinc finger-motif is in particular involved with Protein TF III A.20 It requires zinc for its role as a positive regulator of 5 S RNA transcription.

The structure of zinc-finger motif is an α-helix and β-sheet (two secondary structures of proteins) held in position by a zinc ion, as shown in Figure 6. It contains a tetrahedral metal-binding site, with zinc forming coordination bonds with nitrogen and sulphur atoms, and being held in position by cystine and histidine residues. It binds to DNA through the interaction of amino acids at the periphery of the zinc finger with base pairs at the centre of the DNA double helix.

α-helix and β-sheet structures, being held in position by the central zinc ion.

The zinc ion has completely-filled d-orbitals of electrons, which stabilizes its ligand-filed energy and makes it a suitable ion for this motif. This makes the motif have an enthaplic advantage.

Role in the Brain

Zinc is present in the synaptic vesicles of glutamergic neurons. It is released by electrical stimulation and serves as a neuro-modulator at receptors for a variety of different neurotransmitters. But this only consititues to 8% of zinc levels in the brain. The remainder of the zinc is bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity.

The metabolism of zinc in the brain is regulated by transpot proteins. ZrT1, a zinc transporter, efluxes zinc from the cell and combines with apothionein to form metallothlonein. Metallothloneien incorprotaes zinc into protiens, including several DNA transcription factors. However, under oxidative stress, zinc is readiy released from metallothlonein by disulphides. This may be hazardous, as a relationship exists between oxidative stress and Alzheimer's Disease. 2

Alzheimer's Disease

Alzheimer's diesase (AD) is the most common form of dementia.It is characterized by the loss of neurons and synapses in the cerebral cortex and the accumulation of plaques. Plaques are abnormally folded tau and beta-amyloid (Aβ amyloid) proteins. Aβ amyloid is a fragment of a larger protein called called amyloid precursor protein (APP), which is critical for neuron growth. During AD, APP is divided into smaller fragments of Aβ amyloid.

Zinc has been shown to aggregate Aβ amyloid., The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the APP gene.21 Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. 2

Role in Insulin Secretion

Insulin is the hormone that regulates blood-glucose levels. It is released by the β-cells of the Islets of Langerhans in the pancreas.

Zinc participates in the storage and secretion of insulin,3 although it is unknown how.However, it is known that within the β-cells are insulin-containing secretory vesicles, where zinc is required for zinc-insulin crystallization.6 Within each vesicle, six insulin molecules form solid hexamers with two Zn2+ ions, as shown in Figure 7. This crystal structure remains stable until secretion (stimulated by high glucose blood-level). After stimulation, zinc is secreted locally in the extracellular matrix together with the insulin.It has been suggested that the co-secreted zinc plays a role in regulating glucagon secretion by α-cells.It is proposed that by being involved in islet cell paracrine communication of KATP channels, it exerts a negative control on the secretory process. Zinc may also contribute to beta cell death by a paracrine mechanism. 25 This theory is supported by the fact that release of insulin simultaneously lowers the zinc content in the pancreas. 3

Figure 7. A zinc-insulin hexamer

A hexamer consisting of a Zn2+ and 3 insulin molecules. There are 2 hexamers in one secretory vesicle

Diabetes

There are 2 types of diabetes. In Type 1, there is a lack of insulin production. In Type 2, the body resists the effects of insulin. However, a cause and effect relationship between zinc and diabetes has not been established.Zinc deficiency, however, is related to Type 2 diabetes. It is clear zinc has an important role in the synthesis, storage and secretion of insulin. The decreased zinc content may affect the ability of the islet cell to produce and secrete insulin. 25 It is for this reason that protamime zinc-insulin and globin zinc insulin, two proteins used in the treatment of Type 2 diabetes, contain zinc ions for their functioning.

Zinc Deficiency

Zinc deficiency is very widely prevalent throughout the world.1 It is more prevalent in developing countries, due to the consumption of protein cereals.2 These diets contain high phosphate and phytate content1, which impair the absorption of zinc and also iron.The required zinc uptake is higher for infants and women who are pregnant and lactating.2 The Recommended Dietary Allowance (RDA) for adults is 8 mg/ day for women and 11 mg/day for men.

Prasad et al have shown zinc deficiency may lead to dwarfism and hypogonadism (underproduction of testosterone).In such dwarfs, zinc concentration in plasma, red blood cells, hairs, urine and faeces was found to be less than control subjects. However, zinc supplementation caused improved growth.4 This is because zinc finger protiens are involved in the synthesis of DNA and RNA, and cell division.This also explains why zinc deficiency also affects the development of accquired immunity by preventing the outgrowth and activation of T lymhocyte, Th1 cytokine production, B lymphocyte devolopment and immunoglobulin G production. 5

Zinc deficiency also causes other serious illnesses,1 as shown in Table 1.

Mild Zinc Deficiency

Moderate Zinc Deficiency

Severe Zinc Deficiency

Oligospermia

Growth retardation

Bullous-Pustular dermatitis

Hyperammonemia

Hypogonadism in males

Hypogonadism in males

Weight loss

Skin changes

Weight loss

Poor appetite

Alopecia

Mental lethargy

Diarrhoea

Delayed wound healing

Emotional disorder

Taste abnormalities

Cell mediated immune disorder

Abnormal dark adaptation

Cell mediated immune disorder

Table 1. Diseases of Zinc Deficiency related to Nutrition.

The Table has classified the diseases into 3 categories, according to clinical manfestation. Normal plasma levels of zinc are 67mcg/dl - 183mcg/dl

Zinc Toxicity

Large oral doses of zinc salts causes gastrointestinal disorders including vomiting and diarrhoea.This is because zinc is a strong Lewis acid, so it dissolves readily in stomach acid (hydrochloric acid) to produce corrosive zinc chloride, which causes damage to the stomach lining.However, chronic zinc poisoning has not been described in humans. Highly elevated serum zinc has been reported among some patients treated from renal failure by dialysis.

Conclusion

Various studies have established the role of of zinc as an essential micronutrient for healthy life. Major cellular metabolic functions are dependant on it. Its deficiency leads to multiple system disorders leading to grave consequences for human health. Understanding the biological role of zinc has essentially played an important role in research to mitigate zinc deficiency.

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