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SCIENTISTS are increasingly becoming aware of the exciting and

growing interface between inorganic chemistry and the living world. Nature has selected constituents from not only the organic but also the inorganic world to build the living organisms.

It is only in the 1980s that research on the role of metal ions in the biological system started gaining momentum. Recent research highlights the multidimensional role of metal ions in biological systems. A lot still remains to be unravelled though.

The elements can be broadly categorised into essential, non-essential and toxic.

Essential ElementsConsuming food without table salt would be unthinkable for most of us. But does salt just enhance taste or do the sodium and chloride ions have other important roles as well?

Our heart fl utters occasionally and some people suffer from heart arrhythmia (irregular heartbeats). The contraction and relaxation of heart muscle cells is precisely regulated by electrical impulses generated as sodium, potassium and calcium ions pass through complex molecular channels inside and between

cells. This passage of the ions is tightly regulated.

Professors Filip van Petegem and Christopher Ahern, members of University of British Columbia’s C a r d i o v a s c u l a r Research Group discovered in 2012 that the calcium-modulated protein calmodulin binds to the sodium channel, keeping them open. Calcium ions are responsible for binding the protein to the sodium channel, keeping it open and letting sodium through. Genetic mutations that change the shape of the sodium channel at the part where the protein binds result in disruption of the open/close mechanism of the channel causing irregular heartbeats.

Another study published in the Journal of Biological Chemistry in 2014, reports the structure of sodium channels, specifi cally one β-subunit, which is found to be responsible for ‘fi ne-tuning’ the activity of the channel. And recently, a study published in Osteoporosis International (January 2015) has found

that citrate and bicarbonate salts of potassium found in large quantities in fruits and vegetables prevent the onset of osteoporosis.

A Norwegian Institute of Public Health study in 2013 revealed that drinking water with a relatively high concentration of magnesium protects against hip fractures while a study by Japanese scientists published in the Journal of Biological Chemistry in 2010 indicates that it is actually the calcium channels on the tongue that are the targets of compounds that can enhance taste.

EKTA KUNDRA ARORA & VIBHA SHARMA

Elements play a very essential role in human nutrition, medicine and treatment methodologies. Recent research is throwing more light on their role in our life.

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EKTA KUNDRA ARORA & VIBHA SHARMA

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FEATURE ARTICLEThese wonder minerals are

very essential to our very survival. They are called the essential elements i.e. elements necessary for the proper functioning of the biological system. About 27 elements from the periodic table are required by most biological systems.

In fact, 99% of the human body is made of just four elements – hydrogen, oxygen, carbon and nitrogen. Others like copper, cobalt, zinc and iron are present in much smaller quantities. These biologically essential elements are therefore classifi ed as major or trace depending on the biological abundance, which may vary from organism to organism.

The trace elements are also as signifi cant as the bulk elements. Researchers led by Prof. Eva Wolf of Johannes Gutenberg-University Mainz, have identifi ed the molecular structure of a protein complex, which regulates the circadian rhythm. This complex contains a zinc ion (Cell, 2014). A study published by U.S. Department of Energy’s Lawrence Berkeley National Laboratory in 2013 revealed that proper copper levels are essential to the health of the brain at rest i.e. during sleep.

All elements of the second and third period, many 3d transition elements and a few heavier elements like bromine, iodine, molybdenum and tungsten are considered essential. The concentration range for these essential elements in the biological system is narrow and pathological conditions result due to defi ciency or excess of any of these.

Non-Essential ElementsIt is important to note that not all elements of the periodic table are used in biological systems. For use in a biological system the elements should be available for uptake i.e. abundant in nature and at the same time available in a form in which they are soluble and stable at the biological pH, in a predominantly aqueous environment. Elements that do not satisfy these conditions cannot be utilized by the biological systems and are hence non-essential.

An interesting example is that of titanium. It is the ninth most abundant element and the seventh most abundant metal in the Earth’s crust but still has no biological role to play. Titanium does not interact with the biological system or is biocompatible and hence has some novel

applications including titanium implants for joint replacement. Elements like lithium, platinum, rhodium, metastable technetium99 (an artifi cial element produced by a nuclear reaction) and others have important therapeutic and diagnostic roles.

Toxic ElementsThese elements are toxic even in minute quantities. They may enter the system through food, skin or respiration and have a very narrow concentration window in which they can be tolerated. Toxic elements like lead, cadmium, mercury and arsenic have received much attention because of the public health risks associated with them. The recent controversy highlighted the greater than permissible amount of lead being present in noodles of a particular brand. In fact, the WHO list of ten chemicals of major public health concern published in 2010 include arsenic, lead, cadmium and mercury.

Physiological Role of Essential ElementsOn an average 60% of the body weight is water which accounts for oxygen and hydrogen being bulk essential elements. Carbon forms the backbone of all organic molecules. Nitrogen is the building block of nucleic acids and amino acids. Phosphorus is found in bones as calcium phosphates and also in ATP (Adenosine Triphosphate). ATP is responsible for driving chemical reactions requiring energy in the body.

Chloride ions are the principle negatively charged ions in the body. They play an important role in the conduction of nerve impulses. Hydrochloric acid secreted in the stomach plays a vital role in digestion of food. Sulphur is found in

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Citrate and bicarbonate salts of potassium found in large quantities in fruits and vegetables prevent the onset of osteoporosis

Proper copper levels are essential to the health of the brain at rest i.e. during sleep

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amino acids like cysteine and methionine. The weight of the bulk essential elements per kilogramme of the body weight is shown in Table 1.

Some of the bulk and trace essential elements have signifi cant physiological role to play.

• Sodium and Potassium ions play important roles in signal transduction, neurotransmission and in maintaining the cell structure through osmotic balance.

• Calcium ions are known as the secondary messengers. Due to the insoluble nature of the phosphates of calcium it is used as a structural support material (biomaterial) in bones and teeth. Calcium ions are also important cofactors in the blood clotting cascade and are important in regulation of muscle contraction.

• Magnesium ions are abundant in the cytoplasm and bind ATP to stabilize it. They play an important role in regulating lipid and carbohydrate metabolism, bone and tissue formation, skeletal growth and reproduction.

• Iron ions take up oxygen from the lungs and transport it to the tissues where it is stored by myoglobin without undergoing any change in the oxidation state.

• Zinc (II) is a widely preferred choice for catalysing many chemical reactions in the biological systems.

• Cobalt is processed by microorganisms and ingested by higher organisms as

vitamin B12 where cobalt is present in the corrin ring.

• Chromium imbalance affects the sugar metabolism and hence it is known as the glucose tolerance factor in animals. Brewer’s yeast is a rich source of chromium (III) ions and is used as a supplement in diabetic patients.

• On the other hand chromium in the (VI) oxidation state i.e. as chromate ion is carcinogenic. It enters the cell by sulphate ion uptake pathway and is ultimately reduced to chromium (III) via a chromium (V) intermediate which binds to the DNA producing a kinetically inert and potentially damaging lesion.

• Small amounts of fl uoride help reduce tooth decay.

• The most important role of iodine is as a constituent of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

• Selenium also plays a very important role in the production of Glutathione, the body’s most powerful antioxidant required to eliminate hydrogen peroxide produced during formation of thyroid hormones.

• Only traces of silicon appear to be required by animals. Diatoms, some sponges and silicofl aggelates are known to have skeletal structures made of silica.

Defi ciency Disorders Dietary defi ciency of the essential metal ions per se or their improper regulation (absorbtion, storage and insertion into the proper environment to carry out the biological function) leads to diseases. The treatment of diseases associated with the defi ciency of these essential metal ions

constitutes an important part of medicinal bioinorganic chemistry.

Here are some examples of defi ciency of essential elements:

• Potassium defi ciency (hypokalemia) develops due to the over-excretion of potassium, which may be medication-induced e.g. due to diuretics or secondary to acute gastroenteritis. Fatigue, muscular weakness, confusion, anxiety, temporary memory loss, constipation and sleep disruption are some common symptoms associated with potassium defi ciency.

• Hypocalcemia (low level of calcium in the blood) can occur due to medications such as diuretics, renal failure or hypoparathyroidism. Low calcium levels lead to depletion of calcium stores in the bones resulting in thinning and weakening of the bones (Osteoporosis).

• Defi ciency of vitamin D, phosphorus or magnesium, all of which promote calcium absorption and use, can also cause calcium defi ciency.

• Anaemia associated with iron defi ciency results in insuffi cient oxygen supply because of a decrease in Haemoglobin levels. Many foods are therefore fortifi ed with iron and many iron supplements are available in the market.

• About 2 g of Zinc is required daily in our diet out of which only 15 to 20 mg

Table 1:

Amount of bulk essential elements in

g per kg body weightBulk Essential Amount in g Elements per kg body weightOxygen 650Carbon 180Hydrogen 100Nitrogen 30Phosphorus 10Calcium 15Potassium 2Chloride 1.7Sulphur 1.4Sodium 1.4Magnesium 0.5

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is absorbed. Zinc defi ciency results in growth retardation, skin lesions, poor appetite and loss of body hair.

• Copper is found in the brain and heart and defi ciency results in anaemia and brain diseases.

• Sodium defi ciency, called hyponatremia,is sometimes seen in those on salt-restricted diets to control high blood pressure and rarely in athletes who eat a large amount of fresh food (with very low sodium content) and drink copious amount of water along with strenuous exercise. Hyponatremia can cause the brain to swell with low energy and confusion being some symptoms.

Essential Metal Toxicity Excess consumption of essential elements in the diet and as mineral supplements or a result of metabolic disorders may lead to incapacitation of normal biochemical mechanisms that control the uptake and distribution.

• Excess consumption of sodium ion is associated with high blood pressure and fl uid retention which results in increased risk of heart failure, stroke and chronic kidney disease.

• Excess potassium ion level (hyperka-lemia) is usually caused by abnormal renal functioning, resulting in ineffective elimination of excess potassium from the body.

• Acute iron poisoning cases are common in developed countries due to accidental ingestion of large amount of iron supplements. Hemochromatosis arises as a result of excessive iron uptake from vessels used for cooking. It can corrode the gastrointestinal tract, deposit in liver, kidneys and heart, causing failure of these organs. A study published in Cell Metabolism, 2015 identifi es a protein ZIP14 which is responsible for carrying iron to the liver causing an overload in the organ paving ways for scientists to design

medications targeting ZIP14 to prevent iron overload in the liver.

• A genetically inherited metabolic defect in which copper cannot be tolerated at normal levels due to insuffi cient amount of storage protein ceruloplasmin results in the Wilson’s disease, which manifests as liver failure, neurological damage, brown and green rings in the cornea of the eyes, etc.

• Failure to regulate calcium levels leads to calcifi cation of tissues, formation of kidney stones, and cataract. Excess Zinc results in defi ciencies of other metal ions like calcium, iron and copper though this condition is extremely rare.

• Cobalt poisoning results in gastrointe- stinal distress and heart failure.

Metal Ions in Diagnostics & TreatmentSome metals and their ions play a crucial role as diagnostic agents. For instance, Technetium 99m complexes having radioactive nuclei fi nd many applications in tumor, organ and tissue imaging. They emit low energy gamma radiations that are detected by scintillation cameras to produce images.

Metal complexes of gadolinium (III), iron (III) and manganese (II) are used as contrast agents in Magnetic Resonance Imaging (MRI) to image tissues of biological specimens. Gadolinium (III) complexes have been used to image the brain, ferric (III) chloride the gastrointestinal tract and manganese (II) complexes the heart.

In barium meal follow through test, barium sulphate is administered orally before taking sequential X-ray of the digestive tract. Barium is an X-ray contrast medium, it enhances the visibility of the relevant parts of the gastrointestinal tract

by coating the inside wall of the tract and appearing white on the X-ray fi lm.

Therapeutic UsesApart from the metal ion supplements needed to make up for their defi ciency, metals have myriad therapeutic uses. Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs.

We are familiar with silver being used to prevent infections in burns patients. Zinc is also applied topically to heal wounds and in the ionic form to treat herpes. In fact, many transition metal complexes have antibacterial, antiviral, antifungal and anti-infl ammatory activities.

People with manic depressive disorder are administered lithium carbonate. Similarly, chrysotherapy has been used for many years for treating arthritic disorders in humans and animals. Gold (I) compounds are the only class of pharmaceuticals known to halt progression of rheumatoid arthritis, an autoimmune infl ammatory disease that affects tissues around joints. Sanochrysin, solganol, myochrysin, colloidal gold are some drugs available on doctor’s prescription.

The numerous elements around you, thus, have a very important role to play in the chemistry of life. As research in the fi eld progresses we will have a better understanding of the role of metal ions at a molecular level and in designing of newer medicines and diagnostic agents for a better tomorrow.

Dr. Ekta Kundra Arora (kundraekta@gmail.com) and Dr. Vibha Sharma (vibhasharmastephens@hotmail.com) are Assistant Professors in Chemistry, St. Stephen’s College, Delhi University, Delhi-110007

Titanium implants are used for joint replacement

FEATURE ARTICLE

Metal complexes are used as contrast agents in MRI to image tissues of biological specimens