<br><h3> Chapter One </h3> <b>An Overview of Metals in Biology <p> <p> INTRODUCTION</b> <p> The importance of metals in biology, the environment and medicine has become increasingly evident over the last 25 years. The movement of electrons in the electron-transfer pathways of photosynthetic organisms and in the respiratory chain of mitochondria, coupled to proton pumping to enable the synthesis of ATP, is carried out by iron- and copper-containing proteins (cytochromes, iron–sulfur proteins and plastocyanins). The water-splitting centre of green plants (photosystem II), which produces oxygen, is based on the sophisticated biological use of manganese chemistry. Metals such as cadmium, manganese and lead in our environment represent a serious health hazard. Cadmium is present in substantial amounts in tobacco leaves, so that cigarette smokers on a packet a day can easily double their cadmium intake. Yet, while many metals are toxic, many key drugs are metal based—examples are cisplatin and related anticancer drugs, and lithium carbonate, used in the treatment of manic depression. Paramagnetic metal complexes are widely used as contrast agents for magnetic resonance imaging (MRI). Numerous trace metals are also required to ensure human health; and while metal deficiencies are well known (for example inadequate dietary iron causes anaemia), it is evident that excessive levels of metals in the body can also be toxic. <p> It has been clear from the outset that the study of metals in biological systems can only be approached by a multidisciplinary approach, involving many branches of the physical and biological sciences. The study of the roles of metal ions in biological systems represents the exciting and rapidly growing interface between inorganic chemistry and the living world. It has been defined by chemists as bioinorganic chemistry, and by biochemists as inorganic biochemistry. From 1990 to 1997 the European Science Foundation funded a programme on the Chemistry of Metals in Biological Systems. This resulted, in the course of what turned out to be monumentally important meeting held in the Tuscan town of San Miniato, in the launching of important initiatives around the international consensus name `Biological Inorganic Chemistry'. The outcome was the creation of the Society of Biological Inorganic Chemistry (SBIC) and the Journal of Biological Inorganic Chemistry (JBIC). These then joined the already existing International Congress of Biological Inorganic Chemistry (ICBIC) and European Congress of Biological Inorganic Chemistry (EUROBIC) to form a series of acronyms; all now use the stylized French word for a ballpoint pen `bic' to designate the term biological inorganic chemistry. I use this definition in this book, but would like to indicate to the prospective reader that this text will deal to a much greater extent with the biochemical aspects of metals in living systems rather than with their inorganic chemistry. <p> <p> <b>WHY DO WE NEED ANYTHING OTHER THAN C, H, N AND O (TOGETHER WITH SOME P AND S)?</b> <p> Organic is defined as `designating the branch of chemistry dealing with carbon compounds', or `designating any chemical compound containing carbon', although the interesting codicil is added, in the latter definition, that some of the simple compounds of carbon, such as carbon dioxide, are frequently classified as inorganic compounds. Of course, in the world of organic foodstuffs (grown with only animal or vegetable fertilizers) the word takes a broader connotation, signifying production from the detritus of living organisms. And, when we come to examine the biotope, we quickly perceive that carbon alone does not suffice for life. We also need oxygen, hydrogen, nitrogen, a non-negligible dose of phosphorus, as well as some sulfur. <p> But these elements alone do not enable life as we know it to exist, in its multiple and varied forms we need components of inorganic chemistry as well. If we were to ask for a definition of inorganic chemistry (previously defined in French as mineral chemistry), we would find ourselves confronted with a world that was not organic, nor of animal or vegetable origin-most inorganic compounds do not contain carbon, and are derived from mineral sources. Yet this inanimate chemistry, apparently with nothing to do with living systems, has a crucial role to play in our understanding of the biological world. So we can recognize that in the course of evolution, Nature has selected constituents not only from the organic world but also from the inorganic world to construct living organisms. Some of these inorganic elements, such as sodium and potassium, calcium and magnesium, are present in quite large concentrations, and tend to be known as `bulk elements', on a scale with those cited in the first paragraph. Others, such as cobalt, copper, iron and zinc, are known as `trace elements', with dietary requirements that are much lower than the bulk elements. <p> Indeed, the human body is made up of 99.9% of just 11 elements, 4 of which (hydrogen, oxygen, carbon and nitrogen) account for 99% of the total (62.8%, 25.4%, 9.4% and 1.4%, respectively). Why we require as many as 25 elements in total from the periodic table will become clearer as we advance in this chapter, but one thing shines out, namely that these elements have been selected on the basis of their suitability for the functions that they are called upon to play, in what is predominantly an aqueous environment. <p> Na<sup>+</sup> and K<sup>+</sup> (together with H<sup>+</sup> a nd Cl<sup>-</sup>), which bind weakly to organic ligands (Table 1.1), are ideally suited in generating ionic gradients across membranes and for the maintenance of osmotic balance. In contrast, Mg<sup>2+</sup> and Ca<sup>2+</sup> with intermediate-binding strengths to organic ligands, can play important structural roles, and in the particular case of Ca<sup>2+</sup>, serve as a charge carrier and a trigger for signal transmission. Zn<sup>2+</sup> not only plays a structural role but can also fulfil a very important function as a Lewis acid. Redox metal ions, such as iron and copper, which bind tightly to organic ligands, participate in innumerable redox reactions, besides playing an important role in oxygen transport. We now discuss the essential metal ions and thereafter briefly review their roles. <p> <p> <b>WHAT ARE THE ESSENTIAL METAL IONS?</b> <p> If we look at the periodic table we can find around 25 elements that are required by most, if not all, biological systems. A somewhat idiosyncratic version of this is given in Figure 1.1 (an equally idiosyncratic version can be found in Levi, 1985). <p> Element number 1, hydrogen, is extremely important in biology. It can be incorporated into covalent bonds with many non-metals, such as carbon and nitrogen, notably by the action of light. It can be transferred in an important number of biological redox reactions involving one or two electron transfers, and it can participate in the generation of the proton gradients across biological membranes, which are universally used for ATP synthesis. <p> Helium, like the other members of its family, is an inert gas often used in balloons on account of its low density, and when inhaled results in a comic transposition of the human voice to a significantly higher register (not a realistic way to mimic counter-tenors, but very effective in well-loved Walt Disney cartoon characters)! <p> Lithium, while not required for life, is used therapeutically in the form of lithium carbonate for the treatment of manic depression; although its mechanism of action remains a mystery. Effective treatment requires attaining serum lithium concentrations of between 0.8 and 1.2 mmol/L. <p> Boron is an essential trace element for plants, and may well turn out to be essential for mammals as well. The boron-containing polyether–macrolide antibiotic, boromycin, was isolated as a potent anti-HIV agent. <p> <p> The non-metals carbon, nitrogen and oxygen are all essential for man, as is element number 9, fluorine. Some of the biological effects of the important intracellular messenger, nitric oxide, NO, which is derived from the amino acid arginine, are illustrated in Figure 1.2. The addition of fluoride in drinking water to retard dental caries, particularly in children, has been criticized on the grounds of potential toxicity, but the concentrations used are many orders of magnitude below that which would be required to inhibit enzymes such as enolase in the glycolytic pathway. The key enzyme of DNA synthesis, thymidylate synthase, is inhibited by the anti-tumour drug 5-fluorodeoxythymidylate (Figure 1.2), a so-called `suicide substrate', because it inhibits the enzyme only after undergoing part of its normal catalytic reaction. Neon, of course is an inert gas, but has the property of emitting light in a tube filled with the gas when an electric discharge is applied. <p> Sodium is involved in ionic gradients and in osmotic regulation, and, despite its much higher extracellular concentration, has to be kept out of many cells by the action of an energy-consuming Na<sup>+</sup>/K<sup>+</sup> ATPase. The way in which biological systems manage to select the ions that are transported across membranes will be discussed in later chapters—Figure 1.3 illustrates the selective-binding sites for Na<sup>+</sup>, K<sup>+</sup>, Ca<sup>2+</sup> and Cl<sup>-</sup> in transport proteins. <p> Magnesium has its role intimately intertwined with phosphate: in many phosphoryl transfer reactions, as Mg-ATP in muscle contraction, in the stabilization of nucleic acid structures as well as in the catalytic activity of ribozymes (catalytic RNA molecules). It also serves as a structural component of enzymes, and is found as the metal centre in chlorophylls, which absorbs light energy in photosynthesis. <p> Aluminium, while extremely abundant in the earth's crust, is not used by living organisms: it is a notorious neurotoxin, but its involvement as a cause of Alzheimer's disease seems less likely than was thought a few years ago. It is clear that acid rain, due to sulfur dioxide and nitrogen oxide emissions, increases the solubility and hence the bioavailability of aluminium. In the forests on the mountain slopes of Szklaska Poreba, on the Polish border with the Czech Republic, the pH values reached below 3, with disastrous effects on the tree population. Another effect of acid rain could have been to change the usual association of aluminium in the soil with silicate (predominant above pH 6.5) for phosphate, rendering aluminium more toxic. <p> This may be the reason why silicon is essential, namely that it keeps aluminium in a non-toxic form as aluminium silicate. While silicon is required as a trace element in most animals, in plants, particularly grasses, and in many unicellular organisms, such as diatoms, it is a major structural element. The importance of phosphorus and sulfur is obvious, the latter often associated with iron in an important family of proteins that contains iron–sulfur clusters. <p> Chlorine is another essential element in large part because, with all of the positively charged metal ions around, anions are obviously required for charge neutralization. One of the most common genetic disorders in man, cystic fibrosis (often referred to as mucoviscidosis, because of the viscous nature of bronchial secretions, resulting in frequent respiratory infections), is due to the production by epithelial cells that line the lungs, digestive tract, sweat glands and genitourinary system, of a defective form of a protein called cystic fibrosis transmembrane conductance regulator (CFTR), which is a chloride channel. Detailed structural analysis of closed and open conformations of bacterial chloride channels has shown that they can be closed by a glutamate residue, which replaces a third Cl<sup>-</sup> ion on the extracellular site of the channel (Figure 1.4). In the closed conformation, the ion-binding sites S<sub>int</sub> and S<sub>cen</sub> are occupied by Cl<sup>-</sup> ions and the ion-binding site S<sub>ext</sub> is occupied by the side chain of Glu<sup>148</sup>, whereas in the opened conformation Glu<sup>148</sup> has moved out and the binding site is occupied by a third Cl<sup>-</sup> anion. <p> Argon, an inert gas, has the useful property of being heavier than air, thus making it the ideal medium in which to work anaerobically (keep everything at the bottom of your argon-flushed glove box!). <p> <i>(Continues...)</i> <p> <!-- copyright notice --> <br></pre> <blockquote><hr noshade size='1'><font size='-2'> Excerpted from <b>Biological Inorganic Chemistry</b> by <b>Robert R. Crichton</b> Copyright © 2008 by Elsevier B.V.. Excerpted by permission of ELSEVIER. All rights reserved. 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