Practical Approaches to Biological Inorganic Chemistry 2nd Edition

Book Preface

Metals play many different roles in the biological world, whether by their participation in essential biological processes, as toxic constituents of our environment, or as indispensable diagnostic and therapeutic agents in human medicine. Only a limited number of metal ions are essential for most living organisms (Fig. 1.1), and this short introduction begins by illustrating the biological importance of metals, not only in vital processes such as intermediary metabolism, electron transfer, respiration, and photosynthesis, but also in neurotransmission, cell signaling, apoptosis, and fertilization.
While many essential metals can be toxic, particularly when they are in excess, in our modern environment there are a number of nonessential metals, such as cadmium, lead, mercury, and aluminum, which are themselves highly toxic.
Finally, metals have assumed an extraordinary number of roles in medicine, not only therapeutically as drugs, but also as noninvasive contrast agents and radiopharmaceuticals.
More detailed accounts of these aspects of metal ions are presented in the companion volume to this second edition (Crichton, 2018).

Most living organisms require some 25 elements (Maret, 2016; Chellan and Sadler, 2015) including between 10 and 14 metal ions (Fig. 1.1). In the case of Homo sapiens, there are 10 essential metal ions (sodium, potassium, calcium, magnesium, manganese, iron, cobalt, copper, zinc, and molybdenum). Of these, the first four are considered as “bulk elements” (Na1, K1, Ca21, and Mg21), representing 112 g, 160 g, 1.1 kg, and 25 g, respectively, in an “average” person of body weight 80 kg (The data on the abundance of elements in the 80 kg human body are those given in WebElements: http://www.webelements.com/.). Together, they constitute some 99% of the metal ion content of the human body. The others, manganese, iron, cobalt, copper, zinc, and molybdenum, designated “trace elements,” are present in much lower amounts than the bulk elements (respectively, 16 mg,
4.8 g, 1.6 mg, 80 mg, 2.6 g, and 8 mg in an 80-kg person).
The essential alkali metal ions Na1 and K1 only weakly bind organic ligands, rendering
them extremely mobile, as with H1 and Cl2. This enables them to generate ionic gradients across biological membranes. The distribution of Na1 and K1 in mammals is quite different; Na1, together with Cl2, is the major electrolyte in the extracellular fluid, whereas K1 is retained within the cells. The concentration of Na1 in the plasma is maintained within narrow limits at about 145 mmol/L, and its intracellular concentration is only about 12 mmol/L, whereas the intracellular concentration of K1 is 150 mmol/L, and typically only 5 mmol/L in the extracellular fluids. This concentration differential, maintained by the (Na1
K1)-ATPase of the plasma membrane, ensures a number of major biological processes, such as cellular osmotic balance, signal transduction, and neurotransmission.
(Na1
K1)-ATPase transports three Na1 ions to the outside of the cell and two K1 ions to the inside (Figs. 1.2 and 1.3), contributing to the action potential involved in transmission of nerve impulses along neuronal axons. Action potentials can be generated by presynap-tic neurons at the rate of about 250 per second, accounting for between one-half and two-thirds of their total ATP consumption. The repetitive G-rich sequences found in the telomeres at the ends of eukaryotic chromosomes are stabilized by K1 and Na1 ions. The retention of Na1 (hypernatremia) when Na1 intake exceeds renal clearance is one of the most common electrolyte disorders in clinical medicine. Hyperkalemia has become more common in cardiovascular practice due to the growing population of patients with chronic kidney disease and the broad application of drugs that modulate renal elimination of potassium by reducing the production of angiotensin II.
The alkaline earth metal ions, Mg21 and Ca21, have greater binding strengths to organic ligands than Na1 and K1, and therefore are less mobile. Both play important structural and catalytic roles, with 99% of the body’s Ca21 found in bone and teeth. Although Mg21 is the least abundant of the “bulk elements,” the intracellular concentration of free Mg21 is around 0.5 mM, making it the most abundant cation, and less than 0.5% of total body Mg21 is in the plasma. Half of cytosolic Mg21 is bound to ATP and most of the rest, along with K1, is bound to ribosomes. Unlike the other three bulk cations, Mg21 has a much slower water exchange rate, allowing it to play a structural role, for example, participating in ATP binding in many enzymes involved in phosphoryl transfer reactions—6 of the 10 reactions of glycolysis are phosphoryl transfers.
Ca21 serves as a messenger in virtually all of the important functions of cells. Why Ca21 has ended up in this position is probably due to its unique coordination chemistry, which enables it to bind to sites of irregular geometry even in the presence of large excesses of other cations such as Mg21 (Carafoli and Krebs, 2016). While the total Ca21 concentration inside cells is micromolar, in the cytosol the concentration of free Ca21 is about 10,000 times lower. This nanometer concentration is achieved by ligation of Ca21 by two broad classes of specific proteins. (1) Those which buffer Ca21 in the nanometer range, and in some cases, also process its information, by increasing, or less frequently decreasing, their biological activity upon Ca21 binding by a change in conformation, illustrated for calmodulin in Fig. 1.4—“Ca21 is not an active site metal, it is the allosteric metal par excellence” (Carafoli and Krebs, 2016). (2) Intrinsic membrane proteins which transport Ca21 in or out of cells, or between the cytosol and the lumen of cellular organelles. Apoptosis (programmed cell death) plays a major role in the maintenance of tissue homeo-stasis. Ca21, in addition to its role in the regulation of cellular processes, may act as a proapoptotic agent, and both intracellular Ca21 depletion or overload may trigger apopto-sis (Brini et al., 2013). Hypercalcemia is a common metabolic perturbation and the increase in over-the-counter purchase of Ca21 and vitamin D supplements, notably to combat osteoporosis in the aging population, is a contributory factor.
Of the six essential trace metal ions, Zn has ligand-binding constants intermediate between those of Mg21 and Ca21 and the other five. Manganese, iron, cobalt, copper, and molybdenum all have much stronger binding to organic ligands and are therefore only poorly mobile. In addition, they have access to at least two oxidation states, and therefore can participate in electron transfer and redox catalysis, whereas zinc has access only to the Zn21 state.