Helmut Sigel

Handbook on toxicity of inorganic compounds

This text consists of a total of 74 chapters of which 68 are devoted to individual elements and derived substances. The introductory chapter contains general definitions and describes the manner in which each elemental chapter is organized. For each of these chapters the points covered include chemistry and distribution, technological uses, physiological processes, detoxification mechanisms, levels of tolerance, summary of ecotoxicity, and analytical chemistry as well as a list of references. In addition to the elements, a chapter is also devoted to radiotoxicity. Aside from a discussion of individual elements, the second chapter covers the chemistry of inorganic compounds from the point of view of essentiality in biological systems and the properties and interdependency of these compounds. The third chapter is a very brief description of general principles used in toxicology, with emphasis on metals. The fourth chapter deals specifically with the collection, storage, and handling of biological materials for subsequent analysis. This is followed by chapters on the individual elements. The final chapter is a summary containing various tables describing values for threshold limits, biological tolerance, and acceptable intake.

Interactions of metal ions with nucleotides and nucleic acids and their constituents

Phosphate-metal ion interactions of nucleotides and polynucleotides sugar-metal ion interactions dichotomy of metal ion binding to N1 and N7 of purines general conclusions from sold state studies of nucleotide-metal ion complexes solution studies of nucleotide-metal ion complexes - isomeric equilibria stacking interactions involving nucleotides and metal ion complexes the effect of metal ions on hydrolytic reactions of nucleotides and their phosphoesters metal complexes of sulfur-containing purine derivatives mechanistic insight from kinetic studies on the interaction of model palladium (II) complexes with nucleic acid components platinum (II)-nucleobase interactions - a kinetic approach NMR studies of oligonucleotide-metal ion interactions metal ion interactions with DNA - considerations on structure, stability and effects from metal ion binding electron transfer reactions through the double helix the role of metal ions in ribozymes ternary metal-nucleic acid base-protein complexes metal responsive gene regulation and the zinc metalloregulatory model the role of iron-sulfur proteins in gene regulation current status of structure-activity relationship of platinum anticancer drugs - activation of the trans-geometry cisplatin and derived anticancer drugs - mechanism and current status of DNA binding proteins that bind to and mediate the biological activity of platinum anticancer drug-DNA adducts interactions of metallopharmaceuticals with DNA.

Handbook on Metalloproteins

Interaction of sodium and potassium with proteins structure and function of sodium and potassium channel proteins in membranes magnesium-activated enzyme systems calcium and its enzymes vanadium in proteins and enzymes are there proteins containing chromium? manganese-containing enzymes and proteins iron in heme and related proteins iron-sulfur proteins structure-function of non-heme iron proteins with oxygen and nitrogen dominated coordination iron storage and transport cobalt in vitamin B12 and its enzymes nickel-containing enzymes copper proteins in the transport and activation of dioxygen, and the reduction of inorganic molecules multi-copper oxidases copper in electron transfer proteins proteins of various functions containing copper zinc sites in metalloenzymes and related proteins zinc finger proteins other zinc proteins -metallthioneins and insulin enzymes and proteins containing molybdenum or tungsten emerging themes and patterns among metalloproteins one and three letter symbols for the amino acids the standard genetic code.

Macrochelate formation in monomeric metal ion complexes of nucleoside 5'-triphosphates and the promotion of stacking by metal ions. Comparison of the self-association of purine and pyrimidine 5'-triphosphates using proton nuclear magnetic resonance

The concentration dependence of the chemical shifts of the protons H-2, H-8, and H-I’ or H-5, H-6, and H-1’ of A T P , I T P , and G T P or C T P and U T F ( = N T P ) , respectively, and of the corresponding nucleosides has been measured. The results are consistent with the isodesmic model of indefinite noncooperative stacking; the association constants for NTP4are between 1.3 (ATP4-) and about 0.4 M-’ (UTP4-) and for the nucleosides between 15 (adenosine) and 1.2 M-’ (uridine). The self-stacking tendency decreases within the series adenosine > guanosine > inosine > cytidine uridine. Due to the repulsion of the negatively charged phosphate moieties, this trend is much less pronounced for the corresponding N T F series. The charge effect also governs the series adenosine >> AMP2> ADP3ATP4-. Likewise the self-association tendency of ATP4-, ITP, and GTP‘is promoted by a factor of about 3-5 by the coordination of Mg2+ to the phosphate moiety, which neutralizes part of the negative charge a t this residue. However, the self-association tendency of Zn(ATP)2and Cd(ATP)2is much larger than of Mg(ATP)’-; this is explained by an increased tendency to form an intermolecular metal ion bridge in the dimeric stacks in which Zn2+ or Cd2+ is coordinated to the phosphate moiety of one ATP4and to N-7 of the adenine residue of the other A T P . The shifts of H-8 for complete stacking (6,) agree with this interpretation. There is no significant increase in stability in Zn(ITP)2and Zn(GTP)2-: Le., the stability of these stacks is governed only by the charge neutralization-the effect of Zn2+ is the same as that of Mg2+. Comparison of the shifts of H-8 at infinite dilution (6,) for several systems reveals that an M2+/N-7 interaction exists in the monomeric Zn2+ and CdZt complexes of the purine 5’-triphosphates; Le., a macrochelate is formed through an inrramolecular coordination of the metal ion to the phosphate moiety and to N-7. The position of this concentration-independent equilibrium between the open isomer (with phosphate coordination only) and the macrochelated isomer is estimated by comparing 6o of M(NTP)2with the shifts of H-8 for complete complex formation of the corresponding metal ion-nucleoside complexes, which were also determined. The N M R study gives no hint for such an N-7 interaction either for the corresponding Mg(NTP)2complexes or for a base interaction in any of the pyrimidine 5’-triphosphate complexes. These N M R results prompted an evaluation of stability data (obtained earlier under conditions where no self-association occurs), which give further evidence that macrochelate formation also occurs in the M(NTP)’complexes of purine nucleotides with Mn2+ Co2+, Ni2+, Cu2+, and Zn2+; no evidence for such an interaction is observed in the pyrimidine nucleotide complexes. Ionizkon of the base moiety in I T P , G T F , UTF, and TTP favors, however, the base-metal ion interaction and therefore also the formation of macrochelates in the M(NTP-H)3complexes. The percentage of the macrochelated isomer is estimated for all these systems: the whole range from nearly 100% ring back-bonding to only insignificant traces is observed. The ambivalent coordinating properties of nucleotides and their structural versatility are discussed. I t is now well-known tha t metal ions a r e essential in a large variety of biological processes, including those with nucleic acids and their der ivat ives4 For example, D N A polymerase contains tightly bound Zn2+, and there is evidence that this metal ion binds the enzyme to DNA.5s6 To fulfill its function the enzyme must also be activated by a divalent cation such as Mg2+ or Mn2+, and these metal ions bind the nucleoside triphosphate substrates to the enzyme.’,* Thus the interplay between metal ions and nucleotides, or their derivatives, is receiving much attention at

Comments on potentiometric pH titrations and the relationship between pH-meter reading and hydrogen ion concentration

Abstract It is emphasized and shown that the concept of pH is more complicated than might be thought (and to some extent also unsatisfactory); there are (at least) three pH scales in general use and it is the aim to make this fact recognized. These scales are: (1) an activity scale, where the hydrogen ion activity is measured based on NBS or similar standards by carefully eliminating the liquid-junction potentials of the electrode system via experimental determinations; (2) a practical scale, which has unintentionally developed by convenience over the past ca. 30 years, is based on now generally available combined glass electrodes together with NBS (or related) buffers used for calibration; and (3) a concentration scale which uses strong acids and/or bases for calibration and defines the pH-meter reading in terms of −log[H + ]. Scale (2) is clearly the one least well defined, yet it is also the one most widely used. If a ‘pH’ is measured for a given constant H + concentration in the three scales, its value decreases in the order (1) > (2) > (3). Scales (1) and (3) may be converted into each other by using the single ion activity coefficient of H + , e.g., at 25°C and at ionic strengths of 0.1 and 0.5 M the differences correspond to 0.11 and 0.15 log unit, respectively. The conversion term from scale (2) to (3) corresponds at 25°C and an ionic strength between 0.1 and 0.5 M to about 0.03 log unit. It is evident that any acidity constant, i.e. p K a value, determined for a given system (HA ⇌| A − + H + ) is affected to the same extent; hence, the mentioned conversion factors have to be applied if P K a values determined in different scales are to be compared or used. It may be added that many workers believe that combined glass electrodes measure the hydrogen ion activity and that they are working in sale (1), yet this is not the case, they are actually working in scale (2). Moreover it is also barely (or not at all) recognized that the values in scale (2) are in fact closer to those of scale (3) and not to those of scale (1), as is often assumed. Some general comments regarding potentiometric pH titrations and the determination of equilibrium constants (i.e., p K a values and stability constants of metal ion complexes) are also made, and the advantages of different titration procedures are discussed and pitfalls are pointed out.

A Stability Concept for Metal Ion Coordination to Single-Stranded Nucleic Acids and Affinities of Individual Sites

The three-dimensional architecture and function of nucleic acids strongly depend on the presence of metal ions, among other factors. Given the negative charge of the phosphate-sugar backbone, positively charged species, mostly metal ions, are necessary for compensation. However, these ions also allow and induce folding of complicated RNA structures. Furthermore, metal ions bind to specific sites, stabilizing local motifs and positioning themselves correctly to aid (or even enable) a catalytic mechanism, as, for example, in ribozymes. Many nucleic acids thereby exhibit large differences in folding and activity depending not only on the concentration but also on the kind of metal ion involved. As a consequence, understanding the role of metal ions in nucleic acids requires knowing not only the exact positioning and coordination sphere of each specifically bound metal ion but also its intrinsic site affinity. However, the quantification of metal ion affinities toward certain sites in a single-stranded (though folded) nucleic acid is a demanding task, and few experimental data exist. In this Account, we present a new tool for estimating the binding affinity of a given metal ion, based on its ligating sites within the nucleic acid. To this end, we have summarized the available affinity constants of Mg(2+), Ca(2+), Mn(2+), Cu(2+), Zn(2+), Cd(2+), and Pb(2+) for binding to nucleobase residues, as well as to mono- and dinucleotides. We have also estimated for these ions the stability constants for coordinating the phosphodiester bridge. In this way, stability increments for each ligand site are obtained, and a clear selectivity of the ligating atoms, as well as their discrimination by different metal ions, can thus be recognized. On the basis of these data, we propose a concept that allows one to estimate the intrinsic stabilities of nucleic acid-binding pockets for these metal ions. For example, the presence of a phosphate group has a much larger influence on the overall affinity of Mg(2+), Ca(2+), or Mn(2+) compared with, for example, that of Cd(2+) or Zn(2+). In the case of Cd(2+) and Zn(2+), the guanine N7 position is the strongest intrinsic binding site. By adding up the individual increments like building blocks, one derives an estimate not only for the overall stability of a given coordination sphere but also for the most stable complex if an excess of ligating atoms is available in a binding pocket saturating the coordination sphere of the metal ion. Hence, this empirical concept of adding up known intrinsic stabilities, like building blocks, to an estimated overall stability will help in understanding the accelerating or inhibiting effects of different metal ions in ribozymes and DNAzymes.

Ternary complexes in solution. Influence of 2,2′-bipyridyl on the stability of 1:1 complexes of Co2+, Ni2+, Cu2+, and Zn2+ with hydrogen phosphate, adenosine 5′-monophosphate, and adenosine 5′-triphosphate☆

Abstract Ternary complexes of bivalent metal ions with 2,2′-bipyridyl and hydrogen phosphate, adenosine 5′-monophosphate, and adenosine 5′-triphosphate have been investigated by potentiometric titration and nuclear magnetic resonance spectrometry. Coordination of the phosphate compounds with 1:1 complexes of bipyridyl and Co 2+ or Zn 2+ occurs as readily as with the free metal ions; a stability increase is found with Cu 2+ . The ternary complex of Ni 2+ -bipyridyl-adenosine 5′-triphosphate is slightly less stable than the binary complex of Ni 2+ -adenosine 5′-triphosphate. From NMR spectra it is suggested that neither in the complex of Cu 2+ -bipyridyl- adenosine 5′-monophosphate nor in the Cu 2+ -bipyridyl-adenosine 5′-triphosphate any further interaction of metal ion with the adenyl moiety happens. Overall the results have considerable significance in terms of metal-activated enzymes and substrates wherein the usual formation of ternary complexes leads initially to greater stability and where the reactants are both brought together and activated at the same time. Some examples for biologically important ternary complexes are mentioned.

Nickel and its surprising impact in nature

Volume 2 focuses on the vibrant research area concerning nickel as well as its complexes and their role in Nature. With more than 2800 references and over 130 illustrations, it is an essential resource for scientists working in the wide range from inorganic biochemistry all the way through to medicine. In 17 stimulating chapters, written by 47 internationally recognized experts, Nickel and Its Surprising Impact in Nature highlights critically the biogeochemistry of nickel, its role in the environment, in plants and cyanobacteria, as well as for the gastric pathogen Helicobacter pylori, for gene expression and carcinogenensis. In addition, it covers the complex-forming properties of nickel with amino acids, peptides, phosphates, nucleotides, and nucleic acids. The volume also provides sophisticated insights in the recent progress made in understanding the role of nickel in enzymes such as ureases, hydrogenases, superoxide dismutases, acireductone dioxygenases, acetyl-coenzyme A synthases, carbon monoxide dehydrogenases, methyl-coenzyme M reductases ... and it reveals the chaperones of nickel metabolism. The book opens with the biogeochemistry of this element and its release into the environment, which occurs from both natural and anthropogenic sources, whereby atmospheric distribution plays an important role. In the second chapter the impact of nickel on the metabolism of cyanobacteria and eukaryotic plants including deficiency and toxicity is considered, as is the application of nickel hyperaccumulator plants for phytomining and phytoremediation. Complex formation of nickel(II/III) with amino acids and peptides as well as of nickel(II) with sugar residues, nucleobases, phosphates, nucleosides, and nucleic acids is summarized in Chapters 3 and 4, respectively, by also taking into account intramolecular equilibria and comparisons with related metal ions. Bioinspired nickel coordination chemistry has flourished in recent years and the resulting synthetic models for the active sites of nickel-containing enzymes are reviewed in Chapter 5. In fact, each of the well established biological nickel sites is rather unique with respect to its structure and function. Hence, the following eight chapters are individually devoted to the various nickel enzymes which catalyze rather diverse reactions. For example, urease reduces the half life of urea in water from about 3.6 years to a few microseconds, whereas nickel-iron hydrogenases catalyze the heterolytic conversion of dihydrogen into protons and electrons and vice versa. Next, methyl-coenzyme M reductase and its nickel corphin coenzyme F430 in methanogenic archaea are described in detail as are acetyl-coenzyme A synthases and nickel-containing carbon monoxide dehydrogenases. These critical reviews are followed by in depth considerations on nickel superoxide dismutase, and the nickel-dependent glyoxalase I enzymes. The role of nickel in acireductone dioxygenase and the properties of the nickel-regulated peptidyl-prolyl cis/trans isomerase SlyD are discussed next. Nickel is toxic to cells and therefore the synthesis of nickel enzymes requires carefully controlled nickel-processing mechanisms that range from selective transport of nickel into the cells to productive insertion of nickel into the correct apoproteins. This demanding task is in the focus of Chapter 14 devoted to the chaperones of nickel metabolism. The primary colonization and long-term survival of Helicobacter pylori in the hostile gastric niche and the role of nickel in this environmental adaptation is covered in detail in Chapter 15. Nickel is widely employed in modern industry in conjunction with other metals for the production of alloys for coins, jewellery, and stainless steel; it is also used for plating, battery production, as a catalyst, etc. Workers are exposed to nickel at all stages of the processing of nickel-containing products through air, water or skin contacts. For example, the exposure to airborne nickel-containing particles has long been known to cause acute respiratory symptoms ranging from mild irritation and inflammation of the respiratory system to bronchitis, asthma, and pulmonary fibrosis and edema. Another well known adverse effect is allergic contact dermatitis. The indicated health problems caused by nickel exposure are mediated by an active change in the expression of genes that control inflammation, the response to stress, cell proliferation or cell death. All this and more is covered in Chapter 16. However, the most serious health effects beyond nickel toxicity relate to carcinogenesis; these concerns represent an area of considerable research activity today as is evident from the terminating chapter of Nickel and Its Surprising Impact in Nature.

Quantification of Intramolecular Ligand Equilibria in Metal-Ion Complexes

Abstract That in a metal-ion chelate one binding site may be more weakly bound than another is often expected, though it is not equally well realized that such differences in metal-ion affinities may give rise to intramolecular equilibria between open and closed, i.e. chelated, forms. Quantification procedures for such equilibria are outlined and applied to describe the situation in complexes of N-substituted iminodiacetate and α-substituted acetate ligands. Corresponding procedures are applicable to the characterization of intramolecular ligand-ligand interactions in mixed ligand complexes. Isomerization equilibria are of general importance; e.g. in metal-ion catalyzed or facilitated technical or biological processes.

Effects of (N7)-Coordinated Nickel(II), Copper(II), or Platinum(II) on the Acid–Base Properties of Guanine Derivatives and Other Related Purines[≠]

Guanine is an important nucleobase residue in nucleic acids; for example, the anticancer drug cisplatin, cis-[(NH3)2PtCl2], preferably binds to N7 of this site. In this study the effect of (N7)-coordinated Ni2+ (which is expected to correspond to that of Zn2+), Cu2+, and cis-a2Pt2+ or trans-a2Pt2+ (where a = NH3 or CH3NH2) on the acid–base properties of guanine derivatives (see diagram) is quantified. Several related purines are included for comparison. Micro-acidity-constant evaluations are presented and more than 60 acidity constants are listed.