Inorganic Chemistry

A Wiley Series of Advanced Textbooks

ISSN: 1939-5175

Editorial Board

David Atwood, University of Kentucky, USA

Bob Crabtree, Yale University, USA

Gerd Meyer, University of Cologne, Germany

Derek Woollins, University of St. Andrews, UK

Previously Published Books in this Series

Structural Methods in Molecular Inorganic Chemistry

David W. H. Rankin, Norbert W. Mitzel & Carole A. Morrison; ISBN: 978-0-470-97278-6

Introduction to Coordination Chemistry

Geoffrey Alan Lawrance; ISBN: 978-0-470-51931-8

Chirality in Transition Metal Chemistry

Hani Amouri & Michel Gruselle; ISBN: 978-0-470-06054-4

Bioinorganic Vanadium Chemistry

Dieter Rehder; ISBN: 978-0-470-06516-7

Inorganic Structural Chemistry 2nd Edition

Ulrich Müller; ISBN: 978-0-470-01865-1

Lanthanide and Actinide Chemistry

Simon Cotton; ISBN: 978-0-470-01006-8

Mass Spectrometry of Inorganic and Organometallic Compounds: Tools-Techniques-Tips

William Henderson & J. Scott McIndoe; ISBN: 978-0-470-85016-9

Main Group Chemistry, Second Edition

A.G. Massey; ISBN: 978-0-471-19039-5

Synthesis of Organometallic Compounds: A Practical Guide

Sanshiro Komiya; ISBN: 978-0-471-97195-5

Chemical Bonds: A Dialog

Jeremy Burdett; ISBN: 978-0-471-97130-6

The Molecular Chemistry of the Transition Elements: An Introductory Course

Francois Mathey & Alain Sevin; ISBN: 978-0-471-95687-7

Stereochemistry of Coordination Compounds

Alexander von Zelewsky; ISBN: 978-0-471-95599-3

For more information on this series see: www.wiley.com/go/inorganic

Originally published in the German language by Vieweg+Teubner, 65189 Wiesbaden, Germany, as “Wolfgang Kaim and Brigitte Schwederski:
Bioanorganische Chemie. 4. Auflage (4th Edition)”.
© Vieweg+Teubner/Springer Fachmedien Wiesbaden GmbH 2005.
Springer Fachmedien is part of Springer Science+Business Media

This edition first published 2013
© 2013 John Wiley & Sons, Ltd

First English language edition published 1994

Registered office
John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom

For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com.

The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom. If professional advice or other expert assistance is required, the services of a competent professional should be sought

The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data

Kaim, Wolfgang, 1951–
[Bioanorganische Chemie. English]
Bioinorganic chemistry : inorganic elements in the chemistry of life : an introduction and guide /
written and translated by Wolfgang Kaim, Brigitte Schwederski, Axel Klein. – Second edition.
pages cm
Translation of: Bioanorganische Chemie.
Includes bibliographical references and index.
ISBN 978-0-470-97524-4 (cloth) – ISBN 978-0-470-97523-7 (paper) 1. Bioinorganic chemistry.
I. Schwederski, Brigitte, 1959– II. Klein, Axel, 1964– III. Title.
QP531.K3513 2013
572′.51–dc23
2013011894

A catalogue record for this book is available from the British Library.

HB ISBN: 9780470975244
PB ISBN: 9780470975237

Preface to the Second Edition

The predictably enormous growth of bioinorganic chemistry has made a second edition of this text both necessary and difficult. While there are several extensive and often specialized reviews, major texts and handbooks on this subject, our experience in teaching it has suggested the provision of an updated overview of the classical, novel and applied sections of the field, which has not only become one of the major subdisciplines of inorganic chemistry but, due to its highly interdisciplinary nature, has also pervaded other areas of the life sciences.

The second edition contains updates of many kinds. New structure information on some intricate metalloproteins, such as water oxidase and the molybdopterin-based enzymes, has been included, replacing the earlier speculative models. Emerging developments are referred to at various points, covering such topics as bioorganometallic chemistry, nucleic acid ligation, gasotransmitters, nanoparticles and global cycles of the elements C, P and N. The vastly increased focus on the medical applications of inorganic compounds has required that more space be devoted to this particular aspect. Nonetheless, we have tried to keep the amount of material at a constant, manageable level suitable for an introductory overview, rather than the typical condensed fragments presented in general textbooks of inorganic chemistry or biochemistry. To achieve this, we have tried to concentrate on the facts and on descriptions of function, rather than on model compounds or mechanistic hypotheses (which may vary with time); excellent treatments of the reaction mechanisms of bioinorganic systems are available in T. D. H. Bugg's Introduction to Enzyme and Coenzyme Chemistry, third edition (John Wiley & Sons, 2012) and D. Gamenara, G. Seoane, P. Saenz Mendez and P. Dominguez de Maria's Redox Biocatalysis: Fundamentals and Applications (John Wiley & Sons, 2012). A basic knowledge of inorganic, organic, physical and biological chemistry remains necessary to make optimal use of this text.

Throughout this book, we have made reference to the RCSB Protein Data Bank for biological macromolecules. Each structure deposited therein is given a unique PDB code (e.g. 1SOD), and all information pertaining to that structure can be found using its code. For easy reference, we have included this code with all the structures in this book, so that the reader can refer to the original data online.

For comments and encouragement during the planning and completion of this edition, we thank many of our colleagues. We thank the publishers for their support and patience and Martina Bubrin for help in retrieving crystal structure files and drawing the structures. Most special thanks are due to Angela Winkelmann for her continued contributions to the preparation of the manuscript.

Wolfgang Kaim
Brigitte Schwederski
Axel Klein
Stuttgart and Cologne, January 2013

Instructors can access PowerPoint files of the illustrations presented within this text, for teaching, at: http://booksupport.wiley.com.

Preface to the First Edition

This book originated from a two-semester course offered at the Universities of Frankfurt and Stuttgart (W.K). Its successful use requires a basic knowledge of the modern sciences, especially of chemistry and biochemistry, at a level that might be expected after one year of study at a university or its equivalent. Despite these requirements we have decided to explain some special terms in a glossary and, furthermore, several less conventional physical methods are briefly described and evaluated with regard to their practical relevance at appropriate positions in the text.

A particular problem in the introduction to this highly interdisciplinary and not yet fully mature or definitively circumscribed field lies in the choice of material and the depth of treatment. Although priority has been given to the presentation of metalloproteins and the electrolyte elements, we have extended the scope to therapeutically, toxicologically and environmentally relevant issues because of the emphasis on functionality and because several of these topics have become a matter of public discussion.

With regard to details, we can frequently only offer hypotheses. In view of the explosive growth of this field there is implicit in many of the statements regarding structure and mechanisms the qualification that they are “likely” or “probable”. We have tried to incorporate relevant literature citations up to the year 1993.

Another difficult aspect when writing an introductory and, at the same time, fairly inclusive text is that of the organization of the material. For didactic reasons we follow partly an organizational principle focused on the elements of the periodic table. However, living organisms are opportunistic and could not care less about such systematics; to successfully cope with a problem is all that matters. Accordingly, we have had to be “nonsystematic” in various sections, for example, treating the hemerythrin protein in connection with the similarly O2-transporting hemoglobin (Chapter 5) and not under ‘diiron centers’ (Section 7.6). Several sections are similarly devoted to biological-functional problems such as biomineralization or antioxidant activity and may thus include several different elements or even organic compounds. The simplified version of the P-450 monooxygenase catalytic cycle which we chose for the cover picture illustrates the priority given to function and reactivity as opposed to static-structural aspects.

We regret that the increasingly available color-coded structural representations of complex proteins and protein aggregates cannot be reproduced here. General references to the relevant literature are given in the bibliography at the end of the book while specific references are listed at the end of each chapter in the sequence of appearance.

For helpful comments and encouragement during the writing and correction of manuscripts we thank many of our colleagues. Recent results have become available to us through participation in the special program “Bioanorganische Chemie” of the Deutsche Forschungsgemeinschaft (DFG). We also thank Teubner-Verlag and John Wiley & Sons for their patience and support. Very special thanks are due to Mrs Angela Winkelmann for her continued involvement in the processing of the manuscript.

Wolfgang Kaim
Brigitte Schwederski
Stuttgart, December 1993

1

Historical Background, Current Relevance and Perspectives

The progress of an inorganic chemistry of biological systems has had a curious history.

R. J. P. WILLIAMS, Coord. Chem. Rev. 1990, 100, 573

The description of a rapidly developing field of chemistry as “bioinorganic” seems to involve a contradiction in terms, which, however, simply reflects a misconception going back to the beginning of modern science. In the early 19th century, chemistry was still divided into an “organic” chemistry which included only substances isolated from “organisms”, and an “inorganic” chemistry of “dead matter”.1 This distinction became meaningless after Wöhler's synthesis of “organic” urea from “inorganic” ammonium cyanide in 1828. Nowadays, organic chemistry is defined as the chemistry of hydrocarbons and their derivatives, with the possible inclusion of certain nonmetallic heteroelements such as N, O and S, regardless of the origin of the material.

The increasing need for a collective, not necessarily substance-oriented designation of the chemistry of living organisms then led to the new term “biochemistry”. For a long time, classical biochemistry was concerned mainly with organic compounds; however, the two areas are by no means identical.2 Improved trace analytical methods have demonstrated the importance of quite a number of “inorganic” elements in biochemical processes and have thus revealed a multitude of partially inorganic natural products. A corresponding list would include:

• metalloenzymes (ca. 40% of the known enzymes, especially oxidoreductases (Fe, Cu, Mn, Mo, Ni, V) and hydrolases (e.g. peptidases, phosphatases: Zn, Mg; Ca, Fe);
• nonenzymatic metalloproteins (e.g. hemoglobin: Fe);
• low-molecular-weight natural products (e.g. chlorophyll: Mg);
• coenzymes, vitamins (e.g. vitamin B12: Co);
• nucleic acids: (e.g. DNAn−(M+)n, M = Na, K);
• hormones (e.g. thyroxine, triiodothyronine: I);
• antibiotics (e.g. ionophores: valinomycin/K);
• biominerals (e.g. bones, teeth, shells, coral, pearls: Ca, Si,…).

Some (by today's definition) “inorganic” elements were established quite early as essential components of living systems. Examples include the extractions of potassium carbonate (K2CO3, potash) from plants and of iron-containing complex salts K3,4[Fe(CN)6] from animal blood in the 18th century, and the discoveries of elemental phosphorus (as P4) by dry distillation of urine residues in 1669 and of elemental iodine from the ashes of marine algae in 1811.

In the middle of the 19th century, Liebig's studies on the metabolism of inorganic nutrients, especially of nitrogen, phosphorus and potassium salts, significantly improved agriculture, so that this particular field of science gained enormous practical importance. However, the theoretical background and the analytical methods of that time were not sufficient to obtain detailed information on the mechanism of action of essential elements, several of which occur only in trace amounts. Some very conspicuous compounds which include inorganic elements like iron-containing hemoglobin and magnesium-containing chlorophyll, the “pigments of life”, were analyzed and characterized later within a special subfield of organic chemistry, the chemistry of natural products. It was only after 1960 that bioinorganic chemistry became an independent and highly interdisciplinary research area.

The following factors have been crucial for this development:

In a desire “to accomplish something of real importance”, the biochemist James B. Sumner managed to isolate and crystallize in 1926 a pure enzyme for the first time [2], much to the skepticism and disbelief of most experienced scientists. The chosen enzyme, urease (from jack beans), catalyzes the hydrolysis of urea, O=C(NH2)2, to CO2 and 2 NH3. It contains two closely associated nickel ions per subunit (Section 9.2). It was believed by many then that pure enzymes contained no protein, and only after other enzymes were crystallized was Sumner's discovery accepted. He was honored in 1946 with the Nobel Prize in Chemistry. However, Sumner's belief that urea contained only protein was corrected in 1975 when Dixon et al. proved that urease is a nickel metalloenzyme (Section 9.2).

In a very different research area, the biological reduction of carbon dioxide by hydrogen to produce methane has been investigated by studying the relevant archaebacteria, which are found, for example, in sewage plants. Even though the experiments were carried out under strictly anaerobic conditions and all “conventional” trace elements were supplied (Figure 1.2), the results were only partly reproducible. Eventually it was discovered that during sampling with a syringe containing a supposedly inert stainless steel (Fe/Ni) tip, minute quantities of nickel had dissolved. This inadvertent generation of Ni2+ ions led to a distinctive increase in methane production [4], and, in fact, several nickel containing proteins and coenzymes have since been isolated (see Chapter 9). Incidentally, a similar unexpected dissolution effect of an apparently “inert” metal led to the serendipitous discovery of the inorganic anti-tumor agent cis-PtCl2(NH3)2 (“cisplatin”, Section 19.2.1).

---

2. Efforts to elucidate the mechanisms of organic, inorganic and biochemical reactions have led to an early understanding of the specific biological functions of some inorganic elements. Nowadays, many attempts are being made to mimic biochemical reactivity through studies of the reactivity of model systems, low-molecular-weight complexes or tailored metalloproteins (Section 2.4).

3. The rapid progress in bioinorganic chemistry, an interdisciplinary field of research (Figure 1.3), has been made possible through contributions from:

• physics (→ techniques for detection and characterization);
• various areas of biology (→ supply of material and specific modifications based on site-directed mutagenesis);
• agricultural and nutritional sciences (→ effects of inorganic elements and their mutual interdependence);
• pharmacology (→ interaction between drugs and endogeneous or exogeneous inorganic substances);
• medicine (→ imaging and other diagnostic aids, chemotherapy);
• toxicology and the environmental sciences (→ potential toxicity of inorganic compounds, depending on the concentration).

FIGURE 1.1 Nickel-containing urease, the first enzyme to be crystallized [2]. (a) Crystal structure of the full assembly of Helicobacter pylori urease, redrawn from [3] (PDB code 1E9Z). (b) Active site with two nickel centers (green spheres); histidine, aspartate, and a carbamylated lysine as ligands (Section 9.2).

FIGURE 1.2 Discovery of nickel as an essential trace element in the production of methane by archaea.

FIGURE 1.3 Bioinorganic chemistry as a highly interdisciplinary research field.

A list of examples illustrating the application potential of bioinorganic chemistry could include the following:

• Industrial sector:
  • anaerobic bacterial degradation in sewage plants or in sediments: Fe, Ni, Co;
  • biomining (bacterial leaching; ≈ 15% of the global copper production): Cu, Au, Fe, U.

• Environmental sector:
  • agricultural trace element problems: nitrogen fixation (Fe, Mo, V); Mo/Cu antagonism; Se content of soil;
  • pollution through metal species: Pb, Cd, Hg, As, Al, Cr;
  • detoxification, for example via peroxidases: Fe, Mn, V.
• Biomedical sector:
  • radiodiagnostics (single-photon emission computed tomography (SPECT), positron emission tomography (PET)), radiotherapy: Tc, I, Ga, In, Re;
  • other imaging techniques (magnetic resonance imaging (MRI), x-ray: Gd, Ba, I);
  • chemotherapy: Pt, Au, Li, B, Bi, As;
  • biominerals (biocompatible materials, coping with demineralization processes): Ca, P, C, F;
  • “inorganic” nutrients and noxious food components: deficiency, poisoning; physiological dynamics of resorption, transport, storage, excretion;
  • drug development (oxidative metabolism, metalloenzyme inhibitors): Fe, Zn;
  • biotechnological options: specific mutation, metalloprotein design.

A particularly spectacular example of applied bioinorganic chemistry is the successful use of the simple inorganic complex cis-diamminedichloroplatinum, cis-Pt(NH3)2Cl2 (“cisplatin”), in the therapy of certain tumors (Section 19.2). This compound has been the subject of one of the most successful patent applications ever granted to a university.

Even those areas of chemistry that are not primarily biologically oriented can profit from the research in bioinorganic chemistry. Due to the relentless pressure of evolutionary selection, biological processes show a high efficiency under preset conditions. These continuously self-optimizing systems can therefore serve as useful models for problems in modern chemistry. Among the most current topics of this type are:

• the efficient collection, conversion and storage of energy;
• the catalytic activation of inert substances, especially of small molecules under mild conditions in stepwise fashion;
• the (stereo)selective synthesis of high-value substances with minimization of the yield of unwanted byproducts; and
• the environmentally benign degradation and recycling of substances, especially the detoxification or recycling of chemical elements from the periodic table (Figure 1.4).

FIGURE 1.4 Periodic table of the elements. Indicated are the chapters and sections in which each element is discussed in this book. essential element; presumably essential element for human beings.

Beyond a presentation and description of bioinorganic systems, the major purpose of this book is to reveal the correlation of function, structure and actual reactivity of inorganic elements in organisms. The more biological than chemical question of “Why?” should eventually stimulate a more purposeful use of chemical compounds in nonbiological areas as well.

References

1. R. M. Hazen, The Story of Earth, Viking, New York, 2012.

2. R. D. Simoni, R. L. Hill, M. Vaughan, J. Biol. Chem. 2002, 277, e23: Urease, the first crystalline enzyme and the proof that enzymes are proteins: the work of James B. Sumner.

3. B. E. Dunn, M. G. Grutter, Nat. Struct. Biol. 2001, 8, 480–482: Helicobacter pylori springs another surprise.

4. P. Schönheit, J. Moll, R. K. Thauer, Arch. Microbiol. 1979, 123, 105–107: Nickel, cobalt, and molybdenum requirement for growth of methanobacterium thermoautotrophicum.

1 There is increasing evidence that much of the “inorganic” material on the surface of the earth has undergone transformations during long-term contact with organisms and their metabolic products, such as O2 [1].

2 The term “bioorganic chemistry” is increasingly being used for studies of organic compounds that are directly relevant for biochemistry.