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AN INTRODUCTION AND GUIDE SECOND EDITION BIOINORGANIC CHEMISTRY: INORGANIC ELEMENTS IN THE CHEMISTRY OF LIFE WOLFGANG KAIM BRIGITTE SCHWEDERSKI AXEL KLEIN INORGANIC CHEMISTRY A WILEY TEXTBOOK SERIES
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Page 1: seCond edition BIOINORGANIC CHEMISTRY: INORGANIC ELEMENTS ... · seCond edition BIOINORGANIC CHEMISTRY: INORGANIC ELEMENTS ... Structural Methods in Molecular Inorganic Chemistry

an intRoduCtion and guide

seCond edition

BIOINORGANIC CHEMISTRY: INORGANIC ELEMENTS IN THE CHEMISTRY OF LIFE

Wolfgang KaiMbRigitte sCHWedeRsKiaxel Klein

inoRganiC CHeMistRy a Wiley textbooK seRies

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Page 3: seCond edition BIOINORGANIC CHEMISTRY: INORGANIC ELEMENTS ... · seCond edition BIOINORGANIC CHEMISTRY: INORGANIC ELEMENTS ... Structural Methods in Molecular Inorganic Chemistry

Bioinorganic Chemistry: Inorganic Elements inthe Chemistry of Life

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Inorganic Chemistry

A Wiley Series of Advanced TextbooksISSN: 1939-5175

Editorial Board

David Atwood, University of Kentucky, USABob Crabtree, Yale University, USAGerd Meyer, University of Cologne, GermanyDerek Woollins, University of St. Andrews, UK

Previously Published Books in this Series

Structural Methods in Molecular Inorganic ChemistryDavid W. H. Rankin, Norbert W. Mitzel & Carole A. Morrison; ISBN: 978-0-470-97278-6

Introduction to Coordination ChemistryGeoffrey Alan Lawrance; ISBN: 978-0-470-51931-8

Chirality in Transition Metal ChemistryHani Amouri & Michel Gruselle; ISBN: 978-0-470-06054-4

Bioinorganic Vanadium ChemistryDieter Rehder; ISBN: 978-0-470-06516-7

Inorganic Structural Chemistry 2nd EditionUlrich Muller; ISBN: 978-0-470-01865-1

Lanthanide and Actinide ChemistrySimon Cotton; ISBN: 978-0-470-01006-8

Mass Spectrometry of Inorganic and Organometallic Compounds: Tools-Techniques-TipsWilliam Henderson & J. Scott McIndoe; ISBN: 978-0-470-85016-9

Main Group Chemistry, Second EditionA.G. Massey; ISBN: 978-0-471-19039-5

Synthesis of Organometallic Compounds: A Practical GuideSanshiro Komiya; ISBN: 978-0-471-97195-5

Chemical Bonds: A DialogJeremy Burdett; ISBN: 978-0-471-97130-6

The Molecular Chemistry of the Transition Elements: An Introductory CourseFrancois Mathey & Alain Sevin; ISBN: 978-0-471-95687-7

Stereochemistry of Coordination CompoundsAlexander von Zelewsky; ISBN: 978-0-471-95599-3

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

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Bioinorganic Chemistry:Inorganic Elements in theChemistry of LifeAn Introduction and Guide

Second Edition

Written and Translated by

Wolfgang KaimUniversity of Stuttgart, Institute of Inorganic Chemistry,Stuttgart, Germany

Brigitte SchwederskiUniversity of Stuttgart, Institute of Inorganic Chemistry,Stuttgart, Germany

Axel KleinUniversity of Cologne, Institute of Inorganic Chemistry,Cologne, Germany

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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 officeJohn 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 inthis book please see our website at www.wiley.com.

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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 permissionof the publisher.

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The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes ingovernmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged toreview and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, amongother things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website isreferred 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 informationthe organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work mayhave changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotionalstatements 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 2013572′.51–dc23 2013011894

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

HB ISBN: 9780470975244PB ISBN: 9780470975237

Typeset in 10/12pt Times by Aptara Inc., New Delhi, India

1 2013

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Contents

Preface to the Second Edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

Preface to the First Edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii

1 Historical Background, Current Relevance and Perspectives . . . . . . . . . . . . . . . 1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

2 Some General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.1 Occurrence and Availability of Inorganic Elements in Organisms . . . . . . . . . . . 7

Insertion: The Chelate Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Insertion: “Hard” and “Soft” Coordination Centers . . . . . . . . . . . . . . . . . . 14

2.2 Biological Functions of Inorganic Elements . . . . . . . . . . . . . . . . . . . . . 142.3 Biological Ligands for Metal Ions . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.3.1 Coordination by Proteins-Comments on Enzymatic Catalysis . . . . . . . . 17Insertion: The “Entatic State” in Enzymatic Catalysis . . . . . . . . . . . . . . . . 202.3.2 Tetrapyrrole Ligands and Other Macrocycles . . . . . . . . . . . . . . . . 22Insertion: Electron Spin States in Transition Metal Ions . . . . . . . . . . . . . . . . 282.3.3 Nucleobases, Nucleotides and Nucleic Acids (RNA, DNA) as Ligands . . . . 31Insertion: Secondary Bonding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

2.4 Relevance of Model Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . 34References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

3 Cobalamins, Including Vitamin and Coenzyme B12 . . . . . . . . . . . . . . . . . . . 373.1 History and Structural Characterization . . . . . . . . . . . . . . . . . . . . . . . 37

Insertion: Bioorganometallics I . . . . . . . . . . . . . . . . . . . . . . . . . . . 383.2 General Reactions of Alkylcobalamins . . . . . . . . . . . . . . . . . . . . . . . 41

3.2.1 One-electron Reduction and Oxidation . . . . . . . . . . . . . . . . . . . 413.2.2 Co–C Bond Cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Insertion: Electron Paramagnetic Resonance I . . . . . . . . . . . . . . . . . . . . 43

3.3 Enzyme Functions of Cobalamins . . . . . . . . . . . . . . . . . . . . . . . . . . 453.3.1 Adenosylcobalamin (AdoCbl)-dependent Isomerases . . . . . . . . . . . . 45Insertion: Organic Redox Coenzymes . . . . . . . . . . . . . . . . . . . . . . . . 483.3.2 Alkylation Reactions of Methylcobalamin (MeCbl)-dependent Alkyl

Transferases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513.4 Model Systems and the Enzymatic Activation of the Co–C Bond . . . . . . . . . . . 52

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

4 Metals at the Center of Photosynthesis: Magnesium and Manganese . . . . . . . . . . . 574.1 Volume and Efficiency of Photosynthesis . . . . . . . . . . . . . . . . . . . . . . 574.2 Primary Processes in Photosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . 59

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vi Contents

4.2.1 Light Absorption (Energy Acquisition) . . . . . . . . . . . . . . . . . . . 594.2.2 Exciton Transport (Directed Energy Transfer) . . . . . . . . . . . . . . . . 594.2.3 Charge Separation and Electron Transport . . . . . . . . . . . . . . . . . . 62Insertion: Structure Determination by X-ray Diffraction . . . . . . . . . . . . . . . 65

4.3 Manganese-catalyzed Oxidation of Water to O2 . . . . . . . . . . . . . . . . . . . 67Insertion: Spin–Spin Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . 73References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

5 The Dioxygen Molecule, O2: Uptake, Transport and Storage of an InorganicNatural Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775.1 Molecular and Chemical Properties of Dioxygen, O2 . . . . . . . . . . . . . . . . . 775.2 Oxygen Transport and Storage through Hemoglobin and Myoglobin . . . . . . . . . 825.3 Alternative Oxygen Transport in Some Lower Animals: Hemerythrin and Hemocyanin 92

5.3.1 Magnetism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925.3.2 Light Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935.3.3 Vibrational Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . 93Insertion: Resonance Raman Spectroscopy . . . . . . . . . . . . . . . . . . . . . . 935.3.4 Mossbauer Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . 94Insertion: Mossbauer Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . 945.3.5 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

5.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

6 Catalysis through Hemoproteins: Electron Transfer, Oxygen Activation and Metabolismof Inorganic Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996.1 Cytochromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016.2 Cytochrome P-450: Oxygen Transfer from O2 to Nonactivated Substrates . . . . . . . 1036.3 Peroxidases: Detoxification and Utilization of Doubly Reduced Dioxygen . . . . . . . 1086.4 Controlling the Reaction Mechanism of the Oxyheme Group: Generation

and Function of Organic Free Radicals . . . . . . . . . . . . . . . . . . . . . . . 1106.5 Hemoproteins in the Catalytic Transformation of Partially Reduced Nitrogen

and Sulfur Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112Insertion: Gasotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

7 Iron–Sulfur and Other Non-heme Iron Proteins . . . . . . . . . . . . . . . . . . . . . 1177.1 Biological Relevance of the Element Combination Iron–Sulfur . . . . . . . . . . . . 117

Insertion: Extremophiles and Bioinorganic Chemistry . . . . . . . . . . . . . . . . 1187.2 Rubredoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227.3 [2Fe-2S] Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227.4 Polynuclear Fe/S Clusters: Relevance of the Protein Environment and Catalytic Activity 1237.5 Model Systems for Fe/S Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . 1287.6 Iron-containing Enzymes without Porphyrin or Sulfide Ligands . . . . . . . . . . . . 130

7.6.1 Iron-containing Ribonucleotide Reductase . . . . . . . . . . . . . . . . . 1307.6.2 Soluble Methane Monooxygenase . . . . . . . . . . . . . . . . . . . . . 1327.6.3 Purple Acid Phosphatases (Fe/Fe and Fe/Zn) . . . . . . . . . . . . . . . . 1337.6.4 Mononuclear Non-heme Iron Enzymes . . . . . . . . . . . . . . . . . . . 133References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

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Contents vii

8 Uptake, Transport and Storage of an Essential Element, as Exemplified by Iron . . . . . 139Insertion: Metallome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

8.1 The Problem of Iron Mobilization: Oxidation States, Solubility and Medical Relevance 1408.2 Siderophores: Iron Uptake by Microorganisms . . . . . . . . . . . . . . . . . . . . 141

Insertion: Optical Isomerism in Octahedral Complexes . . . . . . . . . . . . . . . . 1448.3 Phytosiderophores: Iron Uptake by Plants . . . . . . . . . . . . . . . . . . . . . . 1498.4 Transport and Storage of Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

8.4.1 Transferrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1528.4.2 Ferritin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558.4.3 Hemosiderin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

9 Nickel-containing Enzymes: The Remarkable Career of a Long-overlooked Biometal . . 1639.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1639.2 Urease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1649.3 Hydrogenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1669.4 CO Dehydrogenase = CO Oxidoreductase = Acetyl-CoA Synthase . . . . . . . . . . 1699.5 Methyl-coenzyme M Reductase (Including the F430 Cofactor) . . . . . . . . . . . . 172

Insertion: Natural and Artificial (Industrial) C1 Chemistry . . . . . . . . . . . . . . 174Insertion: Bioorganometallics II: The Organometallic Chemistry of Cobalt and Nickel . 176

9.6 Superoxide Dismutase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1779.7 Model Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

10 Copper-containing Proteins: An Alternative to Biological Iron . . . . . . . . . . . . . . 18310.1 Type 1: “Blue” Copper Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

Insertion: Electron Paramagnetic Resonance II . . . . . . . . . . . . . . . . . . . . 18710.2 Type 2 and Type 3 Copper Centers in O2-activating Proteins: Oxygen Transport

and Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19110.3 Copper Proteins as Oxidases/Reductases . . . . . . . . . . . . . . . . . . . . . . . 19510.4 Cytochrome c Oxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20010.5 Cu,Zn- and Other Superoxide Dismutases: Substrate-specific Antioxidants . . . . . . 203

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

11 Biological Functions of the “Early” Transition Metals: Molybdenum, Tungsten,Vanadium and Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21111.1 Oxygen Transfer through Tungsten- and Molybdenum-containing Enzymes . . . . . . 211

11.1.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21111.1.2 Oxotransferase Enzymes Containing the Molybdopterin or

Tungstopterin Cofactor . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Insertion: “Oxidation” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

11.2 Metalloenzymes in the Biological Nitrogen Cycle: Molybdenum-dependentNitrogen Fixation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

11.3 Alternative Nitrogenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22611.4 Biological Vanadium Outside of Nitrogenases . . . . . . . . . . . . . . . . . . . . 22911.5 Chromium(III) in the Metabolism? . . . . . . . . . . . . . . . . . . . . . . . . . 231

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

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12 Zinc: Structural and Gene-regulatory Functions and the Enzymatic Catalysis ofHydrolysis and Condensation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 23512.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23512.2 Carboanhydrase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23812.3 Carboxypeptidase A and Other Hydrolases . . . . . . . . . . . . . . . . . . . . . 24312.4 Catalysis of Condensation Reactions by Zinc-containing Enzymes . . . . . . . . . . 24812.5 Alcohol Dehydrogenase and Related Enzymes . . . . . . . . . . . . . . . . . . . . 24912.6 The “Zinc Finger” and Other Gene-regulatory Zinc Proteins . . . . . . . . . . . . . 25112.7 Insulin, hGH, Metallothionein and DNA Repair Systems as Zinc-containing Proteins . 253

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

13 Unequally Distributed Electrolytes: Function and Transport of Alkali and Alkaline EarthMetal Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25713.1 Characterization and Biological Roles of K+, Na+, Ca2+ and Mg2+ . . . . . . . . . . 257

Insertion: Heteroatom Nuclear Magnetic Resonance . . . . . . . . . . . . . . . . . 26213.2 Complexes of Alkali and Alkaline Earth Metal Ions with Macrocycles . . . . . . . . 26413.3 Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26713.4 Ion Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270

Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273

14 Catalysis and Regulation of Bioenergetic Processes by the Alkaline Earth Metal IonsMg2+ and Ca2+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27714.1 Magnesium: Catalysis of Phosphate Transfer by Divalent Ions . . . . . . . . . . . . 27714.2 The Ubiquitous Regulatory Role of Ca2+ . . . . . . . . . . . . . . . . . . . . . . 283

Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

15 Biomineralization: The Controlled Assembly of “Advanced Materials” in Biology . . . . 29515.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29515.2 Nucleation and Crystal Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

Insertion: Dimensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30015.3 Examples of Biominerals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

15.3.1 Calcium Phosphate in the Bones of Vertebrates and the Global P Cycle . . . . 301Insertion: The Global P Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30515.3.2 Calcium Carbonate and the Global Inorganic C Cycle . . . . . . . . . . . . 306Insertion: The Global C Cycle and the Marine Inorganic C Cycle . . . . . . . . . . . 30715.3.3 Amorphous Silica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30815.3.4 Iron Biominerals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30915.3.5 Strontium and Barium Sulfates . . . . . . . . . . . . . . . . . . . . . . . 310

15.4 Biomimetic Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

16 Biological Functions of the Nonmetallic Inorganic Elements . . . . . . . . . . . . . . . 31516.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31516.2 Boron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31516.3 Silicon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

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Contents ix

16.4 Arsenic and Trivalent Phosphorus . . . . . . . . . . . . . . . . . . . . . . . . . . 31616.5 Bromine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31716.6 Fluorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31716.7 Iodine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31816.8 Selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

17 The Bioinorganic Chemistry of the Quintessentially Toxic Metals . . . . . . . . . . . . 32717.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32717.2 Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32917.3 Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33217.4 Thallium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33417.5 Mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33517.6 Aluminum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34017.7 Beryllium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34217.8 Chromium and Tungsten . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34317.9 Toxicity of Nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

18 Biochemical Behavior of Radionuclides and Medical Imaging Using InorganicCompounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34918.1 Radiation Risks and Medical Benefits from Natural and Synthetic Radionuclides . . . 349

18.1.1 The Biochemical Impact of Ionizing Radiation from Radioactive Isotopes . . 34918.1.2 Natural and Synthetic Radioisotopes . . . . . . . . . . . . . . . . . . . . 35018.1.3 Bioinorganic Chemistry of Radionuclides . . . . . . . . . . . . . . . . . . 351Insertion: Fukushima Daiichi, Chernobyl, Hiroshima and Nuclear Weapons Testing . . 35318.1.4 Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . 35618.1.5 Technetium: A “Synthetic Bioinorganic Element” . . . . . . . . . . . . . . 35918.1.6 Radiotracers for the Investigation of the Metallome . . . . . . . . . . . . . 363

18.2 Medical Imaging Based on Nonradioactive Inorganic Compounds . . . . . . . . . . 36318.2.1 Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . 36318.2.2 X-ray Contrast Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . 364Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365

19 Chemotherapy Involving Nonessential Elements . . . . . . . . . . . . . . . . . . . . . 36919.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36919.2 Platinum Complexes in Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . 369

19.2.1 Discovery, Application and Structure–Effect Relationships . . . . . . . . . . 36919.2.2 Cisplatin: Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . 372

19.3 New Anticancer Drugs Based on Transition Metal Complexes . . . . . . . . . . . . 37819.3.1 Overview and Aims for Drug Development . . . . . . . . . . . . . . . . . 37819.3.2 Nonplatinum Anticancer Drugs . . . . . . . . . . . . . . . . . . . . . . . 379

19.4 Further Inorganic Compounds in (Noncancer) Chemotherapy . . . . . . . . . . . . . 38319.4.1 Gold-containing Drugs Used in the Therapy of Rheumatoid Arthritis . . . . . 38319.4.2 Lithium in Psychopharmacologic Drugs . . . . . . . . . . . . . . . . . . . 38419.4.3 Bismuth Compounds against Ulcers . . . . . . . . . . . . . . . . . . . . . 385

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x Contents

19.4.4 Vanadium-containing Insulin Mimetics and V-containing Anti-HIV Drugs . . 38619.4.5 Sodium Nitroprusside . . . . . . . . . . . . . . . . . . . . . . . . . . . 386

19.5 Bioorganometallic Chemistry of Nonessential Elements . . . . . . . . . . . . . . . 387Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

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Preface to the Second Edition

The predictably enormous growth of bioinorganic chemistry has made a second edition ofthis text both necessary and difficult. While there are several extensive and often specializedreviews, major texts and handbooks on this subject, our experience in teaching it has sug-gested the provision of an updated overview of the classical, novel and applied sections of thefield, 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 someintricate metalloproteins, such as water oxidase and the molybdopterin-based enzymes,has been included, replacing the earlier speculative models. Emerging developments arereferred to at various points, covering such topics as bioorganometallic chemistry, nucleicacid 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 requiredthat more space be devoted to this particular aspect. Nonetheless, we have tried to keep theamount of material at a constant, manageable level suitable for an introductory overview,rather than the typical condensed fragments presented in general textbooks of inorganicchemistry or biochemistry. To achieve this, we have tried to concentrate on the facts and ondescriptions of function, rather than on model compounds or mechanistic hypotheses (whichmay vary with time); excellent treatments of the reaction mechanisms of bioinorganicsystems 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 Mendezand P. Dominguez de Maria’s Redox Biocatalysis: Fundamentals and Applications (JohnWiley & Sons, 2012). A basic knowledge of inorganic, organic, physical and biologicalchemistry remains necessary to make optimal use of this text.

Throughout this book, we have made reference to the RCSB Protein Data Bank forbiological 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 thatthe 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 patienceand 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 thepreparation of the manuscript.

Wolfgang KaimBrigitte Schwederski

Axel KleinStuttgart and Cologne, January 2013

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

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Preface to the First Edition

This book originated from a two-semester course offered at the Universities of Frankfurtand 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 yearof study at a university or its equivalent. Despite these requirements we have decidedto explain some special terms in a glossary and, furthermore, several less conventionalphysical methods are briefly described and evaluated with regard to their practical relevanceat appropriate positions in the text.

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

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

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

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

For helpful comments and encouragement during the writing and correction ofmanuscripts we thank many of our colleagues. Recent results have become available tous through participation in the special program “Bioanorganische Chemie” of the Deutsche

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xiv Preface to the First Edition

Forschungsgemeinschaft (DFG). We also thank Teubner-Verlag and John Wiley & Sonsfor their patience and support. Very special thanks are due to Mrs Angela Winkelmann forher continued involvement in the processing of the manuscript.

Wolfgang KaimBrigitte Schwederski

Stuttgart, December 1993

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1 Historical Background, CurrentRelevance and Perspectives

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

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

The description of a rapidly developing field of chemistry as “bioinorganic” seems to in-volve a contradiction in terms, which, however, simply reflects a misconception going backto the beginning of modern science. In the early 19th century, chemistry was still dividedinto an “organic” chemistry which included only substances isolated from “organisms”,and an “inorganic” chemistry of “dead matter”.1 This distinction became meaningless afterWohler’s synthesis of “organic” urea from “inorganic” ammonium cyanide in 1828. Nowa-days, 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 ofthe 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 twoareas are by no means identical.2 Improved trace analytical methods have demonstratedthe importance of quite a number of “inorganic” elements in biochemical processes andhave thus revealed a multitude of partially inorganic natural products. A corresponding listwould 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, . . . ).

1There is increasing evidence that much of the “inorganic” material on the surface of the earth has undergonetransformations during long-term contact with organisms and their metabolic products, such as O2 [1].2The term “bioorganic chemistry” is increasingly being used for studies of organic compounds that are directlyrelevant for biochemistry.

Bioinorganic Chemistry: Inorganic Elements in the Chemistry of Life – An Introduction and Guide, Second Edition.Written and Translated by Wolfgang Kaim, Brigitte Schwederski and Axel Klein.© 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.

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2 Historical Background, Current Relevance and Perspectives

Some (by today’s definition) “inorganic” elements were established quite early as essen-tial 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 an-imal blood in the 18th century, and the discoveries of elemental phosphorus (as P4) by drydistillation of urine residues in 1669 and of elemental iodine from the ashes of marine algaein 1811.

In the middle of the 19th century, Liebig’s studies on the metabolism of inorganicnutrients, especially of nitrogen, phosphorus and potassium salts, significantly improvedagriculture, so that this particular field of science gained enormous practical importance.However, the theoretical background and the analytical methods of that time were notsufficient to obtain detailed information on the mechanism of action of essential elements,several of which occur only in trace amounts. Some very conspicuous compounds whichinclude inorganic elements like iron-containing hemoglobin and magnesium-containingchlorophyll, the “pigments of life”, were analyzed and characterized later within a specialsubfield of organic chemistry, the chemistry of natural products. It was only after 1960 thatbioinorganic chemistry became an independent and highly interdisciplinary research area.

The following factors have been crucial for this development:

1. Biochemical isolation and purification procedures, such as chromatography, and thenew physical methods of trace element analysis, such as atomic absorption or emissionspectroscopy, require ever smaller amounts of material. These methodical advances havemade it possible not only to detect but also to chemically and functionally characterizetrace elements or otherwise inconspicuous metal ions in biological materials. An adulthuman being, for example, contains about 2 g of zinc in ionic form (Zn2+). Althoughzinc cannot be regarded as a true trace element, the unambiguous proof of its existence inenzymes was established only in the 1930s. Genuine bioessential trace elements such asnickel (Figures 1.1 and 1.2), (Chapter 9) and selenium (Chapter 16.8) have been knownto be present as constitutive components in several important enzymes only since about1970.

KCX-219

HIS-138

(a) (b)

HIS-248

HIS-274ASP-362

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

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Historical Background, Current Relevance and Perspectives 3

reaction: 4 H2 + CO2 CH4 + 2 H2O

methanogenicbacteria

experimental setup:metal ions in the medium:K+

Na+Mn2+

Zn2+

80% H2

NaMg2+

Ca2+

Fe2+

ZnCu2+

Co2+

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2+with Ni

80% H2,20% CO2

trace H2S exhaust (CH4)

bac

teri

al g

row

th

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0 2 4 6 8 10

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

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 chosenenzyme, urease (from jack beans), catalyzes the hydrolysis of urea, O=C(NH2)2, toCO2 and 2 NH3. It contains two closely associated nickel ions per subunit (Section9.2). It was believed by many then that pure enzymes contained no protein, andonly after other enzymes were crystallized was Sumner’s discovery accepted. Hewas honored in 1946 with the Nobel Prize in Chemistry. However, Sumner’s beliefthat urea contained only protein was corrected in 1975 when Dixon et al. provedthat urease is a nickel metalloenzyme (Section 9.2).

In a very different research area, the biological reduction of carbon dioxideby hydrogen to produce methane has been investigated by studying the relevantarchaebacteria, which are found, for example, in sewage plants. Even though theexperiments were carried out under strictly anaerobic conditions and all “con-ventional” trace elements were supplied (Figure 1.2), the results were only partlyreproducible. Eventually it was discovered that during sampling with a syringecontaining a supposedly inert stainless steel (Fe/Ni) tip, minute quantities of nickelhad dissolved. This inadvertent generation of Ni2+ ions led to a distinctive increasein methane production [4], and, in fact, several nickel containing proteins and coen-zymes have since been isolated (see Chapter 9). Incidentally, a similar unexpecteddissolution effect of an apparently “inert” metal led to the serendipitous discoveryof 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 reactionshave led to an early understanding of the specific biological functions of some inorganicelements. Nowadays, many attempts are being made to mimic biochemical reactivity

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4 Historical Background, Current Relevance and Perspectives

Figure 1.3Bioinorganic chemistry as a highly interdisciplinary research field.

through studies of the reactivity of model systems, low-molecular-weight complexes ortailored 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 inor-

ganic substances);◦ medicine (→ imaging and other diagnostic aids, chemotherapy);◦ toxicology and the environmental sciences (→ potential toxicity of inorganic com-

pounds, depending on the concentration).

A list of examples illustrating the application potential of bioinorganic chemistry couldinclude 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.

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H(7

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6 Historical Background, Current Relevance and Perspectives

� 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; physiolog-

ical 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 success-ful 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 thesubject 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 profitfrom the research in bioinorganic chemistry. Due to the relentless pressure of evolution-ary selection, biological processes show a high efficiency under preset conditions. Thesecontinuously self-optimizing systems can therefore serve as useful models for problems inmodern 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 detox-

ification or recycling of chemical elements from the periodic table (Figure 1.4).

Beyond a presentation and description of bioinorganic systems, the major purpose ofthis book is to reveal the correlation of function, structure and actual reactivity of inorganicelements in organisms. The more biological than chemical question of “Why?” shouldeventually stimulate a more purposeful use of chemical compounds in nonbiological areasas 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. Schonheit, J. Moll, R. K. Thauer, Arch. Microbiol. 1979, 123, 105–107: Nickel, cobalt, and

molybdenum requirement for growth of methanobacterium thermoautotrophicum.

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2 Some General Principles

2.1 Occurrence and Availability of Inorganic Elements in Organisms

“Life” is a process which, for an adult organism, can be characterized as a controlled sta-tionary flow equilibrium maintained by energy-consuming chemical reactions (“dissipativesystem”). Input and output are essential requirements for such open systems. They differvery much from the more familiar and mathematically far more easily described “dead”thermodynamic equilibria (Figure 2.1).

Figure 2.1Two kinds of “equilibrium”.

In addition to the energy flux, life requires a continuous material exchange which,in principle, includes all chemical elements (see Figure 1.4). The occurrence of theseelements in organisms depends on external and endogeneous conditions; elements can be“bioavailable” to variable extents but can also be enriched (“bioaccumulated”) by organismsusing active, energy-consuming processes involving a local reduction of entropy. Sometrends are obvious from the most familiar example, the elemental composition of thehuman body (Table 2.1).

The values for O and H in Table 2.1 reflect the high content of (inorganic) water;the “organic” element carbon only comes in third. Calcium as the first metallic elementranks fifth, its main quantitative use being the stabilization of the endoskeleton. Table 2.1further shows relatively large quantities of potassium, chlorine, sodium and magnesium,

Bioinorganic Chemistry: Inorganic Elements in the Chemistry of Life – An Introduction and Guide, Second Edition.Written and Translated by Wolfgang Kaim, Brigitte Schwederski and Axel Klein.© 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.

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8 Some General Principles

Table 2.1 Average elemental composition of a human body (adult, 70 kg) [1].

Element Symbol Mass (g)

oxygen O 43 000carbon C 16 000hydrogen H 7000nitrogen N 1800calcium Ca 1200phosphorus P 780sulfur S 140potassium K 125sodium Na 100chlorine Cl 95magnesium Mg 25fluorine F 5.0 (var.)iron Fe 4.0zinc Zn 2.3silicon Si 1.0 (var.)titaniuma Ti 0.70rubidiuma Rb 0.68strontiuma Sr 0.32brominea Br 0.26leadb Pb 0.12copper Cu 0.07aluminuma Al 0.06ceriuma Ce 0.04tinb Sn 0.03bariuma Ba 0.02cadmiumb Cd 0.02 (var.)boronb B 0.018nickel Ni 0.015iodine I 0.015selenium Se 0.014manganese Mn 0.012arsenicb As 0.007 (var.)lithiuma Li 0.007molybdenum Mo 0.005chromium Cr 0.002 (var.)cobalt Co 0.002

aNot rated essential.bEssential character not unambiguous.

the “mass” or “quantity elements” or “macronutrients”. Iron, zinc and fluorine are distinctlyless abundant inorganic elements. According to one definition, “trace elements” with regardto the human body involve a daily requirement of less than 25 mg (see Table 2.3), and someof them, such as boron, arsenic and tin, have not yet been unambiguously defined withregard to amount, essential character and function [2]. Since humans coexist with a host ofsupporting “lower” organisms – the “microbiome” – their requirements for trace elementswill also have to be added. Elements are essential if their total absence in the organism causessevere, irreversible damage. Sometimes essentiality is invoked if the optimal functioningof organisms is impaired; in such instances the corresponding elements would be betterreferred to as “beneficial”. Table 2.1 illustrates the occurrence of non-negligible quantitiesof obviously nonessential elements such as Ti, Rb, Sr, Br, Al and Li in the human body.

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Occurrence and Availability of Inorganic Elements in Organisms 9

positive

negative

state of „health“

death death

phys

iolo

gica

l res

pons

e

concentration (dose)

defic

ienc

ysy

mpt

oms

toxi

cef

fect

Figure 2.2Schematic dose–response relationship (Bertrand diagram) for an essential element (compare Figure17.1 for exclusively toxic elements).

These elements are probably incorporated due to a chemical similarity (indicated by ↔)with important essential elements (Li+, Rb+, Cs+ ↔ Na+, K+; Sr+, Ba2+ ↔ Ca2+; Br−

↔ Cl−; Al3+, Ti4+ ↔ Fe3+). Elements that are known to be mainly toxic, such as As, Pband Cd, deserve special attention; a positive effect of traces has been discussed for someof these elements, pointing to the ambivalence of many trace elements and to the problemof threshold values (see Figures 2.2 and 2.3). Possibly a physiological – if not alwaysessential – function developed for all naturally occurring elements during the evolution oflife [3].

population section

affected by

very small doses

population section

affected only

by high doses

0

50

100

pe

rce

nta

ge

of a

ffe

cte

d in

div

idu

als

concentration (dose)

Figure 2.3Typical variance of the (toxic) effect of a substance within a population.

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10 Some General Principles

The elements silicon, aluminum and titanium, which are prominent as components ofminerals in the earth’s crust, play only a marginal role in the biosphere. Under normalphysiological conditions (pH ≈ 7), these elements in their usual high oxidation states existas nearly insoluble oxides or hydroxides and are therefore not (bio)available. Molybde-num, on the other hand, is a rare element in the earth’s crust but is quite soluble at pH 7as MoO4

2− and thus relatively abundant in sea water; it has therefore been found as anessential element in many organisms. As a rule, metallic elements are soluble in neutralaqueous media and thus bioavailable in either low (+I, +II, i.e. as hydrated cations) or veryhigh oxidation states (+V, +VI, +VII), as hydrated oxoanions such as MO4

n−. However,one should not underestimate the ability of organisms to actively transport and accumulateinorganic substances. As pointed out in Chapter 13, living systems have developed elabo-rate mechanisms and use much energy to create and maintain concentration gradients forinorganic ions between membrane-separated compartments inside of organisms. Similarly,there are efficient biological mechanisms to accumulate silicate or Fe3+ ions, both of whichare practically insoluble at pH 7, and thus make them bioavailable for structural or otherpurposes (see Chapters 8 and 15). Not surprisingly, the elemental compositions are highlyvariable for different species and even different parts of higher organisms, depending interalia on the kind of metabolism and on the biotope.

The flow equilibrium character of life processes (Figure 2.1) implies that the individualinorganic elements are continuously excreted and replenished even though their overallstationary concentration remains approximately constant (“homeostasis”). The rate of ex-change is strongly dependent on the type of compound (chemical speciation) and on the siteof action or storage in the individual organism. According to established principles of re-action kinetics, ions of low charge are exchanged relatively quickly (K+, Mn2+, MoO4

2−),whereas more highly charged species such as Fe3+ have longer physiological half lives. Itis not surprising that elements such as Ca2+, which find their main quantitative use in thesolid-state skeleton, are on the whole exchanged very slowly. The biological half life canthen amount to several years; nevertheless, a continuous metabolism takes place even for“biominerals” (see Chapter 15).

Which elements are essential, which are beneficial and which are toxic for a certainorganism? Such questions are continuously being discussed in popular science, particularlyfor humans. Quantitatively, this is a matter of the physiological state (i.e. of the ability to“function” properly) or even of the individual disposition of an organism, depending on theconcentration or “dose” of an element, which is often related to its share in the food supply.A dose–response diagram of the type in Figure 2.2 can thus be discussed; this shows theambivalent effects of many substances and illustrates the principle of Paracelsus: “The dosemakes the poison”. An important term here is the therapeutic window, which characterizesthe concentration range causing advantageous physiological effects.

In a more detailed approach, the following aspects have to be considered:

� The type of chemical compound, of which the element is a part, is often crucial forthe response of the organism (chemical speciation). The pathway, the extent and therate of uptake, metabolism, storage and excretion can differ greatly; poor utilization ofan otherwise bioavailable essential trace element may thus be responsible for deficiencysymptoms. The absorption of inorganic compounds by the organism depends primarily onthe solubility and therefore the charge of the system; humans resorb molybdate MoO4

2−

quite well, whereas slowly reacting Cr3+ is resorbed only to a small extent.

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Occurrence and Availability of Inorganic Elements in Organisms 11

� Given the essentiality of biological compartmentalization within and between cells, thetoxicity of an (inorganic) species may depend strongly on the site of action. Manybioessential elements are thus also potent carcinogens, depending on their location.

� It cannot be expected that higher organisms will react uniformly within a population orin the course of their individual development. Therefore, only average statements canbe made with regard to a certain situation, such as for the adult state of a preferentiallyhomogeneous population (Figure 2.3).

� The concentration variation of one particular element frequently affects the concentra-tions and physiological effects of other substances, including compounds of other in-organic elements. This multidimensional interdependence has been known qualitativelyfor a number of elemental nutrients since the experiments of Liebig. Two componentscan interact by mutually promoting corresponding effects (synergism) or by competingand suppressing each other’s effects (antagonism).

An antagonistic relationship in a two-component system can be the result of displace-ment (Zn2+ ↔ Cd2+, Pb2+, Cu2+ or Ca2+) or mutual deactivation (Cu2+ + S2− → CuS(insoluble)). With three components, for example in the system Cu/Mo/S (Chapter 10 andSection 11.1.2), matters get more complicated, and in reality there is a multidimensionalnetwork of synergistic and antagonistic relationships, which is further complicated by thespatially unsymmetrical distribution of inorganic elements in organisms [4]. For instance,there are strongly contrasting distributions of soluble monocations (Na+ vs K+), dications(Ca2+ vs Mg2+) and monoanions (Cl− vs H2PO4

−) in the extra- and intracellular regions,respectively, as outlined in Chapter 13.

Despite this complexity, some deficiency symptoms of individual inorganic elementsare quite familiar, particularly as they concern human beings [2,5] (see the incompletelist in Table 2.2). As far as causal connections are known for the single elements, thesewill be discussed in the relevant chapters within this book. A general syndrome of (trace)element deficiency is growth retardation: the number of truly essential elements seems tobe smaller in fully developed organisms than during growth periods. This assumption was

Table 2.2 Some characteristic symptoms of chemical element deficiency in humans.

Deficient element Typical deficiency symptoms

Ca retarded skeletal growthMg muscle crampsFe anemia, disorders of the immune systemZn skin damage, stunted growth, retarded sexual maturationCu artery weakness, liver disorders, secondary anemiaMn infertility, impaired skeletal growthMo retardation of cellular growth, propensity for cariesCo pernicious anemiaNi growth depression, dermatitisCr diabetes symptomsSi disorders of skeletal growthF dental cariesI thyroid disorders, retarded metabolismSe muscular weakness, esp. cardiomyopathyAs impaired growth (in animals)

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12 Some General Principles

Table 2.3 Essential elements in food for adults and infants.

Inorganic constituent RDA (adults),a in mg AI (infants),b in mg

K 4700 400–700Na 1200–1500 120–370Ca 100–1300 200–260Mg 310–420 30–75Zn 8–11 2–3Fe 8–18 0.27–11.0Mn 1.6–2.3 0.003–0.6Cu 0.9 0.2Mo 0.045 0.002Cr 0.02–0.035 0.0002–0.005Co ∼0.0024 (vitamin B12) 0.0004Cl 1800–2300 180–570PO4

3− 700 100–275F 3–4 0.01–0.5I 0.15 0.11–0.13Se 0.055 0.015–0.020

aRecommended Dietary Allowance (RDA) is derived from the Estimated Average Requirement (EAR [6]). 97.5%of the population meets or exceeds the EAR. Data taken for male and female age groups from 19 to 70 years.bAdequate Intake (AI) is used when an EAR/RDA cannot be developed. The AI level is based on observed orexperimental intakes. Data reflect mean values for infants 0–6 months and 6–12 months old (lower and highervalues, respectively).Sources: National Research Council. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, VitaminD, and Fluoride, 1997; Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, VitaminB12, Pantothenic Acid, Biotin, and Choline, 1998; Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium,and Carotenoids, 2000; Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper,Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc, 2001; Dietary Reference Intakes forWater, Potassium, Sodium, Chloride, and Sulfate, 2005; Dietary Reference Intakes for Calcium and Vitamin D,2011. Washington, DC: The National Academies Press.

confirmed by pioneering experiments in the 1960s, which were designed to guarantee anutritionally complete diet for astronauts during long space flights. The inorganic contentsof such synthetic food are summarized in Table 2.3 in the form of the RDA (RecommendedDietary Allowance [6]) values of the US Food and Drug Administration (FDA). Whethersuch a composition is really sufficient or guaranteed in today’s food supply and how farit can be exceeded via increased uptake or separate supplementation without detrimentalconsequences are still open questions in dietetics, particularly from the popular scientificpoint of view.

According to Figure 2.3, there are not only deficiency symptoms from the lack ofessential elements but also toxic effects resulting from an excess of these, whether causedby insufficient excretion or by excessive uptake [7]. Such poisoning can be treated using“bioinorganic” measures, namely through the application of antagonists or a “chelatetherapy” [8,9], which involves the complexation and excretion of acutely toxic metalions using multidentate chelate ligands ((2.1), Table 2.4). Considering that there are anumber of essential metal ions present in organisms, the problem of selectivity is obvious;selectively coordinating ligands have thus been developed for some specific heavy-metalions. The most successful such ligands offer selectivity either (i) according to the preferredsize of the coordinated ion or (ii) with respect to favored coordinating atoms (S for “soft”heavy metals, N especially for Cu2+, O for “hard” metal centers). Furthermore, suitable

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Occurrence and Availability of Inorganic Elements in Organisms 13

Table 2.4 Chelate ligands for detoxification after metal poisoning.

Ligand (2.1)Trade or trivialname

Preferablycoordinatedmetal ions

Detaileddescription inChapter/Section

(a) 2,3-dimercapto-1-propanol dimercaprol,BAL

Hg2+, As3+, Sb3+,Ni3+

17

(b) D-2-amino-3-mercapto-3-methylbutyric acid(D-�,�-dimethylcysteine)a

D-penicillamine Cu2+, Hg2+ 10, 17

(c) ethylenediaminetetraacetate EDTA Ca2+, Pb2+

(d) deferrioxamine B DFO, desferal Fe2+, AI3+ 8.2, 17.6(e) 3,4,3-LICAMC Pu4+ 18.1.3.3

aThe L-enantiomer is toxic.

chelate ligands must (iii) form kinetically and thermodynamically stable complexes and (iv)facilitate rapid renal excretion, for example by containing hydrophilic hydroxyl groups.

H2C CH CH2OHSHHS

(a)

(CH3)2C CH COO−

+NH2HS

(b)H

N CH2 CH2

CH2

(c)

N

−OOC

CH2−OOC

CH2

CH2

COO−

COO−

(d)

COO−

OH

OHC O

HN

(e)

COO−

OH

OHC O

N

COO−

OH

OHC O

N

COO−

OH

OHC O

NH(CH2)3 (CH2)4 (CH2)3

H: acidic protons which may be substituted by chelated metal ions

2NH2 (CH2)5 (CH2)5(CH2)2N

OH

N

OH

C

O

C

O

C

O

NH CH3

(2.1)

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14 Some General Principles

The Chelate Effect

Ligands that can use more than one nonadjacent donor atom for binding to a metalcenter are referred to as “chelate ligands”. The corresponding chelate complexescontain at least one “metallacycle” ring structure, which restricts the torsional mobilityof the system and contributes to enhanced selectivity. Due to the preference of sp2-and sp3-configured atoms for 120◦ and 109◦ bond angles, the optimum ring size ofthe metallacycles in chelate complexes is five, although four- and six-membered ringscan also occur for very small and very large metal ions, respectively.

Chelate complexes can exhibit enhanced thermodynamic and kinetic stability (the“chelate effect”).

� In addition to the enthalpy gain from optimum metal–donor interaction in suitablecyclic arrangements, an entropic factor favors the formation of chelate complexesbecause the number of free particles (including no-longer-coordinated individualsolvent ligands) is increased.

� The kinetic stabilization of chelate complexes reflects the most unlikely completedissociation of such species, which would require the simultaneous breaking ofseveral metal–donor bonds.

Other things being equal, the chelate effect increases with the ligand “denticity”;that is, with the number of donor atoms and metallacycles being formed. An additionalstabilization is achieved when the chelate rings are part of a larger preformed macro-cyclic arrangement that can be constructed in two (planar tetrapyrrole complexes) orthree dimensions (ionophor complexes, cryptates; Section 2.3.2).

“Hard” and “Soft” Coordination Centers

The susceptibility of atoms and ions to experience a charge shift in their electron shellthrough interaction with a coordination partner differs considerably. This has led toan often loosely used distinction between little-affected “hard” and easily polarizable“soft” coordination centers. Among the soft electron pair donors are thiolates (RS−),sulfide (S2−) and selenides; on the other hand, the fluoride anion (F−) and ligandswith negatively charged oxygen donor centers are classified as hard. In many cases,the observed affinities between metal ions and ligand atoms can be interpreted insuch a way that interactions between centers of the same type – that is, hard–hard(highly ionic bond) and soft–soft (partly covalent bond) – are preferred. One possiblequantitative approach to this rather intuitively used concept is based on a correlationbetween the ratio charge/ionic radius of a metal dication and the measurable secondionization energy.

2.2 Biological Functions of Inorganic Elements

The great efforts made by organisms to take up, accumulate, transport and store inorganicelements are justified only by their important and otherwise unguaranteed function. For


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