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Introduces students to the basics of bioinorganic chemistry
This book provides the fundamentals for inorganic chemistry and biochemistry relevant to understanding bioinorganic topics. It provides essential background material, followed by detailed information on selected topics, to give readers the background, tools, and skills they need to research and study bioinorganic topics of interest to them. To reflect current practices and needs, instrumental methods and techniques are referred to and mixed in throughout the book.
Bioinorganic Chemistry: A Short Course, Third Edition begins with a chapter on Inorganic Chemistry and Biochemistry Essentials. It then continues with chapters on: Computer Hardware, Software, and Computational Chemistry Methods; Important Metal Centers in Proteins; Myoglobins, Hemoglobins, Superoxide Dismutases, Nitrogenases, Hydrogenases, Carbonic Anhydrases, and Nitrogen Cycle Enzymes. The book concludes with chapters on Nanobioinorganic Chemistry and Metals in Medicine. Readers are also offered end-of-section summaries, conclusions, and thought problems.
Appropriate for one-semester bioinorganic chemistry courses, Bioinorganic Chemistry: A Short Course, Third Edition is ideal for upper-level undergraduate and beginning graduate students. It is also a valuable reference for practitioners and researchers in need of a general introduction to the subject, as well as chemists requiring an accessible reference.
ROSETTE M. ROAT-MALONE, PhD is Clarence C. White Professor of Chemistry Emerita at Washington College in Chestertown, Maryland. She developed the advanced bioinorganic chemistry course that formed the basis for this book's two preceding editions. Her research in the chemistry of platinum(IV) compounds as anti-cancer agents led to research appointments at several universities and support from various funding agencies.
Preface xiii
Acknowledgments xvii
Biography xix
About the Companion Page xxi
1 Inorganic Chemistry and Biochemistry Essentials 1
1.1 Introduction 1
1.2 Essential Chemical Elements 1
1.3 Inorganic Chemistry Basics 3
1.4 Electronic and Geometric Structures of Metals in Biological Systems 4
1.5 Thermodynamics and Kinetics 13
1.6 Bioorganometallic Chemistry 16
1.7 Inorganic Chemistry Conclusions 22
1.8 Introduction to Biochemistry 22
1.9 Proteins 23
1.9.1 Amino Acid Building Blocks 23
1.9.2 Protein Structure 26
1.9.3 Protein Function Enzymes and Enzyme Kinetics 30
1.10 DNA and RNA Building Blocks 32
1.10.1 DNA and RNA Molecular Structures 33
1.10.2 Transmission of Genetic Information 40
1.10.3 Genetic Mutations and Site-Directed Mutagenesis 43
1.10.4 Genes and Cloning 44
1.10.5 Genomics and the Human Genome 46
1.10.6 CRISPR 47
1.11 A Descriptive Example: Electron Transport Through DNA 51
1.11.1 Cyclic Voltammetry 55
1.12 Summary and Conclusions 57
1.13 Questions and Thought Problems 57
References 58
2 Computer Hardware, Software, and Computational Chemistry Methods 63
2.1 Introduction to Computer-Based Methods 63
2.2 Computer Hardware 63
2.3 Computer Software for Chemistry 66
2.3.1 Chemical Drawing Programs 67
2.3.2 Visualization Programs 67
2.3.3 Computational Chemistry Software 68
2.3.3.1 Molecular Dynamics (MD) Software 70
2.3.3.2 Mathematical and Graphing Software 71
2.4 Molecular Mechanics (MM), Molecular Modeling, and Molecular Dynamics (MD) 71
2.5 Quantum Mechanics-Based Computational Methods 72
2.5.1 Ab-Initio Methods 72
2.5.2 Semiempirical Methods 73
2.5.3 Density Functional Theory and Examples 73
2.5.3.1 Starting with Schrodinger 74
2.5.3.2 Density Functional Theory (DFT) 75
2.5.3.3 Basis Sets 76
2.5.3.4 DFT Applications 78
2.5.4 Quantum Mechanics/Molecular Mechanics (QM/MM) Methods 81
2.6 Conclusions on Hardware, Software, and Computational Chemistry 81
2.7 Databases, Visualization Tools, Nomenclature, and other Online Resources 82
2.8 Questions and Thought Problems 84
References 85
3 Important Metal Centers In Proteins 89
3.1 Iron Centers in Myoglobin and Hemoglobin 89
3.1.1 Introduction 89
3.1.2 Structure and Function as Determined by X-ray Crystallography and Nuclear Magnetic Resonance 92
3.1.3 Cryo-Electron Microscopy and Hemoglobin Structure/Function 95
3.1.3.1 Introduction 95
3.1.3.2 Cryo-Electron Microscopy Techniques 95
3.1.3.3 Structures Determined Using Cryo-Electron Microscopy 98
3.1.4 Model Compounds 100
3.1.5 Blood Substitutes 102
3.2 Iron Centers in Cytochromes 102
3.2.1 Cytochrome c Oxidase 103
3.2.2 Cytochrome c Oxidase (CcO) Structural Studies 105
3.2.3 Cytochrome c Oxidase (CcO) Catalytic Cycle and Energy Considerations 108
3.2.4 Proton Channels in Cytochrome c Oxidase 110
3.2.5 Cytochrome c Oxidase Model Compounds 113
3.3 Iron-Sulfur Clusters in Nitrogenase 120
3.3.1 Introduction 120
3.3.2 Nitrogenase Structure and Catalytic Mechanism 121
3.3.3 Mechanism of Dinitrogen (N2) Reduction 123
3.3.4 Substrate Pathways into Nitrogenase 127
3.3.5 Nitrogenase Model Compounds 130
3.3.5.1 Functional Nitrogenase Models 130
3.3.5.2 Structural Nitrogenase Models 135
3.4 Copper and Zinc in Superoxide Dismutase 137
3.4.1 Introduction 137
3.4.2 Superoxide Dismutase Structure and Mechanism of Catalytic Activity 139
3.4.3 A Copper Zinc Superoxide Dismutase Model Compound 143
3.5 Methane Monooxygenase 144
3.5.1 Introduction 144
3.5.2 Soluble Methane Monooxygenase 145
3.5.3 Particulate Methane Monooxygenase 148
3.6 Summary and Conclusions 152
3.7 Questions and Thought Problems 153
References 154
4 Hydrogenases, Carbonic Anhydrases, Nitrogen Cycle Enzymes 165
4.1 Introduction 165
4.2 Hydrogenases 166
4.2.1 Introduction 166
4.2.2 [NiFe]-hydrogenases 168
4.2.2.1 [NiFe]-hydrogenase Model Compounds 171
4.2.3 [FeFe]-hydrogenases 174
4.2.3.1 [FeFe]-Hydrogenase Model Compounds 179
4.2.4 [Fe]-hydrogenases 181
4.2.4.1 [Fe]-Hydrogenase Model Compounds 181
4.3 Carbonic Anhydrases 182
4.3.1 Introduction 182
4.3.2 Carbonic Anhydrase Inhibitors 183
4.4 Nitrogen Cycle Enzymes 186
4.4.1 Introduction 186
4.4.2 Nitric Oxide synthase 188
4.4.2.1 Introduction 188
4.4.2.2 Nitric Oxide Synthase Structure 188
4.4.2.3 Nitric Oxide Synthase Inhibitors 189
4.4.3 Nitrite Reductase 194
4.4.3.1 Introduction 194
4.4.3.2 Reduction of Nitrite Ion to Ammonium Ion 194
4.4.3.3 Reduction of Nitrite Ion to Nitric Oxide 195
4.5 Summary and Conclusions 207
4.6 Questions and Thought Problems 207
References 208
5 Nanobioinorganic Chemistry 213
5.1 Introduction to Nanomaterials 213
5.2 Analytical Methods 215
5.2.1 Microscopy 216
5.2.1.1 Scanning Electron Microscopy (SEM) 216
5.2.1.2 Transmission Electron Microscopy (TEM) 216
5.2.1.3 Scanning Transmission Electron Microscopy (STEM) 218
5.2.1.4 Cryo-Electron Microscopy 218
5.2.1.5 Scanning Probe Microscopy (SPM) 218
5.2.1.6 Atomic Force Microscopy (AFM) 219
5.2.1.7 Super-Resolution Microscopy and DNA-PAINT 220
5.2.2 Forster Resonance Energy Transfer (FRET) 221
5.3 DNA Origami 222
5.4 Metallized DNA Nanomaterials 224
5.4.1 Introduction 224
5.4.2 DNA-Coated Metal Electrodes 225
5.4.3 Plasmonics and DNA 225
5.5 Bioimaging with Nanomaterials, Nanomedicine, and Cytotoxicity 228
5.5.1 Introduction 228
5.5.2 Imaging with Nanomaterials 230
5.5.3 Bioimaging using Quantum Dots (QD) 233
5.5.4 Nanoparticles in Therapeutic Nanomedicine 233
5.5.4.1 Clinical Nanomedicine 235
5.5.4.2 Some Drugs Formulated into Nanomaterials for Cancer Treatment: Cisplatinum, Platinum(IV) Prodrugs, and Doxorubicin 236
5.6 Theranostics 239
5.7 Nanoparticle Toxicity 240
5.8 Summary and Conclusions 241
5.9 Questions and Thought Problems 241
References 242
6 Metals In Medicine, Disease States, Drug Development 247
6.1 Platinum Anticancer Agents 247
6.1.1 Cisplatin 249
6.1.1.1 Cisplatin Toxicity 249
6.1.1.2 Mechanism of Cisplatin Activity 250
6.1.2 Carboplatin (Paraplatin) 251
6.1.3 Oxaliplatin 251
6.1.4 Other cis-Platinum(II) Compounds 252
6.1.4.1 Nedaplatin 252
6.1.4.2 Lobaplatin 252
6.1.4.3 Heptaplatin 253
6.1.5 Antitumor Active Trans Platinum compounds 253
6.1.6 Platinum Drug Resistance 258
6.1.7 Combination Therapies: Platinum-Containing Drugs with Other Antitumor Compounds 260
6.1.8 Platinum(IV) Antitumor Drugs 262
6.1.8.1 Satraplatin 262
6.1.8.2 Ormaplatin 263
6.1.8.3 Iproplatin, JM9, CHIP 263
6.1.9 Platinum(IV) Prodrugs 264
6.1.9.1 Multitargeted Platinum(IV) Prodrugs 264
6.1.9.2 Platinum(IV) Prodrugs Delivered via Nanoparticles 266
6.2 Ruthenium Compounds as Anticancer Agents 267
6.2.1 Ruthenium(III) Anticancer Agents 267
6.2.2 Ruthenium(II) Anticancer Agents 269
6.2.3 Mechanism of Ruthenium(II) Anticancer Agent Activity 271
6.2.4 Ruthenium Compounds Tested for Antitumor Activity 271
6.3 Iridium and Osmium Antitumor Agents 274
6.4 Other Antitumor Agents 278
6.4.1 Gold Complexes 278
6.4.2 Titanium Complexes 278
6.4.3 Copper Complexes 279
6.5 Bismuth Derivatives as Antibacterials 281
6.6 Disease States, Drug Discovery, and Treatments 282
6.6.1 Superoxide Dismutases (SOD) in Disease States 282
6.6.2 Amyotrophic Lateral Sclerosis 287
6.6.3 Wilson's and Menkes Disease 291
6.6.4 Alzheimer's disease 296
6.6.4.1 Role of Amyloid ß Protein 296
6.6.4.2 Interactions of Aß Peptides with Metals 298
6.6.4.3 Alzheimer's Disease Treatments 299
6.7 Other Disease States Involving Metals 302
6.7.1 Copper and Zinc Ions and Cataract Formation 302
6.7.2 As2O3 used in the Treatment of Acute Promyelocytic Leukemia (APL) 302
6.7.3 Vanadium-based Type 2 Diabetes Drugs 303
6.8 Summary and Conclusions 305
6.9 Questions and Thought Problems 306
References 308
Index 315
Bioinorganic chemistry involves the study of metal species in biological systems. As an introduction to the basic inorganic chemistry is needed for understanding bioinorganic topics, this chapter will discuss the essential chemical elements, the occurrences and purposes of metal centers in biological species, the geometries of ligand fields surrounding these metal centers and ionic states preferred by the metals. The occurrence of organometallic complexes and clusters in metalloproteins will be discussed briefly and an introduction to electron transfer in coordination complexes will be presented. Since the metal centers under consideration are found in a biochemical milieu, basic biochemical concepts, including a discussion of proteins and nucleic acids, are presented later in this chapter.
Chemical elements essential to life forms can be broken down into four major categories: (i) bulk elements (H/H+, C, N, O2-/O2-·/O22-, P, and S/S2-); (ii) macrominerals and ions (Na/Na+, K/K+, Mg/Mg2+, Ca/Ca2+, Cl-, PO43-, and SO42-); (iii) trace elements (Fe/FeII/FeIII/FeIV, Zn/ZnII, and Cu/CuI/CuIICuIII); and (iv) ultratrace elements, that comprise nonmetals (F/F-, I/I-, Se/Se2-, Si/SiIV, As, and B) and metals (Mn/MnII/MnIII/MnIV, Mo/MoIV/MoV/MoVI, Co/CoII/ CoIII, Cr/CrIII/CrVI, V/VIII/ VIV/ VV/, NiI/ NiII/ NiIII/, Cd/Cd2+, Sn/SnII/SnIV, Pb/Pb2+, and Li/Li+). In the preceding classification, only the common biologically active ion oxidation states are indicated (see references [1, 2d] for more information). If no charge is shown, the element predominately bonds covalently with its partners in biological compounds, although elements such as carbon (C), sulfur (S), phosphorus (P), arsenic (As), boron (B), and selenium (Se) have positive formal oxidation states in ions containing oxygen atoms; i.e. S = +6 in the SO42- ion or P = +5 in the PO43- ion. The identities of essential elements are based on historical work done by Klaus Schwarz in the 1970s [3]. Other essential elements may be present in various biological species. Essentiality has been defined by certain criteria: (i) a physiological deficiency appears when the element is removed from the diet; (ii) the deficiency is relieved by the addition of that element to the diet; and (iii) a specific biological function is associated with the element [4]. Table 1.1 indicates the approximate percentages by weight of selected essential elements for an adult human.
Every essential element follows a dose-response curve, shown in Figure 1.1, as adapted from reference [4]. At lowest dosages, the organism does not survive whereas in deficiency regions the organism exists with less than optimal function. After the concentration plateau of the optimal dosage region, higher dosages cause toxic effects in the organism eventually leading to lethality. Specific daily requirements of essential elements may range from microgram to gram quantities.
Considering the content of earth's contemporary waters and atmospheres, many questions arise as to the choice of essential elements at the time of life's origins 3.5 billion or more years ago. Certainly sufficient quantities of the bulk elements were available in primordial oceans and at shorelines. However, the concentrations of essential trace metals in modern oceans may differ considerably from those found in prebiotic times. Iron's current approximate 10-4 mM concentration in seawater, for instance, may not reflect accurately its prelife-forms availability. If one assumes a mostly reducing atmosphere contemporary with the beginnings of biological life, the availability of the more soluble iron(II) ion in primordial oceans must have been much higher. Thus, the essentiality of iron(II) at a concentration of 0.02?mM in the blood plasma heme (hemoglobin) and muscle tissue heme (myoglobin) may be explained. Beside the availability factor, many chemical and physical properties of elements and their ions are responsible for their inclusion in biological systems. These include ionic charge, ionic radius, ligand preferences, preferred coordination geometries, spin pairings, systemic kinetic control, and the chemical reactivity of the ions in solution. These factors are discussed in detail by daSilva and Williams [1].
TABLE 1.1 Percentage Composition of Selected Elements in the Human Body
Figure 1.1 Dose-response curve for elements.
Source: adapted from Kaim et al. [4].
Ligand preference and possible coordination geometries of the metal center are important bioinorganic principles. Metal ligand preference is closely related to the hard-soft acid-base nature of metals and their preferred ligands. These are listed in Table 1.2.
In general, hard metal cations form their most stable compounds with hard ligands and soft metal cations with soft ligands. Hard cations can be thought of as small dense cores of positive charge whereas hard ligands are usually the small highly electronegative elements or ligand atoms within a hard polyatomic ion, i.e. oxygen ligands in (RO)2PO2- or CH3CO2-.
It is possible to modify a hard nitrogen ligand towards an intermediate softness by increasing the polarizability of its substituents or the p electron cloud about it. The imidazole nitrogen of the amino acid histidine, a ubiquitous ligand in biological proteins, is an example. Increasing the softness of phosphate ion substituents can transform the hard oxygen ligand of (RO)2PO2- to a soft state in (RS)2PO2-. Soft cations and anions are those with highly polarizable, large electron clouds - Hg2+, sulfur ligands as sulfides or thiolates, and iodide ions. Also, note that metal ions can overlap into different categories. Lead as Pb2+, for instance, appears in both the intermediate and soft categories. The Fe3+ ion, classified as a hard cation, coordinates to histidine (imidazole) ligands in biological systems and Fe2+, classified as intermediate, can coordinate to sulfur ligands and the carbon atom of CO (see Sections 3.1-3.3, 3.6, and 4.1).
TABLE 1.2 Hard-soft Acid-base Classification of Metal Ions and Ligands
In biological systems, many factors...
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