Bacterial transition metal homoeostasis or simply 'metallostasis' describes the process by which cells control the intracellular availability of functionally required metal cofactors, from manganese (Mn) to zinc (Zn), avoiding bothmetal deprivation and toxicity. Metallostasis is an emerging aspect of the vertebrate host-pathogen interface that is defined by a 'tug-of-war' for biologically essential metals and provides the motivation for much recent work in this area. The host employs a number of strategies to starve the microbial pathogen of essential metals, while for others attempts to limit bacterial infections by leveraging highly competitive metals. Bacteria must be capable of adapting to these efforts to remodel the transition metal landscape and employ highly specialized metal sensing transcriptional regulators, termed metalloregulatory proteins, and metallochaperones, that allocate metals to specific destinations, to mediate this adaptive response. In this essay, we discuss recent progress in our understanding of the structural mechanisms and metal specificity of this adaptive response, focusing on energy-requiring metallochaperones that play roles in the metallocofactor active site assembly in metalloenzymes and metallosensors, which govern the systems-level response to metal limitation and intoxication.
Specific macromolecular transport systems, ion channels and pumps, provide the pathways to facilitate and control the passage of ions across the lipid membrane. Ion channels provide energetically favourable passage for ions to diffuse rapidly and passively according to their electrochemical potential. Selective ion channels are essential for the excitability of biological membranes: the action potential is a transient phenomenon that reflects the rapid opening and closing of voltage-dependent Na+-selective and K+-selective channels. One of the most critical functional aspects of K+ channels is their ability to remain highly selective for K+ over Na+ while allowing high-throughput ion conduction at a rate close to the diffusion limit. Permeation through the K+ channel selectivity filter is believed to proceed as a 'knockon' mechanism, in which 2-3 K+ ions interspersed by water molecules move in a single file. Permeation through the comparatively wider and less selective Na+ channels also proceeds via a loosely coupled knockon mechanism, although the ions do not need to be fully dehydrated. While simple structural concepts are often invoked to rationalize the mechanism of ion selectivity, a deeper analysis shows that subtle effects play an important role in these flexible dynamical structures.
This chapter focuses on Alkaline metal ions (sodium and potassium ions) and alkaline earth metal ions (magnesium and calcium ions), which play important roles in a plethora of physiological processes. It discusses the mechanisms that are responsible for steering and control of the ion concentrations in the extracellular space and the cytosolic cell compartments. It describes the four main transportation routes for alkaline and alkaline earth metal ions and tackles ion channels — the membrane-bound proteins which are gated by chemical, mechanical, electric, or light stimuli. The chapter also explains the concept of exchange kinetics. Furthermore, it looks at the biomineralization of calcium with special reference to its impact on the stabilization of bone structures through the formation of hydroxyapatite.
This chapter focuses on the health-related consequences of the disruption of iron and copper homeostasis — particularly, as far as copper is concerned, in the context of Menkes disease, Wilson's disease, and Alzheimer's disease. The chapter also considers the mode of operation of drugs based on platinum and gold, as well as the role of bismuth in the treatment of irritations of the gastric mucosa, the therapy of bipolar disorder with lithium prescriptions, and the use of silver as a medicinal disinfectant. Furthermore, it discusses the potential of the phosphate analogue vanadate as an insulin-enhancing, and thus anti-diabetic, agent. The chapter likewise introduces the application of short-lived radionuclei in the treatment of malignant tumours and in the palliation of patients suffering from metastasized bone cancer. Finally, it reviews Paracelsus's relativizing statement on toxic substances in conjunction with the gases carbon monoxide, nitric oxide, and hydrogen sulfide.
This chapter takes a closer look at early transition metals molybdenum, tungsten, and vanadium which are involved in many catalytically conducted two-electron transfer reactions, commonly accompanied by oxygenation and deoxygenation. Nature employs these metals as active centres in enzymes in a variety of oxidation and reduction reactions. These elements are also used in industrial contexts, commonly in steel production or, in the form of their oxides, to catalyze oxidation reactions, exploiting the ease of the change in oxidation states. The chapter discusses the Molybdo- and tungsto-pyranopterins and considers an assortment of representatives of the four Mo/W-pyranopterin families: the xanthine oxidase family, sulfite oxidase family, dimethyl sulfoxide reductase family, and aldehyde: ferredoxin oxidoreductase family. In addition, the chapter tackles the vanadate-dependent haloperoxidases.
This chapter focuses on the enzymes involved in the nitrogen cycle. One of its focal points is nitrogen fixation, or nature's way of converting nitrogen gas reductively to ammonium ions for direct use in life processes. Biological nitrogen fixation is the natural counterpart of industrial nitrogen fixation by the Haber–Bosch process. The chapter also addresses the procedural methodology by which nature cycles nitrogen between ammonia (with nitrogen in its lowest oxidation state), nitrogen gas, and nitrate (with nitrogen in its highest oxidation state), highlighting that the understanding of the versatility and differentiation by which this biochemical processing of nitrogen occurs has been a vital issue in bioinorganic chemistry in the past decades, and will be of prime interest also in the coming years. The chapter tackles nitrogenase models and model reactions and explains nitrification and denitrification. Lastly, it takes a closer look at nitric oxide.
This chapter focuses on oxygen, which became the main atmospheric constituent about 2.4 billion years ago and paved the way for evolutionary processes. The discussion covers the uptake, storage, transport, and reduction of oxygen by iron and copper proteins. The chapter explains oxygen transport by haemoglobin and myoglobin, as well as by haemerythrin and haemocyanin. Then it looks at the respiratory chain which is in the mitochondria of the cells of eukaryotes. It illustrates the electron and proton shuttle in the mitochondrial respiratory chain, discussing the processes taking place in four membrane-bound, interlinked protein complexes. The chapter likewise tackles iron-sulfur proteins and iron porphyrins.
This chapter discusses the role of the transition metal-carbon bond in the activation of substrates such as carbon oxide, carbon dioxide, nitrogen, methane, alkenes, and alkynes, focusing in part on selected examples of metalloenzymes. It looks at the processing of organometal and -metalloid compounds in biogeochemical cycles. The chapter also explores the special role of adenosyl- and methyl-cobalamin (vitamin B12), the latter in the frame of the broad range of physiologically important methyl transfer reactions. Furthermore, it briefly sets out the physiological implications of the selenium-carbon bond. Lastly, the chapter addresses the biogeochemical making and breaking of the metal and -metalloid carbon bond in poisoning by, and detoxification of, mercury, lead, and arsenic.
This chapter addresses both geochemical and biogenic sulfur cycling, including their tight interconnections. It presents the cycling of sulfur between the atmosphere and the marine hydrosphere. The cycling involves redox processes and both biogenic and abiotic methylation and demethylation of sulfur. Two of the key compounds are dimethylsulfoniopropionate and its metabolite dimethyl sulfide. The chapter also provides an overview of key inorganic and organic sulfur compounds that are life-sustaining and/or play a substantial role in sulfur cycling. Then it looks at the biogenic metabolism of sulfur, discussing several of the key steps in the biogenic conversion of inorganic sulfur compounds into organic sulfur species relevant for catabolic processes.
This chapter discusses methane, which plays a key role in the global carbon cycle. The discussion acknowledges that methane is an increasingly important energy source in industrial production, in heating households, and powering alternative fuel cars but is also increasingly contributing to the greenhouse effect. The chapter explains biogenic and non-biogenic methane production. It describes serpentinization, a geochemical process involved in the abiotic formation of methane. The chapter also explains methanogenesis — the conversion of inorganic and organic carbon compounds to methane. Then it tackles the reverse of methanogenesis: the oxidative conversion of methane to carbon species in higher oxidation states. The chapter also provides some insights into some nickel-containing enzymes such as hydrogenases, CO-dehydrogenase and acetyl-coenzyme-A synthetase, urease, and superoxide dismutase.
This chapter provides an overview of electron transporters employing iron, copper, and manganese, emphasizing cofactors involved in the interconversion of oxygen species. It presents some metal-based enzymes that transform and employ oxygen directly or indirectly. The chapter describes ribonucleotide reductases (RNR) that catalyse the reduction of nucleotides — the building blocks of ribonucleic acids (RNA) — to deoxyribonucleotides and thus provide the building blocks for deoxyribonucleic acids (DNA). The discussion in this chapter also covers superoxide dismutases, superoxide reductases, and peroxidases. Then it progresses to explain oxygenases that catalyse the transfer of oxo groups to a substrate, and oxidases that promote the dehydrogenation of substrates.
This chapter explores the chemistry that made life possible on Earth. It probes the question of how life evolved by looking at primordial scenarios for the development of the first cells and their adaptation to an alleged inhospitable environment. In doing so, the chapter tackles the Miller–Urey and Wächtershäuser scenarios. It also describes clay organisms or phyllosilicates that breathe by absorbing and releasing water. Furthermore, it looks at bacterial and archaean species, as well as some eukaryan algae that have adapted to extreme situations and are therefore referred to as extremophiles. This includes extremes in temperature, pressure, pH, salt and toxic metal concentrations, resistance towards UV and γ radiation and carbon sources.
This chapter provides a brief overview of chemical elements that have biological and medicinal functions. It discusses metals that have a direct impact on physiological activity, as well as toxic compounds based on mercury, lead, and arsenic. It presents a periodic table of bio-elements and provides a summary of their main biological function and/or medicinal application. The chapter also tackles the main ligands and ligand functions available for metal ions in biological systems. It uses the term metal ion in a broader sense, including metalloids. Furthermore, the chapter highlights that ligands do not only mediate the transport and storage of metal ions but also fine-tune the metal's physiological actions.
This chapter examines iron, an exceptional transition metal that is abundant in all living organisms. Iron deficiency, dysfunctions of iron metabolism, and iron overload cause severe health problems. The biological importance of iron is linked to the ease with which it shuttles electrons between the ferric and ferrous state, and to switch readily between high- and low-spin electronic states, depending on the coordination environment. Considering this, the chapter explains the mobilization, transport, and delivery of iron. Furthermore, it tackles the biological mineralization of iron by magnetotactic bacteria and by diverse other bacterial activities. The chapter also allots sidebars to explain the concepts of coordination compounds, Mössbauer spectroscopy, as well as magnetism, and spin moment.
This chapter takes a closer look at zinc, the most abundant transition metal in all living organisms next to iron. It provides examples for the following five main categories of proteins in which zinc attains a structural function and/or mediates catalytic processes: Enzymatic activity in hydrolytic processes; substrate activation for oxidative detoxification; interconversion between carbon dioxide and hydrogencarbonate; transcription of the genetic information contained in deoxyribonucleic acid (DNA) for protein synthesis; and demethylation — and thus repair — of DNA damaged by methylation. The chapter addresses questions on how zinc ions mediate the breakdown of proteins in our food, making available amino acids for resorption and thus usage in the synthesis of our body's own proteins; how ethanol is converted to acetaldehyde; how metabolically released carbon dioxide is processed for transport into the lungs; and how the small proteins called thioneins contribute to controlling zinc homeostasis in the body.
This chapter contains sections titled: Introduction Homeostasis of Metals (and Some Nonmetals) Movement of Molecules and Ions Across Membranes Potassium-Dependent Molecules Conclusions References
This chapter contains sections titled: Introduction Essential Chemical Elements Metals in Biological Systems: A Survey Inorganic Chemistry Basics Biological Metal Ion Complexation Electronic and Geometric Structures of Metals in Biological Systems Bioorganometallic Chemistry Electron Transfer Conclusions References
Medicinal inorganic chemistry is a multidisciplinary field combining elements of chemistry (synthesis, reactivity), pharmacology (pharmacokinetics, toxicology), biochemistry (targets, structure, conformational changes), and medicinal chemistry (therapeutics, pharmacodynamics, structure-activity relationships (SAR)). This chapter presents discussion on each of these fields.
