Rare earth elements (REE) are essential for our daily lives. It is not only their use in high technologies like smartphones and computers and in renewable energy applications. The interaction of REE with biomolecules and living organisms and the exploitation of their photo-physical properties for a range of applications in biochemistry research and medicine have been studied for many decades. But this is no longer the only reason to make them an attractive group of elements to investigate. An entirely new area of research has emerged in the past ten years after it was established that many bacteria utilize certain REE in their metabolism. This chapter gives an overview on the most recent developments in this field along with an account of the more established uses of REE in biochemistry, biomining, and medicine.
Zinc finger (ZF) domains, that represent the majority of the DNA-binding motifs in eukaryotes, are involved in several processes ranging from RNA packaging to transcriptional activation, regulation of apoptosis, protein folding and assembly, and lipid binding. While their amino acid composition varies from one domain to the other, a shared feature is the coordination of a zinc ion, with a structural role, by a different combination of cysteines and histidines. The classical zinc finger domain (also called Cys2His2) that represents the most common class, uses two cysteines and two histidines to coordinate the metal ion, and forms a compact ββα architecture consisting in a β-sheet and an α-helix. GAG-knuckle resembles the classical ZF, treble clef and zinc ribbon are also well represented in the human genome. Zinc fingers are also present in prokaryotes. The first prokaryotic ZF domain found in the transcriptional regulator Ros protein was identified in Agrobacterium tumefaciens. It shows a Cys2His2 metal ion coordination sphere and folds in a domain significantly larger than its eukaryotic counterpart arranged in a βββαα topology. Interestingly, this domain does not strictly require the metal ion coordination to achieve the functional fold. Here, we report what is known on the main classes of eukaryotic and prokarotic ZFs, focusing our attention to the role of the metal ion, the folding mechanism, and the DNA binding. The hypothesis of a horizontal gene transfer from prokaryotes to eukaryotes is also discussed.
Cupredoxins host in their scaffold one of the most studied and interesting metal sites in biology: the type 1 (T1) or blue Cu center. Blue Cu proteins have evolved to play key roles in biological electron transfer and have the ability to react with a wide variety of redox partners. The inner coordination sphere of T1 Cu sites conserves two histidines and one cysteine with a short Cu-S(Cys) bond as ligands in a trigonal arrangement, with a variable axial ligand that modulates the electronic structure and reactivity. The structural, electronic and geometric features of T1 Cu centers provide the basis for a site that can be optimized by the protein structure for each biological function. This chapter highlights the properties that make this unique Cu center in biology an efficient and tunable electron transfer site. The contributions of the first coordination shell and the high covalency of the Cu-S(Cys) bond in the T1 Cu site to its distinctive geometric and spectroscopic features are discussed, as well as the role of the protein scaffold in imposing an 'entatic' state with a distorted tetrahedral geometry that minimizes geometric changes upon redox cycling. The analysis of naturally occurring perturbed blue Cu sites provides further insights into how the protein scaffold can tune the properties of the T1 Cu site. Blue Cu sites display a wide range of reduction potentials, as these are tuned to be consistent with their physiologically relevant electron donors and acceptors. The different properties of the protein matrix that play important roles in finetuning the reduction potential of T1 Cu sites are also discussed, including the nature of the axial ligand and outer coordination sphere effects. These concepts are further illustrated by the discussion of examples of biosynthetic blue Cu proteins. Finally, the different features of the T1 Cu site that make it an optimal site for electron transfer (ET) are discussed, in terms of Markus theory for intra- and inter-molecular ET. The active site in multicopper oxidases is used as an example to illustrate the contributions of the anisotropic covalency of the blue Cu site to an efficient ET, while the diverse reactivity of the T1 Cu sites in these enzymes is discussed to dissect the different properties provided by the protein that help tune these unique sites for biological ET.
Iron-sulfur clusters are ubiquitous protein cofactors composed of iron and inorganic sulfur. These cofactors are among the most ancient ones and may have contributed to the birth of life on Earth. Therefore, they are found even today in many enzymes central to metabolic processes like nitrogen fixation, respiration, and DNA processing and repair. Due to the toxicity associated with iron and sulfur ions, living organisms evolved dedicated machineries to synthetize and then transfer iron-sulfur clusters into client proteins. The iron-sulfur cluster (ISC) machinery is responsible for iron-sulfur cluster biogenesis in prokaryotes and in the mitochondrion of eukaryotes; the sulfur mobilization (SUF) machinery is present in prokaryotes and in the chloroplasts of plants; finally, the cytosolic iron-sulfur assembly (CIA) machinery is only present in the cytoplasm of eukaryotes. Genome analysis allowed the prediction of the proteins containing iron-sulfur clusters across a broad variety of living organisms, establishing links between the size and composition of iron-sulfur proteomes and the types of organisms that encode them. For example, the iron-sulfur proteomes of aerobes are generally smaller than those of anaerobes with similar genome size; furthermore, aerobes are enriched in [2Fe-2S] proteins compared to anaerobes, which predominantly use [4Fe-4S] proteins. This relates to the lower bioavailability of iron and the higher lability of [4Fe-4S] clusters within aerobic environments. Analogous considerations apply to humans, where the occurrence and functions of iron-sulfur proteins depend on the cellular compartment where they are localized. For example, an emerging primary role for nuclear iron-sulfur proteins is in DNA maintenance. Given their key functions in metabolism, dysfunctions of mutations in iron-sulfur proteins, or in proteins participating in iron-sulfur cluster biogenesis, are associated with serious human diseases.
Enzymes relying on the interplay of nickel, iron, and sulfur in their active sites are used by prokaryotes to catalyze reactions driving the global carbon and hydrogen cycles. The three enzymes, [NiFe] hydrogenases, Ni,Fe-containing carbon monoxide dehydrogenases and acetyl-CoA synthases share an ancient origin possibly derived from abiotic processes. Although their active sites have different compositions and assemble Ni, Fe, and S in different ways and for different purposes, they share a central role of Ni in substrate binding and activation, with sulfur linking the Ni ion to one or more Fe ions, which, although indispensable for function, supports the catalytic process in less understood ways. The review gives a short overview on the properties of the three individual enzymes highlighting their parallels and differences.
The non-metallic chemical element sulfur, 3216S , referred to in Genesis as brimstone and identified as element by Lavoisier, is the tenth most abundant element in the universe and the fifth most common element on Earth. Important inorganic forms of sulfur in the biosphere are elemental sulfur (S8), sulfate (SO2-4), and sulfide (S2-), sulfite (SO2-3), thiosulfate, (S2O23), and polythionates (S3O62-; S4O62-). Because of its wide range of stable oxidation states, from +6to -2, sulfur plays important roles in central biochemistry as a structural and redoxactive element and is intimately related to life on Earth. Unusual reaction pathways involving sulfur compounds become possible by the specific properties of this element. Sulfur occurs in all the major classes of biomolecules, including enzymes, proteins, sugars, nucleic acids, vitamin cofactors, and metabolites. The flexibility of these biomolecules follows from its versatile chemistry. The best known sulfur mineral is perhaps pyrite (Fool's gold), with the chemical formula, FeS2. Sulfur radical anions, such as [S3].-, are responsible for the intense blue color of lapis lazuli, one of the most desired and expensive artists' materials. In the microbial world, inorganic sulfur compounds, e.g., elemental sulfur and sulfate, belong to the most important electron acceptors. Studies on microbial sulfur metabolism revealed many novel enzymes and pathways and advanced the understanding on metabolic processes used for energy conservation, not only of the microbes, but of biology in general. Transition metal sulfur complexes display intriguing catalytic activities, they provide surfaces and complex cavities in metalloenzymes that activate inert molecules such as H2, CO, N2 or N2O, and they catalyze the transformations of numerous organic molecules. Both thiamine diphosphate- (ThDP) and S-adenosyl- L-methionine- (SAM) dependent enzymes belong to Nature's most powerful catalysts with a remarkable spectrum of catalytic activities. In conclusion, given sulfur's diverse properties, evolution made an excellent choice in selecting sulfur as one the basic elements of life.
The last 20 years have seen a dramatic increase in our mechanistic understanding of the reactions catalyzed by pyranopterin Mo and W enzymes. These enzymes possess a unique cofactor (Moco) that contains a novel ligand in bioinorganic chemistry, the pyranopterin ene-1,2-dithiolate. A synopsis of Moco biosynthesis and structure is presented, along with our current understanding of the role Moco plays in enzymatic catalysis. Oxygen atom transfer (OAT) reactivity is discussed in terms of breaking strong metal-oxo bonds and the mechanism of OAT catalyzed by enzymes of the sulfite oxidase (SO) family that possess dioxo Mo(VI) active sites. OAT reactivity is also discussed in members of the dimethyl sulfoxide (DMSO) reductase family, which possess des-oxo Mo(IV) sites. Finally, we reveal what is known about hydride transfer reactivity in xanthine oxidase (XO) family enzymes and the formate dehydrogenases. The formal hydride transfer reactivity catalyzed by xanthine oxidase family enzymes is complex and cleaves substrate C-H bonds using a mechanism that is distinct from monooxygenases. The chapter primarily highlights developments in the field that have occurred since ~2000, which have contributed to our collective structural and mechanistic understanding of the three canonical pyranopterin Mo enzymes families: XO, SO, and DMSO reductase.
In biological nitrogen fixation, the enzyme nitrogenase mediates the reductive cleavage of the stable triple bond of gaseous N2at ambient conditions, driven by the hydrolysis of ATP, to yield bioavailable ammonium (NH4+). At the core of nitrogenase is a complex, ironsulfur based cofactor that in most variants of the enzyme contains an additional, apical heterometal (Mo or V), an organic homocitrate ligand coordinated to this heterometal, and a unique, interstitial carbide. Recent years have witnessed fundamental advances in our understanding of the atomic and electronic structure of the nitrogenase cofactor. Spectroscopic studies have succeeded in trapping and identifying reaction intermediates and several inhibitor- or intermediate- bound structures of the cofactors were characterized by high-resolution X-ray crystallography. Here we summarize the current state of understanding of the cofactors of the nitrogenase enzymes, their interplay in electron transfer and in the six-electron reduction of nitrogen to ammonium and the actual theoretical and experimental conclusion on how this challenging chemistry is achieved.
Nitrous oxide reductase catalyzes the reduction of nitrous oxide (N2O) to dinitrogen (N2) and water at a catalytic tetranuclear copper sulfide center, named CuZ, overcoming the high activation energy of this reaction. In this center each Cu atom is coordinated by two imidazole rings of histidine side-chains, with the exception of one named CuIV. This enzyme has been isolated with CuZ in two forms CuZ(4Cu1S) and CuZ(4Cu2S), which differ in the CuI-CuIV bridging ligand, leading to considerable differences in their spectroscopic and catalytic properties. The Cu atoms in CuZ(4Cu1S) can be reduced to the [4Cu1+] oxidation state, and its catalytic properties are compatible with the nitrous oxide reduction rates of whole cells, while in CuZ(4Cu2S) they can only be reduced to the [1Cu2C-3Cu1C] oxidation state, which has a very low turnover number. The catalytic cycle of this enzyme has been explored and one of the intermediates, CuZ0, has recently been identified and shown to be in the [1Cu2+-3Cu1+] oxidation state. Contrary to CuZ(4Cu2S), CuZ0 is rapidly reduced intramolecularly by the electron transferring center of the enzyme, CuA, to [4Cu1+] by a physiologically relevant redox partner. The three-dimensional structure of nitrous oxide reductase with the CuZ center either as CuZ(4Cu1S) or as CuZ(4Cu2S) shows that it is a unique functional dimer, with the CuZ of one subunit receiving electrons from CuA of the other subunit. The complex nature of this center has posed some questions relative to its assembly, which are only partially answered, as well as to which is the active form of CuZ in vivo. The structural, spectroscopic, and catalytic features of the two forms of CuZ will be addressed here, as well as its assembly. The understanding of its catalytic features, activation, and assembly is essential to develop strategies to decrease the release of nitrous oxide to the atmosphere and to reduce its concentration in the stratosphere, as well as to serve as inspiration to synthetic inorganic chemists to develop new models of this peculiar and challenging copper sulfide center.
Cytochromes P450 (CYPs) are heme b-binding enzymes and belong to Nature's most versatile catalysts. They participate in countless essential life processes, and exist in all domains of life, Bacteria, Archaea, and Eukarya, and in viruses. CYPs attract the interest of researchers active in fields as diverse as biochemistry, chemistry, biophysics, molecular biology, pharmacology, and toxicology. CYPs fight chemicals such as drugs, poisonous compounds in plants, carcinogens formed during cooking, and environmental pollutants. They represent the first line of defense to detoxify and solubilize poisonous substances by modifying them with dioxygen. The heme iron is proximally coordinated by a thiolate residue, and this ligation state represents the active form of the enzyme. The Fe(III) center displays characteristic UV/Vis and EPR spectra (Soret maximum at 418 nm; g-values at 2.41, 2.26, 1.91). The Fe(II) state binds the inhibitor carbon monoxide (CO) to produce a Fe(II)-CO complex, with the major absorption maximum at 450 nm, hence, its name P450. CYPs are flexible proteins in order to allow a vast range of substrates to enter and products to leave. Two extreme forms exist: substrate-bound (closed) and substrate-free (open). CYPs share a sophisticated catalytic cycle that involves a series of consecutive transformations of the heme thiolate active site, with the strong oxidants compound I and II as key intermediates. Each of these high-valent Fe(IV) species has its characteristic features and chemical properties, crucial for the activation of dioxygen and cleavage of strong C-H bonds.
CuA is a binuclear copper center acting as an electron transfer hub in terminal oxidases such as cytochrome c oxidase and nitrous oxide reductase. Its unique electronic structure is intimately linked to its function and has puzzled the community of biological inorganic chemistry for decades. Here we review the insights provided by different spectroscopic techniques of CuA centers, and the different experimental approaches to tackle its study, that encompass the synthesis of model compounds as well as protein engineering efforts. The contribution of the electronic structure to the thermodynamic and kinetic of electron transfer is extensively discussed. We also describe the proposed mechanism of CuAassembly in different organisms. The recent discovery of a novel CuA site opens new perspectives to this field.
The number of transition metal ions which are essential to life - also often called trace elements - increased steadily over the years. In parallel, the list of biological functions in which transition metals are involved, has grown, and is still growing tremendously. Significant progress has been made in understanding the chemistry operating at the biological sites where metal ions have been discovered. Early on, based on the application of physical, chemical, and biological techniques, it became likely that numerous of these metal centers carry sulfur ligands in their coordination sphere, such as sulfide (S2-), cysteine (RS-), or methionine (RSCH3). Notably, the structure and the reactivity of the metal active sites turned out to be quite different from anything previously observed in simple coordination complexes. Consequently, the prediction of active-site structures, based on known properties of transition metal ion complexes, turned out to be difficult and incorrect in many cases. Yet, biomimetic inorganic chemistry, via synthesis and detailed structural and electronic characterization of synthetic analogues, became an important factor and helped to understand the properties of the metal active sites. Striking advances came from molecular biology techniques and protein crystallography, as documented by the publication of the first high-resolution structures of iron-sulfur proteins and the blue copper protein plastocyanin approximately five decades ago. In this volume of METAL IONS IN LIFE SCIENCES the focus will be on some of the most intriguing, in our view, transition metal-sulfur sites discovered in living organisms. These include the type 1 Cu mononuclear center, the purple mixed-valent [Cu1.5+-(Cys)2-Cu1.5+] CuA, the tetranuclear copper-sulfide catalytic center of nitrous oxide reductase, the heme-thiolate site in cytochrome P450, the iron-sulfur proteins with bound inorganic (S2-) and organic (Cys-) sulfur, the pterin dithiolene cofactor (Moco) coordinated to either molybdenum or tungsten, the [8Fe-7S] P-cluster and the [Mo-7Fe-9S-C]-homocitrate catalytic site of nitrogenase, the siroheme-[4Fe-4S] center involved in the reduction of sulfite (SO32-) to hydrogen sulfide (H2S), the NiFeS sites of hydrogenases and CO dehydrogenase, and the zinc finger domains. We apologize to all researchers and their associates who have made tremendous contributions to our current knowledge of the steadily increasing transition metal sulfur sites in proteins and enzymes but are not mentioned here. These omissions are by no means intentional but merely the consequence of time and space. We are fully aware of the excellent books and authoritative reviews on various aspects of the subject, however, it is our motivation to cover in one single volume this exciting domain of bioinorganic chemistry.
In nature, sulfur exists in a range of oxidation states and the two-electron reduced form is the most commonly found in biomolecules like the sulfur-containing amino acids cysteine and methionine, some cofactors, and polysaccharides. Sulfur is reduced through two pathways: dissimilation, where sulfite (SO2-3) is used as terminal electron acceptor; and assimilation, where sulfite is reduced to sulfide (S2-) for incorporation into biomass. The pathways are independent, but share the sulfite reductase function, in which a single enzyme reduces sulfite by six electrons to make sulfide. With few exceptions, sulfite reductases from either pathway are iron metalloenzymes with structurally diverse configurations that range from monomers to tetramers. The hallmark of sulfite reductase is its catalytic center made of an iron-containing porphyrinoid called siroheme that is covalently coupled to a [4Fe-4S] cluster through a shared cysteine ligand. The substrate evolves through a push-pull mechanism, where electron transfer is coupled to three dehydration steps. Siroheme is an isobacteriochlorin that is more readily oxidized than protoporphyin IX-derived hemes. It is synthesized from uroporphyrinogen III in three steps (methylation, a dehydrogenation, and ferrochelation) that are performed by enzymes with homology to those involved in cobalamin synthesis. Future research will need to address how the siroheme-[4Fe-4S] clusters are assembled into apo-sulfite and nitrite reductases. The chapter will discuss how environmental microbes use sulfite reductase to survive in a range of ecosystems; how atomic-resolution structures of dissimilatory and assimilatory sulfite reductases reveal their ancient homology; how the siroheme-[4Fe-4S] cluster active site catalyzes the six-electron reduction of sulfite to sulfide; and how siroheme is synthesized across diverse microrganisms.
Vanadium has been known for centuries to have beneficial effects on health and has the potential to be used as an alternative to other diabetic and anticancer medicines. The beneficial effects of vanadium salts or organic compounds have been explored in vitro, ex vivo, and in vivo in animal and human studies. A consensus among researchers is that increased bioavailability of these compounds could markedly increase the efficacy of this class of compounds. In addition, because many commercially available vanadium derivatives are being used by body builders to enhance performance, more understanding of their mode of action is desirable. Future studies of various vanadium compounds need to evaluate their biodistribution, biotransformation, and the effects of food and formulation on the bioavailability of the compounds. To date, most studies in humans have employed vanadium salts, mainly vanadyl sulfate, and dose-limiting side effects were reported at therapeutic doses. One organic vanadium compound, bis(ethylmaltolato)oxovanadium(IV), had improved efficacy compared to the vanadyl sulfate and was selected for Phase 1 and 2 clinical trials. Future studies should be conducted as randomized, placebo controlled trials lasting several months, with monitoring of both fasting blood glucose and hemoglobin A1c. Now, the most promising potential uses of vanadium compounds are as nutritional supplements to control glucose levels and perhaps, as an anticancer agent potentiated by immunotherapy.
It is an old wisdom that metals are indispensable for life. Indeed, several of them, like sodium, potassium, and calcium, are easily discovered in living matter. However, the role of metals and their impact on life remained largely hidden until inorganic chemistry and coordination chemistry experienced a pronounced revival in the 1950s. The experimental and theoretical tools created in this period and their application to biochemical problems led to the development of the field or discipline now known as Bioinorganic Chemistry, Inorganic Biochemistry, or more recently also often addressed as Biological Inorganic Chemistry. By 1970 Bioinorganic Chemistry was established and further promoted by the book series Metal Ions in Biological Systems founded in 1973 (edited by H. S., who was soon joined by A. S.) and published by Marcel Dekker, Inc., New York, for more than 30 years. After this company ceased to be a family endeavor and its acquisition by another company, we decided, after having edited 44 volumes of the MIBS series (the last two together with R. K. O. S.) to launch a new and broader minded series to cover today’s needs in the Life Sciences. Therefore, the Sigels new series is entitled
This chapter is devoted to the chelation treatment of transfusion-dependent thalassemia patients. After a brief overview on the pathophysiology of iron overload and on the methods to quantify it in different organs, the chelation therapy is discussed, giving particular attention to the chemical and biomedical requisites. The main tasks of an iron chelator should be the scavenging of excess iron, allowing an equilibrium between iron supplied by transfusions and that removed with chelation, and protection of the individual from the poisonous effects of circulating iron. The chelating agents in clinical use are presented, illustrating the main chemical and pharmacological features, together with a comparative cost analysis of their treatments. As a final section, an overview is provided on chelators undergoing clinical trials, and on research in progress.
Manganese is an essential dietary element that functions primarily as a coenzyme in several biological processes. These processes include, but are not limited to, macronutrient metabolism, bone formation, free radical defense systems, and in the brain, ammonia clearance and neurotransmitter synthesis. It is a critical component in dozens of proteins and enzymes, and is found in all tissues. Concentrated levels of Mn are found in tissues rich in mitochondria and melanin, with both, liver, and pancreas having the highest concentrations under normal conditions. However, overexposure to environmental Mn via industrial occupation or contaminated drinking water can lead to toxic brain Mn accumulation that has been associated with neurological impairment. The objective of this chapter is to address the biological importance of Mn (essentiality), routes of exposure, factors dictating Mn status, a brief discussion of Mn neurotoxicity, and proposed methods for neurotoxicity remediation.
Metal compounds seem to be a promising approach in the search of new therapeutic solutions for neglected tropical diseases. In this chapter, efforts in the design of prospective metal-based drugs for the treatment of Chagas disease, human African trypanosomiasis, and leishmaniasis are discussed. Careful selection of the metal center (including organometallic cores) and the types and number of coordinated ligands is essential for controlling the reactivity of the complexes and hence, tuning their biological properties. In a target-based approach, some targets that have been validated for organic antiparasitic compounds are expected to remain targets for metal complexes of these compounds. In addition, specific targets for metal compounds, like parasitic enzymes or DNA, would also be included for these metal complexes leading to potential additive or even synergistic effects between organic ligand and metal ion. However, even though a good number of prospective antiparasitic metal-based drugs have been developed, further systematic efforts are needed for these metal compounds to accomplish the regulatory guidelines that let them reach the different stages of clinical trials.
