Metal Ions in Life Sciences

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...

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...

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...

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...

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...

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...

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...

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...

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...

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 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...

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)...

Physiological metabolism of cyanide takes place by a single major pathway that forms non-toxic thiocyanate that is subsequently excreted. Rhodanese is the primary enzyme to execute metabolism of cyanide with minor pathways from other sulfurtransferases in vivo. The rhodanese enzyme depends on sulfur donor availability to metabolize cyanide and poisoning occurs at elevated cyanide concentrations in vivo. Cyanide interacts with over 40 metalloenzymes, but its lethal action is non-competitive inhibition of cytochrome c oxidase, halting cellular respiration and causing hypoxic anoxia...

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...

Copper is an essential trace element that plays a critical role in a variety of basic biological functions, and serves as a key component in a number of copper-dependent enzymes that regulate such processes as cell proliferation, angiogenesis, and motility. A growing body of preclinical work has demonstrated that copper is essential to metastatic cancer progression, and may have a role in tumor growth, epithelial-mesenchymal transition, and the formation of the tumor microenvironment and pre-metastatic niche...

The use of metals in medicine has grown impressively in recent years as a result of greatly advanced understanding of biologically active metal complexes and metal-containing proteins. One landmark in this area was the introduction of cisplatin and related derivatives as anticancer drugs. As the body of literature continues to expand, it is necessary to inspect sub-classes of this group with more acute detail. This chapter will review preclinical research of cobalt complexes coordinated by Schiff base ligands...

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...

After 40 years of significant work, it was generally accepted that chromium in its trivalent valence state, Cr(III), is an essential micronutrient for humans. This view began to be challenged around the turn of the millennium. Some investigators argue that its effects on glucose and lipid metabolism reflect a pharmacological rather than a nutritional mode of action while yet others express concern about the toxicity and safety of supplemental chromium. Understanding the conjectures requires a reflection on the different definitions of "essential" and a perspective on the development of the field, which in itself is a remarkable snippet of science history and education...

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...

Antimicrobial resistance is a major global health problem, and novel approaches to solving this crisis are urgently required. The 'Trojan Horse' approach to solving this problem capitalizes on the innate need for iron by pathogens. Siderophores are low-molecular-weight iron chelators secreted extracellularly by pathogens to scavenge iron. Once bound to iron, the iron-siderophore complex returns to the pathogen to deliver its iron treasure. "Smuggling" antimicrobials into the pathogen is accomplished by linking them to siderophores for transport...