Metal ions in life sciences最新文献

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.

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. Cobalt-Schiff base complexes have a wide variety of potential therapeutic functions, including as antimicrobials, anticancer agents, and inhibitors of protein aggregation. While providing a broad introduction to this class of agents, this chapter will pay particular attention to agents for which mechanisms of actions have been studied. Appropriate methods to assess activity of these complexes will be reviewed, and promising preclinical complexes in each of the following therapeutic areas will be highlighted: antimicrobial, antiviral, cancer therapy, and Alzheimer's disease.

With the impressive development of molecular life sciences, one may have the feeling that biopharmaceuticals will dominate the world of drug design and production. This is partly due to the evolution of pharmaceutical industry, especially since the 1980s. As a matter of fact, small molecules are still dominating the field of drug innovation, in contradiction with claims predicting their downfall and the exponential raise of biopharmaceuticals. The strong association of chemistry with biochemistry and pharmacology has been the scientific base of the establishment and the success of strong powerful pharmaceutical companies throughout the twentieth century. To meet the needs of new therapeutic agents, it is necessary to assess the role and future position of medicinal chemistry. In fact, the reasonable balance between small molecules and biopharmaceuticals will depend on scientific and economic factors, including the goal of having highly efficient drugs to cure the largest possible number of patients, at a cost that is compatible with the limits of national health budgets. In the present chapter, we would like to emphasize the future important role of small molecules based on new chemicals, to build a new portfolio of efficient, safe and affordable drugs to solve major therapeutic challenges. Two examples are then given. In the blood parasitic diseases such as malaria and schistosomiasis, the iron of heme is an "old" and relevant therapeutic target to kill the parasite. Investigations on the mechanism of action of the antimalarial endoperoxide sesquiterpene artemisinin, have paved the way to the design of new efficient synthetic endoperoxide drugs. In the case of Alzheimer's disease, the loss of copper homeostasis in patient brain is one of the key features of neurodegeneration. The development of small copper specific ligands able to retrieve copper from its pathological sinks to reintroduce it into physiological circulation is a challenging but promising approach to effective therapy.

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.

Intravenous (IV) iron is widely used to provide supplementation when oral iron is ineffective or not tolerated. All commercially available intravenous iron formulations are comprised of iron oxyhydroxide cores coated with carbohydrates of varying structure and branch characteristics. The diameter of the iron-carbohydrate complexes ranges from 5-100 nm and meets criteria for nanoparticles. Clinical use of IV iron formulations entered clinical practice beginning of the late 1950s, which preceded the nanomedicine exploration frontier. Thus, these agents were approved without full exploration of labile iron release profiles or comprehensive biodistribution studies. The hypothesis for the pathogenesis of acute oxidative stress induced by intravenous iron formulations is the release of iron from the iron-carbohydrate structure, resulting in transient concentrations of labile plasma iron and induction of the Fenton chemistry and the Haber-Weiss reaction promoting formation of highly reactive free radicals such as the hydroxyl radical. Among available IV iron formulations, products with smaller carbohydrate shells are more labile and more likely to release labile iron directly into the plasma (i.e., before metabolism by the reticuloendothelial system). The proposed biologic targets of labile-iron-induced oxidative stress include nearly all systemic cellular components including endothelial cells, myocardium, liver as well as low density lipoprotein and other plasma proteins. Most studies have relied on plasma pharmacokinetic analyses that require many model assumptions to estimate contribution of the iron-carbohydrate complex to elevations in serum iron indices and hemoglobin. Additionally, the commercially available formulations have not been well studied with regard to optimal dosing regimens, long-term safety and comparative efficacy. The IV iron formulations fall into a class defined by the Food and Drug Administration as "Complex Drugs" and thus present considerable challenges for bioequivalence evaluation.

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. While simple in concept, it has taken many decades of work to accomplish the difficult hurdle of transporting antimicrobials across the cell membranes of pathogens. This review discusses information learned about siderophore structure, production, and transport, and lessons learned from the successes and failures of siderophore-conjugate drugs evaluated during the development of novel agents using the 'Trojan horse' approach.

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.

A dynamic interplay between the host and pathogen determines the course and outcome of infections. A central venue of this interplay is the struggle for iron, a micronutrient essential to both the mammalian host and virtually all microbes. The induction of the ironregulatory hormone hepcidin is an integral part of the acute phase response. Hepcidin switches off cellular iron export via ferroportin-1 and sequesters the metal mainly within macrophages, which limits the transfer of iron to the serum to restrict its availability for extracellular microbes. When intracellular microbes are present within macrophages though, the opposite regulation is initiated because infected cells respond with increased ferroportin-1 expression and enhanced iron export as a strategy of iron withdrawal from engulfed bacteria. Given these opposing regulations, it is not surprising that disturbances of mammalian iron homeostasis, be they attributable to genetic alterations, hematologic conditions, dietary iron deficiency or unconsidered iron supplementation, may affect the risk and course of infections. Therefore, acute, chronic or latent infections need to be adequately controlled by antimicrobial therapy before iron is administered to correct deficiency. Iron deficiency per se may negatively affect growth and development of children as well as cardiovascular performance and quality of life of patients. Of note, mild iron deficiency in regions with a high endemic burden of infections is associated with a reduced prevalence and a milder course of certain infections which may be traced back to effects of iron on innate and adaptive immune function as well as to restriction of iron for pathogens. Finally, absolute and functional causes of iron deficiency need to be differentiated, because in the latter form, oral iron supplementation is inefficient and intravenous application may adversely affect the course of the underlying disease such as a chronic infection. This chapter summarizes our current knowledge on the regulation of iron metabolism and the interactions between iron and the immune response against microbes. Moreover, some of the unanswered questions on the association of iron administration and infections are addressed.

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. As a result, copper depletion has emerged as a novel therapeutic strategy in the treatment of metastatic cancer. We present a review of the physiologic role of copper with a discussion of relevant enzymes of the copper proteome in both normal tissue and in cancer. We conducted a comprehensive review of the available preclinical data of several copper chelation agents, including penicillamine, trientine, disulfiram, clioquinol, and tetrathiomolybdate (TM), across a variety of tumor types. We also present the existing early phase clinical trial data for the use of the copper chelator TM in the treatment of breast cancer and other malignancies.