ZROZUMIENIE HOMEOSTAZY JONÓW METALI U MIKRORGANIZMÓW SZANSĄ NA NOWE STRATEGIE OBRAZOWANIA I TERAPII ZAKAŻEŃ

Metal ions widely exist in biological systems and participate in many vital biochemical processes. Monitoring and analyzing metal ions in biological systems can help reveal physiological processes and understand disease causes. There are various detection methods for metal ions, among which organic small-molecule fluorescent probes have significant advantages, such as high fluorescence quantum yield, easy modification, good biocompatibility, high sensitivity, and fast real-time detection. This review presents recent studies on fluorescent probes for alkali and alkaline earth metal ions (including Na+, K+, Ca2+, and Mg2+) in biological systems. All the candidates are organized according to their structures, and the sensing mechanisms of fluorescent probes are also highly taken into account. Finally, the challenges, trends and prospects of fluorescent probes in metal ion detection are discussed. We hope that this review can provide guidance for the development of fluorescent molecular probe-based alkali and alkaline earth metal ion detection methods in the future.

We have used a systems biology approach to address the hitherto insoluble problem of the quantitative analysis of non-equilibrium binding of aqueous metal ions by competitive ligands in heterogeneous media. To-date, the relative proportions of different metal complexes in aqueous media have only been modelled at chemical equilibrium and there are no quantitative analyses of the approach to equilibrium1. While these models have improved our understanding of how metals are used in biological systems they cannot account for the influence of kinetic factors in metal binding, transport and fate2. Here we have modelled the binding of aluminium in blood serum by the iron transport protein transferrin (Tf) as it is widely accepted that the biological fate of this non-essential metal is not adequately described by experiments, in vitro and in silico, which have consistently demonstrated that at equilibrium 90% of serum Al(III) is bound by Tf3-5. We have coined this paradox 'the blood-aluminium problem'6 and herein applied a systems biology approach which utilised well-found assumptions to pare away the complexities of the problem such that it was defined by a comparatively simple set of computational rules and, importantly, its solution assumed significant predictive capabilities. Here we show that our novel computational model successfully described the binding of Al(III) by Tf both at equilibrium and as equilibrium for AlTf was approached. The model provided an explanation of why the distribution of Al(III) in the body cannot be adequately described by its binding and transport by Tf and it highlighted the significance of kinetic in addition to thermodynamic constraints in defining the fate of metal ions in biological systems. This is the first model of non-equilibrium metal binding in a biological system and it should prove to be a valuable predictive tool in furthering our understanding of the bioinorganic chemistry of metals.

Mammalian metallothionein-4 (MT-4) was found to be specifically expressed in stratified squamous epithelia where it plays an essential but poorly defined role in regulating zinc or copper metabolism. Here we report on the organization, stability, and the pathway of metal-thiolate cluster assembly in MT-4 reconstituted with Cd(2+) and Co(2+) ions. Both the (113)Cd NMR studies of (113)Cd(7)MT-4 and the spectroscopic characterization of Co(7)MT-4 showed that, similar to the classical MT-1 and MT-2 proteins, metal ions are organized in two independent Cd(4)Cys(11) and Cd(3)Cys(9) clusters with each metal ion tetrahedrally coordinated by terminal and bridging cysteine ligands. Moreover, we have demonstrated that the cluster formation in Cd(7)MT-4 is cooperative and sequential, with the Cd(4)Cys(11) cluster being formed first, and that a distinct single-metal nucleation intermediate Cd(1)MT-4 is required in the cluster formation process. Conversely, the absorption and circular dichroism features of metal-thiolate clusters in Cd(7)MT-4 indicate that marked differences in the cluster geometry exist when compared with those in Cd(7)MT-1/2. The biological implication of our studies as to the role of MT-4 in zinc metabolism of stratified epithelia is discussed.

Towards a model of non-equilibrium binding of metal ions in biological systems

(1984). A Review of: “Metal Ions in Biological Systems, Volume 12, Properties of Copper H. Sigel, Editor, xx + 353 pages, Marcel Dekker, Inc., New York and Basel, 1981. $57.50.”. Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry: Vol. 14, No. 3, pp. 431-432.

(1983). A review of: “Zinc and Its Role in Biology and Nutrition, Volume 15 of Metal Ions in Biological Systems, H. Sigel, Editor, xxii + 493 pages, Marcel Dekker, Inc., New York, 1983.”. Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry: Vol. 13, No. 7, pp. 959-960.

Stability constants of bio-relevant, redox-active metals with amino acids: The challenges of weakly binding ligands

Metal ions are widely present in biological systems and participate in many critical biochemical processes such as material transportation, energy conversion, information transmission and metabolic regulation, making them indispensable substance in our body. They can cause health problems when deficiency or excess occurs. To understand various metabolic processes and facilitate diseases diagnosis, it is very important to measure the content and monitor the distribution of metal ions in individual cells, tissues and whole organisms. Among the various methods for metal ion detection, fluorescent sensors with organic dyes have attracted tremendous attention due to many advantages such as high fluorescence quantum yield, facile modification approaches and biocompatibility in addition to operation ease, high sensitivity, fast detection speed, and real-time detection. This review summarizes the recent progress on the detection and imaging of the metal ions in biological systems including Na + , K + , Ca 2+ , Mg 2+ , Fe 2+ /Fe 3+ , Zn 2+ , and Cu 2+ provides an opinion on remaining challenges to be addressed in this field.

Robert (Bob) J. P. Williams who, after a short illness, died on the 21st March 2015 at the age of 89, was professor emeritus at the University of Oxford and was internationally recognized as a founding father of bioinorganic chemistry. His pioneering studies on the roles of metal ions in biological systems brought unprecedented insights into the structure, function, and dynamics of metalloproteins, and established a better understanding of biological signaling, electron-transfer processes, and enzyme catalysis. As one of the inaugural members of the Oxford Enzyme Group in 1972, he employed new developments in high-field NMR spectroscopy to reveal the connection between conformational change and biological function in iron- and calcium-binding proteins, cytochromes, and kinases. In the latter part of his career, Williams initiated a new area of study elucidating the chemical principles responsible for the structure, morphology, and function of calcium carbonate, silica, and iron oxide biominerals. Williams studied chemistry at Merton College, Oxford for both his BA and DPhil (1944–1950). During his undergraduate research project, he published, with Harry M. N. H. Irving, a seminal paper in Nature (1948) on the relative stabilities of metal-ion transition-metal complexes, that became widely known as the Irving–Williams series. After Oxford, Williams took up a one-year postdoctoral position with Arne Tiselius in Uppsala, Sweden, where he developed chromatographic techniques for protein isolation, and published, as sole author, a ground-breaking paper in Biological Reviews (1953) entitled “Metal ions in biological systems”. There he also met Jelly Büchli, whom he married in 1952. He returned to Merton College as a Junior Research Fellow (1951–1955), and was appointed in 1955 as Tutor in Chemistry at Wadham College and University Lecturer in the Inorganic Chemistry Laboratory. He subsequently switched to teaching biochemistry to undergraduates to widen his knowledge. Williams took sabbatical leave at Harvard Medical School in 1966 to work with Bert Vallee, which led to a long collaboration on the isolation of the Zn carboxypeptidase and the replacement of the ZnII ion with the spectroscopically active CoII ion. After his retirement in 1995 he held emeritus positions at Oxford. Bob’s long, outstanding career has been recognized by numerous international honors. He was elected as a Fellow of the Royal Society in 1972, and was a member of four further national academies, as well as the recipient of several honorary degrees. He was also recognized with many distinguished awards and titled lectures. He published over 700 articles, including several highly original books offering novel insights on general inorganic chemistry, the inorganic chemistry of life, the natural selection of the elements, and most recently, the co-evolution of the chemistry of the environment and life (such as The Biological Chemistry of the Elements—The Inorganic Chemistry of Life (with J. J. R. Fausto); and Evolution’s Destiny: Co-evolving Chemistry of the Environment and Life (with R. Rickaby)). In recognition of his distinguished career, Wadham College established no less than three academic positions that bear his name. Bob was awarded an MBE (Member of the Most Excellent Order of the British Empire) in 2010 in recognition of his contributions to his local community in Oxford. Bob Williams was a gifted man, wonderfully creative, highly inspirational, a brilliant teacher and supervisor, and passionate about many areas of science. He was a true polymath, with an encyclopedic knowledge of chemistry, biochemistry and geochemistry. With a sharp mind and fertile imagination he always sought to discover the larger picture and underlying principles hidden behind the facts. Bob was generous in sharing his insights sometimes before there was strong experimental evidence. Others were not slow to seize on his ideas. In 1960, he wrote papers describing a mechanism for the long-range conversion of the energy of reaction of oxygen and hydrogen into localized proton gradients and connecting this coupling to ATP production. Thus began an interest in the chemical processes of respiration and an examination of the possible roles of chains of catalysts within mitochondrial membranes. These ideas contrasted sharply with those of biochemists who were hunting for high-energy phosphorylated intermediates. After a lengthy correspondence with Williams, P. D. Mitchell took up the essence of these ideas to formulate his chemiosmotic hypothesis. Later, Williams developed a deep interest in how chemical constraints were fundamental to the evolution of life. Williams’ legacy to chemistry and biochemistry is enormous. His influence lives on amongst a widespread cadre of scientists beyond those who worked directly with him. No fewer than six of his former students have been elected to the Royal Society. Bob had a lively and engaging personality, and was generous and considerate to his students. The affection and loyalty felt by many extends across the world. Bob Williams will be sadly missed.

The replacement of the nondescript term ‘heavy metals’ by a biologically and chemically significant classification of metal ions

Metals play crucial roles in life processes. It is increasingly recognized that metals are involved in cellular and subcellular functions. With the application of new and sophisticated machines to study biological and biochemical systems the true role of inorganic salts in living systems can be revealed. Inorganic chemistry is not the “Dead Chemistry” that some people may think. Today, it is known that metals are important ingredients in life, just as the organic molecules. For instance, the divalent magnesium and calcium ions play important regulatory roles in cells. Metallothionins are proteins rich in metal ions found in living systems. The divalent cations Zn2+, Ca2+ and Mg2+ prevent cytotoxicity and in vivo antagonize Cd-induced carcinogenesis. Lack of body iron is common in cancer patients and it is associated with complications in surgery and in animal experiments. The transport of iron and other metal ions by the blood plasma is achieved through the formation of protein complexes. Copper is recognized as an essential metalloelement and is primarily associated with copper-dependent cellular enzymes. Metals are also used as inorganic drugs for many diseases.

As the most abundant cation in archaeal, bacterial, and eukaryotic cells, potassium (K+) is an essential element for life. While much is known about the machinery of transcellular and paracellular K transport–channels, pumps, co-transporters, and tight-junction proteins—many quantitative aspects of K homeostasis in biological systems remain poorly constrained. Here we present measurements of the stable isotope ratios of potassium (41K/39K) in three biological systems (algae, fish, and mammals). When considered in the context of our current understanding of plausible mechanisms of K isotope fractionation and K+ transport in these biological systems, our results provide evidence that the fractionation of K isotopes depends on transport pathway and transmembrane transport machinery. Specifically, we find that passive transport of K+ down its electrochemical potential through channels and pores in tight-junctions at favors 39K, a result which we attribute to a kinetic isotope effect associated with dehydration and/or size selectivity at the channel/pore entrance. In contrast, we find that transport of K+ against its electrochemical gradient via pumps and co-transporters is associated with less/no isotopic fractionation, a result that we attribute to small equilibrium isotope effects that are expressed in pumps/co-transporters due to their slower turnover rate and the relatively long residence time of K+ in the ion pocket. These results indicate that stable K isotopes may be able to provide quantitative constraints on transporter-specific K+ fluxes (e.g., the fraction of K efflux from a tissue by channels vs. co-transporters) and how these fluxes change in different physiological states. In addition, precise determination of K isotope effects associated with K+ transport via channels, pumps, and co-transporters may provide unique constraints on the mechanisms of K transport that could be tested with steered molecular dynamic simulations.

Small angle scattering reveals the orientation of cytochrome P450 19A1 in lipoprotein nanodiscs

The use of ion-exchange resins for studying ion transport in biological systems

The ability of nanoparticles to penetrate and transport through soft tissues is essential to delivering therapeutics to treat diseases or signaling agents for advanced imaging and sensing. Nanoparticle transport in biological systems, however, is challenging to predict and control due to the physicochemical complexity of tissues and biological fluids. Here, we demonstrate that nanoparticles suspended in a novel class of soft matter-polymer-linked emulsions (PLEs)-exhibit characteristics essential for mimicking transport in biological systems, including subdiffusive dynamics, non-Gaussian displacement distributions, and decoupling of dynamics from material viscoelasticity. Using multiple particle tracking, we identify the physical mechanisms underlying this behavior, which we attribute to a coupling of nanoparticle dynamics to fluctuations in the local network of polymer-linked droplets. Our findings demonstrate the potential of PLEs to serve as fully synthetic mimics of biological transport.