Bioinorganic chemistry

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Bioinorganic chemistry is a field that examines the role of metals in biology. Bioinorganic chemistry includes the study of both natural phenomena such as the behavior of metalloproteins as well as artificially introduced metals, including those that are non-essential, in medicine and toxicology. Many biological processes such as respiration depend upon molecules that fall within the realm of inorganic chemistry. The discipline also includes the study of inorganic models or mimics that imitate the behaviour of metalloproteins. [1]

Contents

As a mix of biochemistry and inorganic chemistry, bioinorganic chemistry is important in elucidating the implications of electron-transfer proteins, substrate bindings and activation, atom and group transfer chemistry as well as metal properties in biological chemistry. The successful development of truly interdisciplinary work is necessary to advance bioinorganic chemistry. [2]

Composition of living organisms

About 99% of mammals' mass are the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, phosphorus, oxygen and sulfur. [3] The organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen and most of the oxygen and hydrogen is present as water. [3] The entire collection of metal-containing biomolecules in a cell is called the metallome.

History

Paul Ehrlich used organoarsenic (“arsenicals”) for the treatment of syphilis, demonstrating the relevance of metals, or at least metalloids, to medicine, that blossomed with Rosenberg's discovery of the anti-cancer activity of cisplatin (cis-PtCl2(NH3)2). The first protein ever crystallized (see James B. Sumner) was urease, later shown to contain nickel at its active site. Vitamin B12, the cure for pernicious anemia was shown crystallographically by Dorothy Crowfoot Hodgkin to consist of a cobalt in a corrin macrocycle. The Watson-Crick structure for DNA demonstrated the key structural role played by phosphate-containing polymers.

Themes in bioinorganic chemistry

Several distinct systems are of identifiable in bioinorganic chemistry. Major areas include:

Metal ion transport and storage

A diverse collection of transporters (e.g. the ion pump NaKATPase), vacuoles, storage proteins (e.g. ferritin), and small molecules (e.g. siderophores) are employed to control metal ions concentration and bio-availability in living organisms. Crucially, many essential metals are not readily accessible to downstream proteins owing to low solubility in aqueous solutions or scarcity in the cellular environment. Organisms have developed a number of strategies for collecting and transporting such elements while limiting their cytotoxicity.

Enzymology

Many reactions in life sciences involve water and metal ions are often at the catalytic centers (active sites) for these enzymes, i.e. these are metalloproteins. Often the reacting water is a ligand (see metal aquo complex). Examples of hydrolase enzymes are carbonic anhydrase, metallophosphatases, and metalloproteinases. Bioinorganic chemists seek to understand and replicate the function of these metalloproteins.

Metal-containing electron transfer proteins are also common. They can be organized into three major classes: iron–sulfur proteins (such as rubredoxins, ferredoxins, and Rieske proteins), blue copper proteins, and cytochromes. These electron transport proteins are complementary to the non-metal electron transporters nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). The nitrogen cycle make extensive use of metals for the redox interconversions.

4Fe-4S clusters serve as electron-relays in proteins. FdRedox.png
4Fe-4S clusters serve as electron-relays in proteins.

Toxicity

Several metal ions are toxic to humans and other animals. The bioinorganic chemistry of lead in the context of its toxicity has been reviewed. [4]

Oxygen transport and activation proteins

Aerobic life make extensive use of metals such as iron, copper, and manganese. Heme is utilized by red blood cells in the form of hemoglobin for oxygen transport and is perhaps the most recognized metal system in biology. Other oxygen transport systems include myoglobin, hemocyanin, and hemerythrin. Oxidases and oxygenases are metal systems found throughout nature that take advantage of oxygen to carry out important reactions such as energy generation in cytochrome c oxidase or small molecule oxidation in cytochrome P450 oxidases or methane monooxygenase. Some metalloproteins are designed to protect a biological system from the potentially harmful effects of oxygen and other reactive oxygen-containing molecules such as hydrogen peroxide. These systems include peroxidases, catalases, and superoxide dismutases. A complementary metalloprotein to those that react with oxygen is the oxygen evolving complex present in plants. This system is part of the complex protein machinery that produces oxygen as plants perform photosynthesis.

Myoglobin is a prominent subject in bioinorganic chemistry, with particular attention to the iron-heme complex that is anchored to the protein. Myoglobin.png
Myoglobin is a prominent subject in bioinorganic chemistry, with particular attention to the iron-heme complex that is anchored to the protein.

Bioorganometallic chemistry

Bioorganometallic systems feature metal-carbon bonds as structural elements or as intermediates. Bioorganometallic enzymes and proteins include the hydrogenases, FeMoco in nitrogenase, and methylcobalamin. These naturally occurring organometallic compounds. This area is more focused on the utilization of metals by unicellular organisms. Bioorganometallic compounds are significant in environmental chemistry. [5]

Structure of FeMoco, the catalytic center of nitrogenase. FeMoco cluster.svg
Structure of FeMoco, the catalytic center of nitrogenase.

Metals in medicine

A number of drugs contain metals. This theme relies on the study of the design and mechanism of action of metal-containing pharmaceuticals, and compounds that interact with endogenous metal ions in enzyme active sites. The most widely used anti-cancer drug is cisplatin. MRI contrast agent commonly contain gadolinium. Lithium carbonate has been used to treat the manic phase of bipolar disorder. Gold antiarthritic drugs, e.g. auranofin have been commercialized. Carbon monoxide-releasing molecules are metal complexes have been developed to suppress inflammation by releasing small amounts of carbon monoxide. The cardiovascular and neuronal importance of nitric oxide has been examined, including the enzyme nitric oxide synthase. (See also: nitrogen assimilation.) Besides, metallic transition complexes based on triazolopyrimidines have been tested against several parasite strains. [6]

Environmental chemistry

Environmental chemistry traditionally emphasizes the interaction of heavy metals with organisms. Methylmercury has caused major disaster called Minamata disease. Arsenic poisoning is a widespread problem owing largely to arsenic contamination of groundwater, which affects many millions of people in developing countries. The metabolism of mercury- and arsenic-containing compounds involves cobalamin-based enzymes.

Biomineralization

Biomineralization is the process by which living organisms produce minerals, often to harden or stiffen existing tissues. Such tissues are called mineralized tissues. [7] [8] [9] Examples include silicates in algae and diatoms, carbonates in invertebrates, and calcium phosphates and carbonates in vertebrates. Other examples include copper, iron and gold deposits involving bacteria. Biologically-formed minerals often have special uses such as magnetic sensors in magnetotactic bacteria (Fe3O4), gravity sensing devices (CaCO3, CaSO4, BaSO4) and iron storage and mobilization (Fe2O3•H2O in the protein ferritin). Because extracellular [10] iron is strongly involved in inducing calcification, [11] [12] its control is essential in developing shells; the protein ferritin plays an important role in controlling the distribution of iron. [13]

Types of inorganic substances in biology

Alkali and alkaline earth metals

Like many antibiotics, monensin-A is an ionophore that tightly bind Na (shown in yellow). Monensin2.png
Like many antibiotics, monensin-A is an ionophore that tightly bind Na (shown in yellow).

The abundant inorganic elements act as ionic electrolytes. The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate, and bicarbonate. The maintenance of precise gradients across cell membranes maintains osmotic pressure and pH. [15] Ions are also critical for nerves and muscles, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cytosol. [16] Electrolytes enter and leave cells through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules. [17]

Transition metals

The transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant. [18] [19] [20] These metals are used as protein cofactors and signalling molecules. Many are essential for the activity of enzymes such as catalase and oxygen-carrier proteins such as hemoglobin. [21] These cofactors are tightly to a specific protein; although enzyme cofactors can be modified during catalysis, cofactors always return to their original state after catalysis has taken place. The metal micronutrients are taken up into organisms by specific transporters and bound to storage proteins such as ferritin or metallothionein when not being used. [22] [23] Cobalt is essential for the functioning of vitamin B12. [24]

Main group compounds

Many other elements aside from metals are bio-active. Sulfur and phosphorus are required for all life. Phosphorus almost exclusively exists as phosphate and its various esters. Sulfur exists in a variety of oxidation states, ranging from sulfate (SO42−) down to sulfide (S2−). Selenium is a trace element involved in proteins that are antioxidants. Cadmium is important because of its toxicity. [25]

See also

Related Research Articles

Hemoprotein Protein containing a heme prosthetic group

A hemeprotein, or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen carrying, oxygen reduction, electron transfer, and other processes. Heme is bound to the protein either covalently or noncovalently or both.

Metalloprotein Protein that contains a metal ion cofactor

Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins contain zinc-binding protein domains although there may be up to 3000 human zinc metalloproteins.

Trace metal

Trace metals are the metals subset of trace elements; that is, metals normally present in small but measurable amounts in animal and plant cells and tissues and that are a necessary part of nutrition and physiology. Many biometals are trace metals. Ingestion of, or exposure to, excessive quantities can be toxic. However, insufficient plasma or tissue levels of certain trace metals can cause pathology, as is the case with iron.

A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.

Cofactor (biochemistry) Non-protein chemical compound or metallic ion

A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst. Cofactors can be considered "helper molecules" that assist in biochemical transformations. The rates at which these happen are characterized in an area of study called enzyme kinetics. Cofactors typically differ from ligands in that they often derive their function by remaining bound.

Siderophore Low-molecular-weight compounds produced by microorganisms and plants that aid in the transport and sequestration of iron

Siderophores (Greek: "iron carrier") are small, high-affinity iron-chelating compounds that are secreted by microorganisms such as bacteria and fungi. They help the organism accumulate iron. Although a widening range of siderophore functions is now being appreciated. Siderophores are among the strongest (highest affinity) Fe3+ binding agents known. Phytosiderophores are siderophores produced by plants.

Iron–sulfur proteins are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, coenzyme Q – cytochrome c reductase, succinate – coenzyme Q reductase and nitrogenase. Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of electron transport in mitochondria and chloroplasts. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally, some Fe–S proteins regulate gene expression. Fe–S proteins are vulnerable to attack by biogenic nitric oxide, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.

In biochemistry, the metallome is the distribution of metal ions in a cellular compartment. The term was coined in analogy with proteome as metallomics is the study of metallome: the "comprehensive analysis of the entirety of metal and metalloid species within a cell or tissue type". Therefore, metallomics can be considered a branch of metabolomics, even though the metals are not typically considered as metabolites.

Human iron metabolism Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

A Holoprotein or conjugated protein is an apoprotein combined with its prosthetic group.

Catechol oxidase is a copper oxidase that contains a type 3 di-copper cofactor and catalyzes the oxidation of ortho-diphenols into ortho-quinones coupled with the reduction of molecular oxygen to water. It is present in a variety of species of plants and fungi including Ipomoea batatas and Camellia sinensis. Metalloenzymes with type 3 copper centers are characterized by their ability to reversibly bind dioxygen at ambient conditions. In plants, catechol oxidase plays a key role in enzymatic browning by catalyzing the oxidation of catechol to o-quinone in the presence of oxygen, which can rapidly polymerize to form the melanin that grants damaged fruits their dark brown coloration.

Nitrite reductase refers to any of several classes of enzymes that catalyze the reduction of nitrite. There are two classes of NIR's. A multi haem enzyme reduces NO2− to a variety of products. Copper containing enzymes carry out a single electron transfer to produce nitric oxide.

Iron-binding proteins are carrier proteins and metalloproteins that are important in iron metabolism and the immune response. Iron is required for life.

Biometal (biology) Metal in biology, biochemistry, and medicine

Biometals are metals normally present, in small but important and measurable amounts, in biology, biochemistry, and medicine. The metals copper, zinc, iron, and manganese are examples of metals that are essential for the normal functioning of most plants and the bodies of most animals, such as the human body. A few are present in relatively larger amounts, whereas most others are trace metals, present in smaller but important amounts. Approximately 2/3 of the existing periodic table is composed of metals with varying properties, accounting for the diverse ways in which metals have been utilized in nature and medicine.

Bioorganometallic chemistry is the study of biologically active molecules that contain carbon directly bonded to metals or metalloids. The importance of main-group and transition-metal centers has long been recognized as important to the function of enzymes and other biomolecules. However, only a small subset of naturally-occurring metal complexes and synthetically prepared pharmaceuticals are organometallic; that is, they feature a direct covalent bond between the metal(loid) and a carbon atom. The first, and for a long time, the only examples of naturally occurring bioorganometallic compounds were the cobalamin cofactors (vitamin B12) in its various forms. Due to the recent (21st century) discovery of new systems containing carbon-metal bonds in biology, bioorganometallic chemistry is rapidly emerging as a distinct subdiscipline of bioinorganic chemistry that straddles organometallic chemistry and biochemistry. Naturally occurring bioorganometallics include enzymes and sensor proteins. Also within this realm are synthetically prepared organometallic compounds that serve as new drugs and imaging agents (technetium-99m sestamibi) as well as the principles relevant to the toxicology of organometallic compounds (e.g., methylmercury). Consequently, bioorganometallic chemistry is increasingly relevant to medicine and pharmacology.

QPNC-PAGE, or quantitative preparative native continuous polyacrylamide gel electrophoresis, is a bioanalytical, high-resolution and highly accurate technique applied in biochemistry and bioinorganic chemistry to separate proteins quantitatively by isoelectric point. This standardized variant of native gel electrophoresis is used by biologists to isolate biomacromolecules in solution, for example, active or native metalloproteins in biological samples or properly and improperly folded metal cofactor-containing proteins or protein isoforms in complex protein mixtures.

Amy C. Rosenzweig is a professor of Chemistry and Molecular Biosciences at Northwestern University. She was born in 1967 in Pittsburgh, Pennsylvania. Her current research interests include structural biology and bioinorganic chemistry, metal uptake and transport, oxygen activation by metalloenzymes, and characterization of membrane protein. For her work, she has been recognized by a number of national and international awards, including the MacArthur "Genius" Award in 2003.

Metals in medicine are used in organic systems for diagnostic and treatment purposes. Inorganic elements are also essential for organic life as cofactors in enzymes called metalloproteins. When metals are scarce or high quantities, equilibrium is set out of balance and must be returned to its natural state via interventional and natural methods.

Evolution of metal ions in biological systems refers to the incorporation of metallic ions into living organisms and how it has changed over time. Metal ions have been associated with biological systems for billions of years, but only in the last century have scientists began to truly appreciate the scale of their influence. Major and minor metal ions have become aligned with living organisms through the interplay of biogeochemical weathering and metabolic pathways involving the products of that weathering. The associated complexes have evolved over time.

A large fraction of the chemical elements that occur naturally on the earth's surface are essential to the structure and metabolism of living things. Four of these elements are essential to every living thing and collectively make up 99% of the mass of protoplasm. Phosphorus and sulfur are also common essential elements, essential to the structure of nucleic acids and amino acids, respectively. Chlorine, potassium, magnesium, calcium and phosphorus have important roles due to their ready ionization and utility in regulating membrane activity and osmotic potential. The remaining elements found in living things are primarily metals that play a role in determining protein structure. Examples include iron, essential to hemoglobin; and magnesium, essential to chlorophyll. Some elements are essential only to certain taxonomic groups of organisms, particularly the prokaryotes. For instance, the lanthanide series rare earths are essential for methanogens. As shown in the following table, there is strong evidence that 19 of the elements are essential to all living things, and another 17 are essential to some taxonomic groups. Of these 17, most have not been extensively studied, and their biological importance may be greater than currently supposed.

References

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  24. ↑ Cracan, Valentin; Banerjee, Ruma (2013). "Chapter 10 Cobalt and Corrinoid Transport and Biochemistry". In Banci, Lucia (ed.). Metallomics and the Cell. Metal Ions in Life Sciences. Vol. 12. Springer. pp. 333–74. doi:10.1007/978-94-007-5561-1_10. ISBN   978-94-007-5560-4. PMID   23595677. electronic-book ISBN   978-94-007-5561-1 ISSN   1559-0836 electronic- ISSN   1868-0402
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