CHEMICAL BIOLOGY

Inorganic Chemistry in Biology

 

Ivano Bertini and Paola Turano, University of Florence, Florence, Italy

doi: 10.1002/9780470048672.wecb250

 

Several inorganic chemical elements play fundamental roles in biological processes. The contribution of inorganic chemistry to the understanding of biological processes is presented here from a historical perspective: from the first discoveries of metal ions in living organisms to the modern approaches of inorganic structural biology and bioinformatics, through the characterization of metal binding sites in proteins and in biomimetic model compounds. Definitions are provided for the fundamental concepts of metal cofactor, metalloprotein, and metalloenzyme.

 

The importance of inorganic chemistry for chemical biology is based on the distribution of the elements of the periodic table in living organisms, which is summarized in Fig. 1. Amino acids, nucleic acids, carbohydrates, lipids, organic cofactors (e.g., ATP, ADP, and NADH), and metabolites are composed of the six bulk biological elements: carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur. The chemistry of these elements in living systems is the subject of classic biological chemistry. However, it has been established that at least 20 elements other than C, H, N, O, P, and S are essential for life, even though they are considered generally “inorganic” (Fig. 1). The first metal-containing species identified in living systems were pigments such as chlorophylls and hemoglobin, whose discovery dates back to the nineteenth century. To complement the work aimed at the chemical characterization of these molecules, several studies showed that some metal ions, such as zinc and iron, are essential for life. Hemoglobin, myoglobin, and cytochromes were among the first biological macromolecules to be investigated at the molecular level because of their abundance in living organisms and their intense color, which eased their detection. Nevertheless, it was only in the second half of the twentieth century that the contribution of inorganic chemistry to the characterization of biological systems translated into a well-defined discipline, named bioinorganic chemistry (and later also called biological inorganic chemistry). The establishment of this new branch of science paralleled advancements in spectroscopic tools, in structural methods, and in the development of inorganic chemistry as the chemistry of coordination compounds. This ensemble of approaches has provided momentum and has given great impulse to the characterization of the binding mode of metal ions in biological macromolecules and to the understanding of their reactivity. Two primary approaches have guided the study of metal binding sites in proteins: 1) the synthesis and characterization of model compounds and 2) the direct characterization of metalloenzymes and metalloproteins.

 

 

Figure 1. The periodic table of the elements. Those elements known to be relevant for living organisms are highlighted.

 

Metal Cofactors

Typically, metal ions are cofactors that function as catalytic centers in several fundamental biological reactions, play a role in electron transfer reactions, or impart structural stabilization to the macromolecular fold. Proteins offer such a large variety of metal binding sites associated with widely disparate functions that biological inorganic chemistry focuses primarily on the study of metal ions in proteins. Other areas of research in the field include the metal-RNA and metal-DNA interactions. However, these aspects are not addressed here, as the chemistry is largely electrostatic in nature. On the contrary, the ability of proteins to bind metal ions is related essentially to the presence of amino acid side chains that can act as metal ligands. Figure 2 represents the possible binding modes of these side chains. In some cases, the coordination geometry of the metal ion is completed by exogenous ligands such as H2O or OH-, or by protein backbone amides or carbonyls.

Traditionally, when the association between the metal ion and the protein is relatively strong (i.e., binding constant higher than 108 M-1) the complex is called a metalloprotein. When the protein is performing catalytic activity at the metal center, it is called a metalloenzyme.

Although the different sequences and folds of proteins provide the most disparate metal binding sites (some examples of which are provided in Fig. 3), Nature has evolved to select other organic or inorganic ligands for metal ions in proteins, which we call “special metal cofactors.” These cofactors can be grouped into two broad classes: tetrapyrroles and metalloclusters.

Tetrapyrroles are macrocyclic ligands that provide a common skeleton to hemes (that contains iron), chlorophylls (that contains magnesium), corrinoids (that contains cobalt), siroheme (that contains iron), and methanogenesis factor F430 (that contains nickel).

Iron-porphyrins are a widespread group of tetrapyrroles present in heme proteins (1). They are all derived from protoporphyrin IX, but they have different substituents (Fig. 4). The so-called heme b coincides with protoporphyrin IX. Heme o differs from heme b by the presence of a farnesylhydroxyethyl group at position 2, and it differs from heme a by the presence of a farnesylhydroxyethyl group at position 2 and a formyl group at position 8. In heme c, the two vinyl groups are substituted with thioether bridges that involve sulfhydryl groups of protein cysteine residues, which results in two covalent linkages between the porphyrin and the protein matrix. Heme P460 can be viewed as a c-type heme with an additional covalent bond between the α-meso position and a Ce of a nearby tyrosine ring. Heme d, heme d1, and siroheme have unconjugated pyrrole rings. The common oxidation states for iron in heme proteins are +2 and +3, although the iron(IV) = O moiety is often encountered as a nonresting-state form in the catalytic cycle of several heme enzymes (1).

 

 

 

Figure 2. Possible binding modes of amino acid side chains. The coordinated metal ion is indicated by the circle labeled M.

 

 

Figure 3. Examples of metal cofactors in proteins: (a) the zinc center of carbonic anhydrase, (b) the blue-copper center of plastocyanin, (c) the iron center in 2,3-dihydroxybiphenil dioxygenase, (d) the iron binding site of transferrin, and (e) the dinuclear copper site of CUA in cytochrome c oxidase.

 

 

Figure 4. Some commonly encountered hemes: (a) heme b, (b) heme o, (c) heme a, (d) heme c, and (e) heme P460. In each, the iron atom is the central sphere. In (a), the heme substituent positions are labeled according to the commonly used nomenclature. The hemes are all shown with the same orientation. The numbering of A holds for each of them.

 

Metalloclusters consist of at least two metal ions associated with inorganic and/or otherwise nonprotein ligands. Bimetallic centers in which the metal ion ligands are composed of H2O/OH- ligands in addition to amino acid side chains are excluded from the definition of a metallocluster. Several metallo-clusters have been characterized structurally in metalloproteins.

Among the most abundant metalloclusters are those of the iron-sulfur family (2, 3). Iron-sulfur clusters are characterized by iron ions that exhibit almost exclusively tetrahedral coordination to donor sulfur atoms, provided by either Sγ of cysteines or by bridging sulfides (sometimes called inorganic sulfurs). Metalloproteins contain basic cluster types with two, three, or four iron ions, as depicted in Fig. 5. In this figure, the mononuclear iron center of rubredoxin is shown: This iron center is not a cluster but can be considered as the “prototype” of the tetrahedral iron units that constitute the FeS clusters. The simplest type of iron-sulfur cluster is represented by the diamond structure of the Fe2S2 center, in which the two iron ions are coordinated to two bridging sulfides. Each iron is then bound to two Cys or two His ligands (the latter in the case of Rieske proteins, Fig. 5). The Fe4S4 unit is constituted by four iron ions and four sulfide ions arranged in a cubane structure. Again, the tetra-coordination of each iron ion is accomplished on binding of the sulfur of a Cys protein residue. The Fe3S4 cluster seems to be derived from the Fe4S4 cluster by the removal of one iron. Rubredoxins are electron transfer proteins in which the iron oxidation state cycles between +3 and +2. In the clusters, the number of potential oxidation states increases with the number of metal ions. Assuming that each iron can exist formally in the ferric and ferrous states, an iron-sulfur cluster with n irons can exhibit a maximum number of n + 1 oxidation states. Nevertheless, only a few oxidation states have been observed in proteins. For instance, in Fe2S2 systems, only two of the possible three oxidation states are found: the one that contains two ferric ions [i.e., the (Fe2S2)2+ state] and the one that contains one ferric and one ferrous ion [(Fe2S2)+]. This type of cluster is typical of electron transfer proteins or of electron transfer centers in multidomain redox metalloenzymes. The Fe2S2 cluster in which the iron coordination is completed by two Cys per iron is present in ferredoxins.

In recent years, X-ray crystallography has led to the discovery of several novel metalloclusters of complex architecture that contain at least four metal ions (4, 5). They represent the active site of several redox enzymes that contain molybdenum, nickel, and manganese, as well as the most commonly encountered iron and copper (Fig. 6). These enzymes are extremely specialized in the oxidation or reduction reactions of the smallest molecules and anions (which include N2, CO, and H2). A common feature of such clusters is that they are present in enzymes as part of a more extensive electron transfer chain that involves a series of metallocenters (often heme and iron-sulfur centers) that serve to carry electrons into and out the active site. For several of them, extensive spectroscopic and functional studies are required to unravel oxidation states, substrate binding sites, and reaction mechanisms at these sites.

The first and second coordination sphere modulates the reactivity of metal ions so that the functional roles of a given ion may be largely different, as summarized in Table 1.

 

Table 1. Main biologic functions of metal ions

 

Element

Role

Calcium

Structure stabilization—Signaling—Enzyme activator

Cobalt

Redox catalyst

Copper

ET—Redox catalyst—O2 carrier

Heme iron

ET—Redox catalyst—O2 carrier

Iron in FeS clusters

ET—Redox catalyst

Nonheme nonFeS iron

Redox catalyst—O2 carrier

Magnesium

Enzyme activator—DNA structure stabilization—Ribozymes

Manganese

Redox catalist—Activator of hydrolases, ligases and transferases

Molybdenum

Redox catalyst (nitrogenase, oxotransferases)

Nickel

Hydrolitic activity—Redox catalyst

Potassium

ATPase pumping—Structure stabilization—Electrostatic effects on the reduction potential of distant centers

Rubidium

Function similar to that of K in some plants

Selenium

Redox catalyst

Sodium

ATPase pumping—Structure stabilization—Electrostatic effects on the reduction potential of distant centers

Srlicium

Funtion similar to that of Ca in some plants

Tungsten

Replaces Mo in some hyperthermophilic archea

Vanadium

Peroxidase and nitrogenase activity in some algae and possibly fungi

Zinc

Hydrolitic activity—Structure stabilization—Transcription factor

 

 

Figure 5. The most commonly encountered FeS centers: (a) the monoiron center of rubredoxin, (b) the Fe2S2 cluster of plant-type ferredoxins, (c) the Fe2S2 cluster of Rieske proteins, (d) the Fe3S4 cluster of ferredoxins, and (e) the Fe4S4 cluster of ferredoxins and high potential iron-sulfur proteins (HiPiPs).

 

A good example of the effects of the first and second coordination sphere on modulating the reactivity of metal cofactors in proteins is provided by heme proteins (1). Heme-iron in heme proteins can be five-coordinate or six-coordinate. Axial ligation seems to be related strongly to protein function. Six-coordination (His/His or His/Met) is typical of cytochromes and electron transfer proteins in which the heme iron has to cycle between the iron(III) and the iron(II) oxidation states for its function. Usually, penta-coordination is found in globins that bind oxygen and in redox heme-enzymes. In globins, the imidazole ring of the “proximal” His residue provides the fifth heme iron ligand; the other axial heme iron position remains essentially free for O2 coordination. In heme-enzymes, the sixth coordination position is available for substrate binding. The basicity of the fifth (or proximal) His ligand modulates the redox potential of the heme iron. In peroxidases, the His has a strong imidazolate character because of a strong H-bond between the Nδ1 of the imidazole ring and a nearby Asp residue; this bond facilitates the higher oxidation states for the heme iron (6). The resting state of these enzymes contains iron(III), and higher oxidation states are reached during the catalytic cycle. In globins the His is essentially neutral, with a weak H-bond between the imidazole and a backbone carbonyl, and these proteins are commonly in the iron(II) state.

 

Model Compounds

The discovery of metal centers in metalloproteins has stimulated inorganic chemists to synthesize compounds capable of mimicking the spectroscopic and functional properties of the protein metal cofactors. Biomimetic model compound chemistry has flourished since the 1970s, when several advantages existed in the study of the model compound instead of the protein itself. The much smaller size of the model compound made it more suitable for biophysical studies, and advancements in chemical synthesis offered opportunities to play with ligands and metal geometries. Some notable examples of the synthetic analog approach deal with iron-porphyrin model compounds (and metalloporphyrins in general) (7), iron-sulfur clusters (3), and model compounds aimed at reproducing the unusual spectroscopic and electrochemical properties of blue copper proteins (8). In more recent times, synthetic models have been developed to reproduce the characteristic features of the binuclear CuA electron-transfer center of cytochrome c oxidase (9) (Fig. 3e), of high-nuclearity Mo/Fe/S clusters of the cofactors of nitrogenases (10) (Fig. 6a), and of the CuZ center of nitrous oxide reductase (11) (Fig. 6d).

Today, the advancements in spectroscopic, structural, and biological tools make it easier than ever before to study metal centers in their biological context. As a consequence, the impact of model compounds has been reduced; although from an inorganic point of view, biological metal centers may represent a synthetic challenge and are relevant for science beyond their importance as model compounds.

The synthetic approach is also suffering from the intrinsic difficulties encountered in the design of ligands capable of mimicking the secondary coordination sphere effects and the stereo and enantio-selectivity of the metal centers. In a novel approach, biotechnological skills are used to engineer novel metal centers in natural protein scaffolds, which makes ample use of site directed mutagenesis (12). Such a de novo design approach has been used for example to change the function of oxygen binding proteins into that of peroxidases, or from cytochromes into that of globins upon substitution of one or several key residues. Engineering of entire protein fragments within another protein scaffold has been used to transform blue copper proteins (Fig. 3b) into binuclear CuA centers (Fig. 3e).

 

 

Figure 6. (a) The FeMo-cofactor of nitrogenases: The overall stoichiometry is MoFe7S9, and it can be viewed as a MoFe3S3 cluster and a Fe4S3 cluster, bridged by three sulfides. The molybdenum is also bound to a homocitrate molecule. (b) The C-cluster of carbon monoxide dehydrogenase: This can be viewed as a Fe3S4 cluster bridged to a binuclear Ni-Fe center. (c) The oxygen-evolving center of photosystem II: A cubane-like Mn3CaO4 cluster is linked to a fourth Mn ion (Mn4) by a μ-oxo bridge. (d) The tetranuclear CuZ center of nitrous oxide reductase: Three of four copper ions bind two His, the fourth binds a single His, and it has been suggested that it represents the substrate coordination site.

 

Biogeochemical Cycles

The second half of the twentieth century has observed the illustration of many of the central reaction steps and enzymatic catalysts of biogeochemical cycles, which led to the discovery of key complex cofactors that contain transition metal ions. Indeed, the key catalysts in the global cycles of oxygen (13, 14), nitrogen (15-18), carbon (19-24), sulfur (25-32), and hydrogen (33, 34) are redox metalloenzymes that contain unique metal cofactors. The cycles are represented in Fig. 7 and describe the natural transformations of several “inorganic” molecules and ions. The biogeochemical cycles of C, O, H, S, and N are interlinked intimately. The O2 produced in the oxygen cycle serves as an oxidant for the reduced compounds of C, N, and S by both biological and human activities. H2 is a key carrier to reduce equivalents in the anaerobic world. The full understanding of these enzymatic mechanisms represents a challenge for biological inorganic chemistry at present.

 

The occurrence of metalloproteins

Between 1995, when the first genome (Haemophilus influenzae) was sequenced and, when the first draft of the human genome was published, a revolution in the approach to the study of gene products (i.e., proteins) occurred. This revolution has led to so-called post-genomic research. Genome sequencing projects provide researchers with lists of all the proteins that an investigated organism can produce and their amino acid sequences. From a bioinorganic point of view, however, the question is which proteins need a metal ion to perform their physiologic function. This question is fundamental, and the answer cannot be derived from genomic information alone. Bioinformatic tools have been developed to identify metalloproteins in genome databanks (35-37). This method relies on the exploitation of known metal binding-patterns (MBPs), which are available experimentally from the three-dimensional structures deposited in the protein data bank. MBPs are strings of the type AXnBXmC..., where A, B, C, ... are the amino acids that act as metal ligands, and n, m, ... are the number of amino acidic residues in between two subsequent ligands. Gene banks are then browsed to search for MBPs and primary structure. Such an approach has been used successfully to identify all zinc, nonheme iron, and copper proteins. The human genome encodes approximately 2800 zinc-proteins, 250 nonheme-iron proteins, and 100 copper-proteins. These figures correspond to 10%, 0.8% and 0.3% of the human proteome, respectively. Corresponding averages for five eukaryotes of known genome sequence are 8.8%, 1.1%, and 0.3%, respectively and for 40 selected bacterial organisms are 3.9%, 4.9%, and 0.3%, respectively.

 

 

Figure 7. Simplified global biogeochemical cycles. (a) Combined C and O cycles. The biomass formed by photosynthesis can be transformed anaerobically by bacteria and fungi to produce small C-containing molecules such as CO, CO2, formate, and acetate. These products can be transformed (anaerobically) into methane by archea. CH4 can then be converted aerobically into CO2. (b) The hydrogen cycle, with the indication of the nature of the metal centers at the catalytic site of the involved enzymes. (c) The sulfur cycle. The top part of the external cycle (thick arrows) summarizes the key steps of the aerobic sulfide oxidation; the bottom part summarizes the steps of sulfate respiration. Thiosulphate, trithionate, and tetrathionate may also represent possible intermediates for this cycle. The inner cycle describes the cycling between HS- and S° performed by different organisms with respect to those involved in the outer cycle. The thin arrows that connect SO22-, HSO3-, and HS-represent the essential steps of an assimilatory pathway. (d) The nitrogen cycle. Denitrification is the anaerobic use by certain bacteria of nitrogen oxide species (NO3-, NO2-, NO, and N2O) as terminal electron acceptors instead of O2. The final product N2 is released into the atmosphere; therefore, the process is referred to as dissimilatory. The nitrogen fixation reaction is carried out by the enzyme nitrogenase. The lower part of the cycle represents the assimilatory nitrate reduction that leads to the incorporation of reduced nitrogen species into biomass. The upper part of the cycle describes the nitrification process (i.e., the oxidation of reduced nitrogen compounds in the presence of oxygen).

 

Metal homeostasis

It is well established that for each metal ion a dose-dependent effect exists (Fig. 8). Still, the optimal concentration for healthy organisms should not be considered as the concentration of the free metal ions, which is generally extremely low, but rather as the concentration of the metal ions bound to proteins and other metal ligands. The way in which organisms uptake and control the trafficking of metal ions has attracted the attention of researchers in recent times (38-40). This research has led to the identification of several metallochaperones. No established molecules that serve this function were known before 1997, but today metal trafficking pathways have been identified for metal ions such as copper, manganese, and zinc, although at different degrees of understanding. The comprehension of such processes requires the identification of the proteins involved in metal uptake; transfer and incorporation into the final metallo-enzymes; and identification at the molecular level of the factors that control the specificity, selectivity and efficiency of the mechanisms. Even essential elements, at high concentrations, can become toxic. Organisms have developed mechanisms to detoxify from nonessential metal ions or from excess of essential metal ions (40): The study of these pathways is another aspect of the quest to understand metal homeostasis.

 

 

Figure 8. Dose dependent-effect of toxic and essential metal ions.

 

Metal-based drugs

A special application of inorganic chemistry to biological problems concerns the use of metal-containing compounds as therapeutic or diagnostic agents. The greatest success of met- allotherapeutics dates back to 1978, when cisplatin was first approved to treat clinically genito-urinary tumors after the discovery in 1965 that cisplatin inhibits cell division (41). The biological target of cisplatin is DNA, where its primary binding site is the major groove N7 of guanine. The bending and local unwinding of the DNA double helix induced by cisplatin binding causes the loss of important structural motifs to recognize and to process damaged DNA. The need for a new anticancer drug that can overcome the limitations of cisplatin (high toxicity, activity against a wider range of cancer types, resistance to cisplatin after repeated treatment) has prompted chemists to develop new generation platinum drugs or compounds that contain different metal ions (e.g., palladium, ruthenium, gallium). Metal complexes are also employed to treat other diseases, for example gold(I) compounds are used as antiarthritic drugs.

Metal compounds are used largely in imaging and diagnostics. Several radionuclides of metal ions (e.g., Ga, In, Tl, Tc) are suitable as radiodiagnostic and radioimaging agents. Finally, gadolinium (III) compounds are largely used as contrast agents for magnetic resonance imaging because of the effectiveness of this metal ion to relax H2O protons.

 

Perspectives

It is clear from the discussion of metal homeostasis that the full characterization of a protein requires not only its study in the isolated form but also the investigation of its relevant interactions. Therefore, the interactions of metal-binding proteins with small molecules and other proteins are an obvious perspective in biological inorganic research. This implies the importance of the identification and structure characterization of weak protein-protein complexes that represent the key steps of the biochemical processes discussed here. Moreover, metal-mediated protein-protein interactions are just beginning to be identified and will become an important field of research.

 

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Further Reading

Bertini I, Gray HB, Valentine JS, Stiefel EI, eds. Biological Inorganic Chemistry: Structure & Reactivity. 2006. University Science Books, Sausalito, CA.

Bertini I, Sigel A, Sigel H, eds. Handbook on Metalloproteins. 2001. Marcel Dekker, New York.

Ciurli S, Musiani F. High potential iron-sulfur proteins and their role as soluble electron carriers in bacterial photosynthesis: tale of a discovery. Photosynth. Res. 2005; 85:115-131.

Frausto da Silva JJR, Williams RJP. The Biological Chemistry of the Elements: The Inorganic Chemistry of Life. 1996. Oxford University Press, Oxford.

Holm RH, Solomon EI, guest eds. Thematic issue on “Biomimetic inorganic chemistry.” Chem. Rev. 2004; 104:347-1200.

Que L Jr, ed. Physical Methods in Bioinorganic Chemistry: Spectroscopy and Magnetism. 2000. University Science Books, Sausalito, CA.

Solomon EI, Holm RH, guest eds. Thematic issue on “Bioinorganic enzymology.” Chem. Rev. 1996; 96:2237-3042.

 

See Also

Electron Transfer Chain, Chemistry of

Hemes in Biology

Hemoglobin and Myoglobin, Chemistry of

Metalloenzymes

Metalloregulatory Proteins