Iron-containing Biomolecules

Biomolecules that contain iron are the most prevalent group, which can be divided into heme and nonheme types. The dominant forms are iron porphyrin (heme) proteins. These appear in a large number of systems, and have diverse roles including as oxygen transport and storage proteins (hemoglobin and myoglobin), for catalytic dehydrogenation or oxidation of organic molecules (peroxidases, cytochrome P450) and for reduction (cytochrome c oxidase) and electron transport (cytochrome c). We shall examine some selected examples.

Myoglobin is a small mononuclear globular protein with a single heme unit attached to an c- helical protein chain (Figure 8.4). It stores oxygen in muscle tissue until it is required for ox- idative phosphorylation, thus providing a ready reserve of oxygen to cope with intense respiration demands. Hemoglobin has the primary role of transporting oxygen (although its full function is somewhat more complicated and also includes transporting carbon dioxide) and

Figure 8.4 Structure of myoglobin (Protein Data Bank; DOI: 10.2210/pdb1mbn/pdb) and detail of the heme of hemoglobin.

is found in red blood cells. It is a larger and more complicated protein referred to as an α2β2 heterotetramer meaning there are pairs of two classes of polypeptide chains in the proteins each containing one heme unit that each bind dioxygen. In both myoglobin and hemoglobin the oxygen binds to an iron(II) centre bound covalently also to the four N-donors of a porphyrin which is an aromatic 16-membered tetraaza-macrocycle. The porphyrin is an easily-built compound in chemistry. In nature, the heme is assembled from precursor com ponents that leave substituents on the macrocycle ring of the heme (Figure 8.4). The heme in hemoglobin is embedded in a protein crevice where it is surrounded by hydrophobic groups, and where the Fe (II) is covalently bonded at one axial site by close approach of one imidazole group nitrogen that is part of a histidine amino acid residue (called the ‘proximal’ histidine) of a protein chain. Another imidazole nitrogen is located near the other ‘empty’ axial site, approaching but not achieving a bonding distance (this is called the ‘distal’ histidine); it is at this protected site that dioxygen coordinates as a monodentate ligand, taking the iron(II) from a five-coordinate to a preferred six-coordinate octahedral complex without oxidizing the metal centre. Only the coordinate bond from the proximal histidine to the iron binds the heme to the protein; if this bond is broken, the small heme unit can be removed from the protein. Degradation is initiated by this Fe N bond breaking which is followed by release and destruction of the heme accomplished by special oxygenase and reductase enzymes.

The role of the protein ‘pocket’ in which the heme unit sits in hemoglobin is twofold. It provides a water-resistant hydrocarbon-based environment of low dielectric constant that is unsuited to highly ionic character in the heme. This leads to the redox potential for the Fe(II)/(III) couple being altered sufficiently to make oxidation impossible by available biological oxidants. Thus dioxygen can bind, but will not oxidize the iron centre. The severe steric constraints imposed by the heme environment means that it is also impossible for another heme iron centre to approach the embedded heme, thus prohibiting unwanted formation of stable oxidized bridging oxygen-linked dimers of the form Fe^III-O^2-− Fe^III.

Figure 8.5 The geometry change at the iron centre of the heme unit in myoglobin or hemoglobin upon dioxygen coordination. Potential modes of coordination of a diatomic molecule are also shown, with the bent form favoured for dioxygen binding employed in the drawing of the complex.

This removes one of the common reactions of iron complexes ‘in the beaker’ and is an example of the role and importance of the enveloping biopolymer in the natural system. The Fe (II) centre, in the absence of oxygen, has a five-coordinate square pyramidal geometry. When oxygen binds at the ‘vacant’ sixth site, opposite the histidine imidazole, the molecule changes to six-coordinate octahedral geometry. This requires the Fe to move from being displaced above the plane of the macrocycle ring (by ∼60 pm), as expected for the square pyramidal shape, to lying in the plane as expected for an octahedral shape (Figure 8.5). In achieving this, the protein is required to adjust its conformation, to retain the required Fe N(histidine) bond distance. Release of oxygen allows relaxation back to the five-coordinate square-based pyramidal shape around the iron. No permanent change in the protein is involved, and hence re-use of the protein can occur. Another point to consider is the way dioxygen binds to the heme. In principle there are four ways a diatomic molecule can bind to a metal ion: linear, bent, chelated or dissociated into two separate atoms (Figure 8.5). Examples of all four modes exist: linear is found in carbonyl complexes M CO; bent is found in M NO+ complexes; chelated is found for CO in [IrCl (CO)(PR₃)] and dissociated is found for H₂ following its addition to some four coordinate organometallic complexes. The very large number of atoms in a biomolecule makes it very difficult to determine the structural detail accurately by X-ray crystal structure analysis which is not a problem encountered in the case of low molecular mass molecules. The biological structure has been supported through examining low molecular weight model compounds that bind dioxygen reversibly and from spectroscopic methods. The ‘bent’ mode (Figure 8.5) is now well defined for dioxygen binding in hemoglobin and myoglobin.

Whereas oxygen binding in humans and many other animals involves heme units not all life-forms bind and carry dioxygen in this way. Hemerythrin is a nonheme iron protein used by sipunculid and brachiopod marine invertebrates for oxygen transfer and/or storage.

Figure 8.6 The geometry at the iron centres of the bridged dinuclear unit in hemerythrin in its dioxygen-free deoxy (left) and oxygenated oxy (right) forms with changes upon dioxygen coordination shown.

The complete enzyme has a complicated polymeric structure including a large number of subunits, each of which is an active site for oxygen addition. Each subunit has a molecular weight of around 14 000 Dalton, contains two iron atoms, and binds one molecule of oxygen. This di-iron oxo protein contains octahedral iron (III) centres linked by one oxo (O2−) and two carboxylato (-COO−) bridges. The oxygen-free form deoxy emery thrin is a colourless complex with two high-spin d6 Fe(II) centres bridged by a hydroxide ion; one Fe is six-coordinate (bound to three histidine residue N-donors, two peptide carboxylate groups, and the bridging hydroxide ion), the other one is five-coordinate (bound to two histidine residue N-donors, two peptide carboxylate groups and the bridging hydroxide ion) and has the one ‘vacant’ site where dioxygen can bind. The dioxygen-bound form, ox hemerythrin is red-violet in colour, and now contains two six-coordinate low-spin d5 Fe(III) centres (Figure 8.6). The O₂ binds to the five-coordinate iron(II) centre and abstracts a H-atom from the bridging hydroxo group, forming a FeOOH group that remains strongly hydrogen-bonded to what is now a bridging oxo group. Oxygen uptake is also accompanied by one-electron oxidation of both Fe(II) centres to Fe(III) meaning that the dioxygen undergoes two electron reduction to bound peroxide ion.

Once dioxygen arrives at a cell it is reduced to water in order to yield the energy necessary to convert adenosine diphosphate (ADP) to adenosine triphosphate (ATP), the ‘energy carrier’ for cell processes. This oxygen ‘burning’ (8.1) is mediated in turn by a series of metalloenzymes, such as cytochrome oxidase which contains one heme Fe and one Cu in the active site.

O₂ +4H₃O+ +4e− →6H₂O                                              (8.1)

Since dioxygen reduction provides much more energy (∼400 kJ mol–1) than is needed to form a single ATP from ADP + phosphate (∼30 kJ mol–1), it is to the cell’s advantage to carry out the reduction stepwise. The actual process yields six ATP (i.e. ∼45% efficient) per dioxygen. This involves intermediate oxygen reduction products, superoxide (O²⁻) and

peroxide (O₂²⁻⁾, which are hazardous to biochemical systems if they ‘escape’. Special metalloenzymes ‘mop up’ these ions. Free superoxide is dealt with by superoxide dismutase (SOD) via a dismutation reaction (8.2) in which, for two molecules of the same type, one is oxidized and the other reduced.

2O²⁻ +4H+ →O₂+2H₂O₂                                                     (8.2)

People with inherited motor neurone disease have mutations of SOD; over 100 mutations have been identified. Free peroxide is inherently unstable to a disproportionation reaction (8.3) to form water and oxygen.

2H₂O₂ →2H₂O+O₂                                  (8.3)

This is accelerated by the iron heme protein catalase, a particularly efficient enzyme with one of the highest turnover numbers of all known enzymes (at ∼4×107 molecules per second). This high rate reflects the important role for the enzyme and its capacity for detoxifying hydrogen peroxide.

There are a family of nonheme iron proteins that participate in electron transfer that all contain iron bound to sulfur of cysteine (cys, HS CH₂ CH(NH₂) COOH) amino acid residues present in a protein backbone. The simplest of these is the small protein (MW ∼6000) rubredoxin,foundinsulfur-containingbacteria,that consists of a protein containing about 50 amino acids and one iron bound by the S atoms of four cysteine amino acid residues The iron is bound to four S atoms in a distorted tetrahedral arrangement. It has a FeII/III redox potential of ∼0 V, meaning it can be oxidized and reduced readily by biological redox reagents. The iron centre lies close to the surface of each protein (Figure 8.7), providing good access for interaction with and electron transfer to other compounds. This location of the metal redox centre near the exterior of a protein is common in those proteins with a redox role. This makes outer sphere electron transfer easier and faster. In addition to this simple compound, there are a number of related compounds, the ferredoxins, which contain several iron centres closely linked in small FemSn clusters. In addition to cys-S they contain ‘labile S’ that can be released as H2S on addition of acid, being present in the biomolecules as coordinated and bridging S2−. The 2-Fe cluster contains 2 labile S ions, and is often designated as Fe2S2 (although 4 other cys-S are also coordinated), whereas the 4-Fe cluster contains four labile S ions (the cluster is thus designated as Fe4S4) with a central Fe4S4 core with a distorted cubic box-like structure. A form of the latter structure with one iron ‘missing’ from a corner of the cube, termed aFe3S4 species, is also known. In all cases, each iron centrelie in a distorted tetrahedral environment of four S-donor ligands.

Iron is the most important and used metal in higher animals, and thus having a ready supply of bioavailable iron is essential to their proper function. To achieve this, higher animals have developed a way of storing iron. Iron is bound and transported in the body via transferrin and stored in ferritin protein, made of carboxylate-rich peptide subunits assembled into

Figure 8.7 A rubredoxin oxygen carrier with the FeS4 centre highlighted (Protein Data Bank; DOI: 10.2210/pdb5rxn/pdb), and drawings of the cores of rubredoxin and diiron (Fe2S2) and tetrairon (Fe4S4) ferredoxins. a hollow spherical shell. The hollow sphere formed is ∼8000 pm in diameter, with walls ∼1000pmthick. Channels in the sphere are formed at the intersections of peptide subunits. These channels are the key to ferritin’s ability to release iron in a controlled manner. The iron in the ferritin is stored in the core of the hollow sphere as iron(III) hydroxide in a crystalline solid, [FeO(OH)]8·[FeO (OPO3H₂)]. The best simple model for the ferritin core is the well-known mineral ferrihydrite, FeO(OH). The complete particle of ferritin provides a readily available e source from which biological chelates can ‘collect’ iron and transfer it to usable sites. Iron is released by reduction to form soluble Fe(H₂O)6²⁺ that departs via the channels in the shell, after which chelates ‘collect’ it. Two types, fourfold and threefold channels, exist. These two types of channels have different properties, and perform different functions. The threefold channels are lined with polar amino acids (aspartate and glutamate), which allow favourable interaction with the aquated Fe2+ ion. This interaction allows Fe2+ to pass through the channel; essentially the channel acts like an ion-exchange resin in a column. The fourfold channel is lined with nonpolar amino acid groups and is thought to be the path for the electron transfer process to form Fe(II) but this process is not fully elucidated.

Iron storage and supply in bacteria yeasts and fungi is by small molecular weigh to ctahedral iron (III) complexes. These are categorized, because of their simplicity, as nonproteins. Most known microbial organisms biosynthesise these siderophores, which solubilize and transport environmental iron into the cells during aerobic growth. These are intensely coloured red-brown compounds, where the chelating ligands are hydroxamates in fungi and yeasts and either hydroxamates or substituted catechols in bacteria. These ligands

Figure 8.8 The basic hydroxamate and catecholate chelate rings, as well as an example of three catecholate chelates attached to a larger ring binding to an octahedral iron(III) centre.

are basically didentate chelates (Figure 8.8), and three are bound to form very stable six coordinate octahedral and chiral Fe(III) complexes. In fact, the three chelate units are part of larger single molecules, which means these effectively act as hexadentate ligands, forming complexes with Fe(III) with very high stability constants. The ligands are highly selective for Fe(III), even over Fe(II). A number of common compounds are known. Ferrichrome is a hydroxamate complex with the hydroxamates as sidechains to peptide ring. Ferrioxamine complexes contain the hydroxamates as part of a simple peptide chain. Enterobacter is a catechol complex in which the catechols are side chains of a cyclic ester. Hydroxamates release Fe by metal ion reduction, so the ligand can be reused once the reduced Fe(II) is dissociated. Whereas the formation constants are high for Fe(III), they are much lower for Fe(II), so reduction provides one mechanism for iron release, with other chelates then able to compete successfully for the Fe(II). However, simply complex destruction provides another mode of iron release. Catechols, with E◦ near −0.75 V are not reducible biologically (as no reducing agent with a suitable potential is available) and so iron release is by ligand destruction meaning the ligand cannot be reused. This seems curiously inefficient but then these species originate from very early in the evolutionary process. There are many other examples of iron-containing proteins that we could draw upon but this is better left to a specialist course in bioinorganic chemistry.

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