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OJELADE, Tunmise 14/SCI03/012 BCH 415 Question: Write on the role of metalloenzymes in biological systems. Many enzymes coordinate one or more metal atoms. It has been estimated that 40% of enzymes require one or more metal ions to be able to carry out their biological function in cells. About twelve different metals are found in association with enzymes in living systems, showing a great variety of protein-metal coordination modes, as well as biochemical and structural functions. Twelve metals, Na, K, Mg, Ca, Mn, Fe, Co, Ni, Cu, Zn, Mo and W appear as cations coordinated by one or more amino acid residues of the protein molecule or by protein-bound cofactors. Some, notably Mg, Fe, Co, Mo and W are often or always found as components of cofactors. There also are some additional borderline cases, such as Cr and V (Claudia et al., 2009; Majorie et al., 2010). Metals are the simplest, but most versatile, cofactors in protein biochemistry with a plethora of distinctive properties such as electron-acceptor ability, positive charge, flexible coordination sphere, specific ligand affinity, varying valence state, low- or high-spin configuration, and high mobility or diffusivity (Claudia et al., 2013). Metal-binding enzymes are involved in a high number of cellular and physiological processes in life. Among the others, metal atoms have functional roles in intra-cellular and inter-cellular signaling, respiration, photosynthesis, oxygen transport, biosynthesis, electron transfer, biodegradation, drug metabolism, proteolysis and hydrolysis of amides and esters, environmental carbon, sulfur and nitrogen cycles, and disease mechanisms (Todor, 2013). Metal ions also often have a structural role in enzymes. The most prominent example is probably calcium, whose binding is known as an important stabilizing feature in several enzymes. Moreover, metal coordination can impose changes to protein structure and dynamics, which, in some cases, result in the modulation of function (Robert, 2011). This mechanism is indeed exploited by the cellular machinery, in which Ca2+ acts as a physiological and cellular signal carrier. One of the most relevant examples of this behavior is the protein calmodulin, a calcium sensing protein in which calcium binding or unbinding affects its ability to bind to different protein targets, thus activating or deactivating different downstream signal cascades depending on calcium availability (Neus et al., 2002; Christopher et al., 2013)). Importantly, metal ions, especially those from the transition metal series, are involved in catalytic mechanisms of enzymes. Enzymes in which one or more metal atoms are essential for activity are thus collectively named metalloenzymes. More in general, enzymes are classified according to a rational system called Enzyme Commission (EC), in which a unique numeric identifier is assigned to each enzyme-catalyzed reaction. Enzymes are divided into six main classes (oxidoreductase, transferases, hydrolases, lyases, isomerases and ligases), and each of them is further divided into subclasses and sub-subclasses according to a hierarchical scheme (AriasMoreno et al., 2011). Among the enzymes with known structure, at least 558 EC numbers include metal-dependent enzymes, spanning among all the six main EC classes. This number represents about 40% of all the enzymes with known structure in the Protein Data Bank (PDB), indicating the pervasiveness of metal ions in enzymes. Furthermore, metal-dependent enzymes occur in the 76% of all the subclasses covered by PDB, indicating that metal ions are involved in an extremely large variety of catalytic mechanisms (http://www.chem.qmul.ac.uk/iubmb/enzyme/; Claudia et al., 2009). Metalloenzymes usually coordinate metals through donor atoms in the functional groups of amino acid side chains. Of the 20 canonical amino acids present in enzymes, only a relatively small number are potential metal ligands. The ligand groups, which are encountered most often are the thiolate of Cysteine, the imidazole of Histidine, the carboxylates of Glutamate and Aspartate, and the phenolate of Tyrosine. Less frequently, metals can be coordinated by the thioether group of Methionine, the amino group of Lysine and the guanidine group of Arginine, and the amide groups of Asparagine and Glutamine. Metal ions can also bind to backbone atoms, through the carbonyl or the deprotonated amide nitrogen, and to the terminal amino and carboxyl groups of the protein. In many cases metal ions are not bound directly to the protein structure; instead, they are coordinated by a prosthetic group which is bound to the protein structure through covalent bonds or non-covalent interactions. This happens mostly with transition metals which are somehow involved in redox reactions. The most popular example of this case is that of the heam prosthetic group, which consists of a single functional iron atom coordinated by the heterocyclic organic ring of a porphyrin (Todor, 2014). Coordination geometries vary by atomic element, oxidation state and number of ligands. It is not surprising that metallic ions preferentially bind different ligands according to their hardness or softness, i.e. to the respective degree of Lewis acidity. Hard Lewis acids such as K+, Ca2+, Mg2+ and Fe3+ bind preferentially to hard bases, such as oxygen atoms of carboxylates. This withstanding, even within this class, different elements feature varying coordination geometries due to differences in the specific charge-to-size ratio. For instance, Mg2+ and Ca2+, which are very close in the periodic table, feature quite different coordination preferences. The Magnesium ion, which is significantly smaller than Calcium ion, is generally characterized by a strict octahedral coordination geometry, whereas calcium features an irregular coordination geometry, with sensible variations in the coordination number (Claudia et al., 2008), bond length and angles (Todor, 2014). The different physico-chemical properties of the two ions allowed evolution to assign different roles to them, since Calcium mostly has a structural role while the Magnesium ion is involved in catalysis (http://www.chem.qmul.ac.uk/iubmb/enzyme/). In the case of ions with softer character, which usually are transition metals such as Cu+ or Fe2+, the directional covalent character of the coordination bond is prevalent and the ligands tend to dispose along the "ideal" coordination geometries for the given element, oxidation state and spin multiplicity. Nonetheless, the protein structure can exert significant strain, thus imposing important and sometimes dramatically geometrical distortions. Depending on the single case, these softer ions are more often associate with S or N ligands, such as thiolates of Cysteine residues and the nitrogen atoms of the imidazole rings of histidine. Besides, several centers which include transition metals feature quite unique coordination environments, as for example exotic non protein ligands such as inorganic sulfur atoms, CN− or CO (Todor, 2014; Claudia et al., 2008). While different metal species are generally more prone to catalyze specific reaction types, there is no strict one-to-one relationship between individual metals and functions, so that the same metal can carry out different functions or more than one metal can provide similar functions. This reflects the fact that metals have been selected for biological functions according to constraints other than mere functional characteristics, such as their relative abundance and availability in the environment. The choices taken by evolution thus reflect the adaptation to various conditions of metal bioavailability, which can change across space and has, sometimes dramatically, changed over time (http://www.chem.qmul.ac.uk/iubmb/enzyme/). References 1. http://www.chem.qmul.ac.uk/iubmb/enzyme 2. Arias-Moreno, X., Abian, O., Vega, S., Sancho, J. and Velazquez-Campoy, A. Proteincation interactions: structural and thermodynamic aspects. Current Protein & Peptide Science, 12(4):325–338, 2011. 3. Christopher, J.W., Maturo, M.,Long, B., McIntosh-Smith, S. and Mulholland, A.J. Analysis and assay of oseltamivir-resistant mutants of influenza neuraminidase via direct observation of drug unbinding and rebinding in simulation. Biochemistry, 52(45):8150– 8164, 2013. 4. Claudia, A., Ivano, B., Cavallaro, G., Holliday, L. G. and Thornton, J.M. Metal ions in biological catalysis: from enzyme databases to general principles. Journal of 5. Biological Inorganic Chemistry, 13(8):1205–1218, 2008. 6. Claudia, A., Ivano, B., Cavallaro, G., Holliday, L. G. and Thornton, J.M. Metal-MACiE: a database of metals involved in biological catalysis. Bioinformatics, 25(16):2088–2089, 2009. 7. Claudia, A., Ivano, B. and Antonio, R. Metalloproteomes: A bioinformatic approach. Accounts of Chemical Research, 42(10):1471–1479, 2009. 8. Claudia, A., Cavallaro, G., Lorenzini, S. and Antonio, R. MetalPDB: a database of metal sites in biological macromolecular structures. Nucleic Acids Research, 41(D1):D312D319, 2013. 9. Marjorie, M,. Harding, Matthew, W., Nowicki, Malcolm, D. and Walkinshaw. Metals in protein structures: a review of their principal features. Crystallography Reviews, 16(4):247–302, 2010. 10. Neus, A., Oriol, B., Nati, R. and Priam V., Modulation of the ras/raf/MEK/ERK pathway by Ca2+, and calmodulin. Cellular Signalling, 14(8):649–654, August 2002. 11. Todor, D.,. Modeling metal binding sites in proteins by quantum chemical calculations. Modeling Metal Binding Sites in Proteins by Quantum Chemical Calculations, 2:19–21, 2014.