Download Write on the role of metalloenzymes in biological systems.

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
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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–
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