Metalloprotein
Overview
 
Metalloprotein is a generic term for a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that contains a metal ion cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....

. Metalloproteins have many different functions in cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

, such as enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s, transport and storage proteins, and signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

 proteins. Indeed, about one quarter to one third of all proteins require metals to carry out their functions. The metal ion is usually coordinated by nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

, oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 or sulfur
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...

 atoms belonging to amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s in the polypeptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 chain and/or a macrocyclic ligand incorporated into the protein.
Encyclopedia
Metalloprotein is a generic term for a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that contains a metal ion cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....

. Metalloproteins have many different functions in cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

, such as enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s, transport and storage proteins, and signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

 proteins. Indeed, about one quarter to one third of all proteins require metals to carry out their functions. The metal ion is usually coordinated by nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

, oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 or sulfur
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...

 atoms belonging to amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s in the polypeptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 chain and/or a macrocyclic ligand incorporated into the protein. The presence of the metal ion allows metalloenzymes to perform functions such as redox reactions that cannot easily be performed by the limited set of functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...

s found in amino acids.

Oxygen carriers

Hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...

, which is the principal oxygen carrier in humans has four sub-units in which the iron(II) ion is coordinated by the planar, macrocyclic ligand protoporphyrin IX
Porphyrin
Porphyrins are a group of organic compounds, many naturally occurring. One of the best-known porphyrins is heme, the pigment in red blood cells; heme is a cofactor of the protein hemoglobin. Porphyrins are heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at...

 (PIX) and the imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...

 nitrogen atom of a histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

 residue. The sixth coordination site contains a water molecule or a dioxygen molecule. myoglobin
Myoglobin
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is related to hemoglobin, which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. The only time myoglobin is found in the...

 has only one such unit. The active site is located in an hydrophobic pocket. This is important as, without it, the iron(II) would be irreversibly oxidised to iron(III). The equilibrium constant
Stability constants of complexes
A stability constant is an equilibrium constant for the formation of a complex in solution. It is a measure of the strength of the interaction between the reagents that come together to form the complex...

 for the formation of HbO2 is such that oxygen is taken up or released depending on the partial pressure
Partial pressure
In a mixture of ideal gases, each gas has a partial pressure which is the pressure which the gas would have if it alone occupied the volume. The total pressure of a gas mixture is the sum of the partial pressures of each individual gas in the mixture....

 of oxygen in the lungs or in muscle. In hemoglobin the four sub-units show a cooperativity effect which allows for easy oxygen transfer from hemoglobin to myoglobin.

In both hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...

 and myoglobin
Myoglobin
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is related to hemoglobin, which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. The only time myoglobin is found in the...

 it is sometimes incorrectly stated that the oxygenated species contains iron(III). It is now known that the diamagnetic nature of these species is due to the fact that the iron(II) is in the low-spin state. In oxyhemoglobin the iron atom is located in the plane of the porphyrin ring, but in the paramagnetic deoxyhemoglobin the iron atom lies above the plane of the ring. The change in spin state is a cooperative effect of higher crystal field splitting
Crystal field theory
Crystal field theory is a model that describes the electronic structure of transition metal compounds, all of which can be considered coordination complexes. CFT successfully accounts for some magnetic properties, colours, hydration enthalpies, and spinel structures of transition metal complexes,...

 and smaller ionic radius of Fe2+ in the oxy- moiety.

Hemerythrin
Hemerythrin
Hemerythrin is an oligomeric protein responsible for oxygen transport in the marine invertebrate phyla of sipunculids, priapulids, brachiopods, and in a single annelid worm, magelona. Recently, hemerythrin was discovered in methanotrophic bacterium Methylococcus capsulatus...

 is another iron-containing oxygen carrier. The oxygen binding site is a binuclear iron center. The iron atoms are coordinated to the protein through the carboxylate side chains of a glutamate and aspartate and five histidine residues. The uptake of O2 by hemerythrin is accompanied by two-electron oxidation of the reduced binuclear center to produce bound peroxide (OOH-). The mechanism of oxygen uptake and release have been worked out in detail.

Hemocyanin
Hemocyanin
Hemocyanins are respiratory proteins in the form of metalloproteins containing two copper atoms that reversibly bind a single oxygen molecule . Oxygenation causes a color change between the colorless Cu deoxygenated form and the blue Cu oxygenated form...

s carry oxygen in the blood of most molluscs, and some arthropods such as the horseshoe crab
Horseshoe crab
The Atlantic horseshoe crab, Limulus polyphemus, is a marine chelicerate arthropod. Despite its name, it is more closely related to spiders, ticks, and scorpions than to crabs. Horseshoe crabs are most commonly found in the Gulf of Mexico and along the northern Atlantic coast of North America...

. They are second only to hemoglobin in biological popularity of use in oxygen transport. On oxygenation the two copper(I) atoms at the active site are oxidised to copper(II) and the dioxygen molecules is reduced to peroxide, O22-.

Cytochromes

Oxidation and reduction
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

 reactions are not common in organic chemistry as few organic molecules can act as oxidizing or reducing agents. Iron(II), on the other hand, can easily be oxidized to iron(III). This functionality is used in cytochrome
Cytochrome
Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as monomeric proteins or as subunits of bigger enzymatic complexes that catalyze redox reactions....

s which function as electron-transfer vectors.
The iron atom in most cytochromes is contained in a heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...

 group. The differences between those cytochromes lies in the different side-chains. For instance Cytochrome a has a heme a
Heme a
Heme A is a heme, a coordination complex consisting of a macrocyclic ligand called a porphyrin, chelating an iron atom. Heme a is a biomolecule and is produced naturally by many organisms.-Relationship to other hemes:...

 prosthetic group and cytochrome b has a heme b
Heme b
Heme B or haem B is the most abundant heme, both hemoglobin and myoglobin are examples of oxygen transport proteins that contain heme B. The peroxidase family of enzymes also contain heme B...

 prosthetic group. These differences result in different Fe2+/Fe3+ redox potentials such that various cytochromes are involved in the mitochondrial electron transport chain.

Cytochrome P450 enzymes perform the function of inserting an oxygen atom into a C—H bond, an oxidation reaction.

Rubredoxin

Rubredoxin
Rubredoxin
Rubredoxins are a class of low-molecular-weight iron-containing proteins found in sulfur-metabolizing bacteria and archaea. Sometimes rubredoxins are classified as iron-sulfur proteins; however, in contrast to iron-sulfur proteins, rubredoxins do not contain inorganic sulfide.Like cytochromes,...

 is an electron-carrier found in sulfur-metabolizing bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 and archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...

. The active site contains an iron ion which is coordinated by the sulphur atoms of four cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

 residues forming an almost regular tetrahedron. Rubredoxins perform one-electron transfer processes. The oxidation state of the iron atom changes between the +2 and +3 states. In both oxidation states the metal is high spin, which helps to minimize structural changes.

Plastocyanin

Plastocyan is one of the family of blue copper proteins
Copper proteins
Copper proteins are proteins that contain one or more copper ions as prosthetic groups. The metal centres in the copper proteins can be classified into several types:...

 which are involved in electron transfer reactions. The copper binding site is described as a ‘distorted trigonal pyramidal’. The trigonal plane of the pyramidal base is composed of two nitrogen atoms (N1 and N2) from separate histidines and a sulfur (S1) from a cysteine. Sulfur (S2) from an axial methionine forms the apex. The ‘distortion’ occurs in the bond lengths between the copper and sulfur ligands. The Cu-S1 contact is shorter (207 picometers) than Cu-S2 (282 pm).
The elongated Cu-S2 bonding destabilises the CuII form and increases the redox potential of the protein. The blue colour (597 nm peak absorption) is due to the Cu-S1 bond where S to Cudx2-y2 charge transfer occurs.

In the reduced form of plastocyanin, His-87 will become protonated with a pKa
Acid dissociation constant
An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...

 of 4.4. Protonation prevents it acting as a ligand and the copper site geometry becomes trigonal planar.

Iron storage and transfer

Iron is stored as iron(III) in ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

. The exact nature of the binding site has not yet been determined. The iron appears to be present as an hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

 product such as FeO(OH). Iron is transported by transferrin
Transferrin
Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. In humans, it is encoded by the TF gene.Transferrin is a glycoprotein that binds iron very tightly but reversibly...

 whose binding site consists of two tyrosines, one aspartic acid and one histidine.

The human body has no mechanism for iron excretion. This can lead to iron-overload problems in patients treated with blood transfusions, as, for instance, with β-thallasemia.

Ceruloplasmin

Ceruloplasmin is the major copper-carrying protein in the blood. Ceruloplasmin exhibits oxidase activity, which is associated with possible oxidation of Fe2+ (ferrous iron) into Fe3+ (ferric iron), therefore assisting in its transport in the plasma in association with transferrin, which can only carry iron in the ferric state.

Metalloenzymes

Metalloenzymes all have one feature in common, namely, that the metal ion is bound to the protein with one labile coordination site. As with all enzymes, the shape of the active site is crucial. The metal ion is usually located in a pocket whose shape fits the substrate. The metal ion catalyzes reactions which are difficult to achieve in organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

.

Carbonic anhydrase

CO2 + H2O H2CO3

This reaction is very slow in the absence of a catalyst, but quite fast in the presence of the hydroxide
Hydroxide
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and a hydrogen atom held together by a covalent bond, and carrying a negative electric charge. It is an important but usually minor constituent of water. It functions as a base, as a ligand, a nucleophile, and a...

 ion
CO2 + OH- HCO3-

A reaction similar to this is almost instantaneaous with carbonic anhydrase
Carbonic anhydrase
The carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...

. The structure of the active site in carbonic anhydrases is well-known from a number of crystal structures. It consists of a zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

 ion coordinated by three imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...

 nitrogen atoms from three histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

 units. The fourth coordination site is occupied by a water molecule. The coordination sphere of the zinc ion is approximately tetrahedral. The positively charged zinc ion polarizes the coordinated water molecule and nucleophilic attack by the negatively charged hydoxide portion on carbon dioxide (carbonic anhydride) proceeds rapidly. The catalytic cycle produces the bicarbonate ion and the hydrogen ion as the equilibrium
H2CO3 HCO3- + H+

favours dissociation of carbonic acid
Carbonic acid
Carbonic acid is the inorganic compound with the formula H2CO3 . It is also a name sometimes given to solutions of carbon dioxide in water, because such solutions contain small amounts of H2CO3. Carbonic acid forms two kinds of salts, the carbonates and the bicarbonates...

 at biological pH values.

Vitamin B12-dependent enzymes

Vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...

 catalyzes the transfer of methyl (-CH3) groups between two molecules, which involves the breaking of C-C bonds, a process that is energetically expensive in organic reactions. The metal ion lowers the activation energy
Activation energy
In chemistry, activation energy is a term introduced in 1889 by the Swedish scientist Svante Arrhenius that is defined as the energy that must be overcome in order for a chemical reaction to occur. Activation energy may also be defined as the minimum energy required to start a chemical reaction...

 for the process by forming a transient Co-CH3 bond. The structure of the coenzyme was famously determined by Dorothy Hodgkin and co-workers, for which she received a Nobel prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...

. It constists of a cobalt
Cobalt
Cobalt is a chemical element with symbol Co and atomic number 27. It is found naturally only in chemically combined form. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal....

(II) ion coordinated by four nitrogen atoms of a corrin
Corrin
Corrin is an heterocyclic compound. It is the parent macrocycle related to substituted derivative that is found in vitamin B12. Its name reflects that it is the "core" of vitamin B12 .-Coordination chemistry:...

 rings and a fifth Nitrogen atom from an imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...

 group. In the resting state there is a Co—C σ bond with the 5' carbon atom of adenosine. This is a naturally occurring organometallic compound, which explains its function in trans-methylation reactions, such as the reaction carried out by methionine synthase
5-methyltetrahydrofolate-homocysteine methyltransferase
Methionine synthase also known as MS, MeSe, MetH is an enzyme that in humans is encoded by the MTR gene . This enzyme is responsible for the regeneration of methionine from homocysteine...

.

Nitrogenase (nitrogen fixation)

The fixation of atmospheric nitrogen is a very energy-intensive process, as it involves breaking the very stable triple bond
Triple bond
A triple bond in chemistry is a chemical bond between two chemical elements involving six bonding electrons instead of the usual two in a covalent single bond. The most common triple bond, that between two carbon atoms, can be found in alkynes. Other functional groups containing a triple bond are...

 between the nitrogen atoms. The enzyme nitrogenase
Nitrogenase
Nitrogenases are enzymes used by some organisms to fix atmospheric nitrogen gas . It is the only known family of enzymes that accomplish this process. Dinitrogen is quite inert because of the strength of its N-N triple bond...

 is one of the few enzymes that can catalyze the process. The enzyme occurs in certain bacteria. There are three components to its action: a molybdenum
Molybdenum
Molybdenum , is a Group 6 chemical element with the symbol Mo and atomic number 42. The name is from Neo-Latin Molybdaenum, from Ancient Greek , meaning lead, itself proposed as a loanword from Anatolian Luvian and Lydian languages, since its ores were confused with lead ores...

 atom at the active site, Iron-sulfur cluster
Iron-sulfur cluster
For biological Fe-S clusters, see iron-sulfur proteins.Iron-sulfur clusters are ensembles of iron and sulfide centres. Fe-S clusters are most often discussed in the context of the biological role for iron-sulfur proteins. Many Fe-S clusters are known in the area of organometallic chemistry and as...

s which are involved in transporting the electrons needed to reduce the nitrogen and an abundant energy source. The energy is provided by a symbiotic relationship between the bacteria and a host plant, often a legume. The relationship is symbiotic because the plant supplies the energy by photosynthesis
Photosynthesis
Photosynthesis is a chemical process that converts carbon dioxide into organic compounds, especially sugars, using the energy from sunlight. Photosynthesis occurs in plants, algae, and many species of bacteria, but not in archaea. Photosynthetic organisms are called photoautotrophs, since they can...

 and benefits by obtaining the fixed nitrogen. The reaction may be written symbolically as
N2 +16 MgATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 +8e- → 2NH3 + 16 MgADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....

 +16 Pi + H2

where Pi stands for inorganic phosphate. The precise structure of the active site has been difficult to determine. It appears to contain a MoFe7S8 cluster which is able to bind the dinitrogen molecule and, presumably, enable the reduction process to begin. The electrons are transported by the associated "P" cluster, which contains two cubical Fe4S4 clusters joined by sulphur bridges.

Superoxide dismutase

The superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

 ion, O2- is generated in biological systems by reduction of molecular oxygen. It has an unpaired electron, so it behaves as a free radical. It is a powerful oxidising agent. These properties render the superoxide ion very toxic and are deployed to advantage by phagocytes to kill invading micro organisms. Otherwise, the superoxide ion must be destroyed before it does unwanted damage in a cell. The superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

 enzymes perform this function very efficiently.

The formal oxidation state of the oxygen atoms is ½. In solutions at neutral pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

, the superoxide ion disproportionates to molecular oxygen and hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...

.
2 O2 + 2 H+ → O2 + H2O2

In biology this type of reaction is call a dismutation reaction. It involves both oxidation and reduction of superoxide ions. The superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

 group of enzymes, abbreviated as SOD, increase the rate of reaction to near the diffusion limited rate. The key to the action of these enzymes is a metal ion with variable oxidation state which can act as either an oxidizing agent or as a reducing agent.
Oxidation: M(n+1)+ + O2 → Mn+ + O2
Reduction: Mn+ + O2 + 2H+ → M(n+1)+ + H2O2.


In human SOD the active metal is copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...

, as Cu2+ or Cu+, coordinated tetrahedrally by four histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

 residues. This enzyme also contains zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

 ions. Other isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...

s may contain iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...

, manganese or nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...

. Ni-SOD is particularly interesting as it involves nickel(III), an unusual oxidation state for this element. The active site Ni geometry cycles from square planar Ni(II), with thiolate (Cys2 and Cys6) and backbone nitrogen (His1 and Cys2) ligands, to square pyramidal Ni(III) with an added axial His1 side chain ligand.

Chlorophyll-containing proteins

Chlorophyll plays a crucial role in photosynthesis
Photosynthesis
Photosynthesis is a chemical process that converts carbon dioxide into organic compounds, especially sugars, using the energy from sunlight. Photosynthesis occurs in plants, algae, and many species of bacteria, but not in archaea. Photosynthetic organisms are called photoautotrophs, since they can...

. It contains a magnesium enclosed in a chlorin
Chlorin
In organic chemistry, a chlorin is a large heterocyclic aromatic ring consisting, at the core, of three pyrroles and one pyrroline coupled through four methine linkages...

 ring. However, the magnesium ion is not directly involved in the photosynthetic function and can be replaced by other divalent ions with little loss of activity. Rather, the photon is absorbed by the chlorin ring, whose electronic structure is well-adapted for its purpose.

Initially, the absorption of a photon causes an electron to be excited into a singlet state of the Q band. The excited state undergoes an intersystem crossing
Intersystem crossing
Intersystem crossing is a radiationless process involving a transition between two electronic states with different spin multiplicity.-Singlet and triplet states:...

 from the singlet state to a triplet state
Triplet state
A spin triplet is a set of three quantum states of a system, each with total spin S = 1 . The system could consist of a single elementary massive spin 1 particle such as a W or Z boson, or be some multiparticle state with total spin angular momentum of one.In physics, spin is the angular momentum...

 in which there are two electrons with parallel spin. This species is, effectively, a free radical, and is very reactive and allows an electron to be transferred to acceptors which are adjacent to the chlorophyll in the chloroplast
Chloroplast
Chloroplasts are organelles found in plant cells and other eukaryotic organisms that conduct photosynthesis. Chloroplasts capture light energy to conserve free energy in the form of ATP and reduce NADP to NADPH through a complex set of processes called photosynthesis.Chloroplasts are green...

. In the process chlorophyll is oxidized. Later in the phosynthetic cycle, chlorophyll is re-reduced. This reduction ultimately draws electrons from water, yielding molecular oxygen as a final oxidation product.

Calmodulin

Calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...

 is an example of a signal-transduction protein. It is a small protein which contains four EF-hand motifs, each of which can bind a Ca2+ ion.

In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. Six Glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...

 and Aspartic acid
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...

 residues involved in the binding are in positions 1, 3, 5, 7, 9 of the polypeptide chain. At position 12 there is a glutamate or aspartate ligand which behaves as a (bidentate ligand), providing two oxygen atoms. The ninth residue in the loop is necessarily glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

 due to the conformational requirements of the backbone. The coordination sphere of the calcium ion contains only carboxylate oxygen atoms and no nitrogen atoms. This is consistent with the hard nature of the calcium ion.

The protein has two approximately symmetrical domains, separated by a flexible "hinge" region. Binding of calcium causes a conformational change to occur in the protein. Calmodulin participates in an intracellular signalling system by acting as a diffusible second messenger to the initial stimuli.

Transcription factors

Many transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

s contain a structure known as a zinc finger
Zinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...

, this is a structural module where a region of protein folds around a zinc ion. The zinc does not directly contact the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 that these proteins bind to, instead the cofactor is essential for the stability of the tightly-folded protein chain. In these proteins the zinc ion is usually coordinated by pairs of cysteine and histidine side chains.

Other metalloenzymes

IonExamples of enzymes containing this ion
Magnesium Glucose 6-phosphatase
Glucose 6-phosphatase
Glucose 6-phosphatase is an enzyme that hydrolyzes glucose-6-phosphate resulting in the creation of a phosphate group and free glucose. Glucose is then exported from the cell via glucose transporter membrane proteins...


Hexokinase
Hexokinase
A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product....


DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....

Vanadium vanabins
Vanabins
Vanabins are a specific group of vanadium-binding metalloproteins. Vanabins are found almost exclusively in the blood cells, or vanadocytes of some ascidians and tunicates . The vanabins extracted from tunicate vanadocytes are often called hemovanadins...

Manganese Arginase
Arginase
Arginase is a manganese-containing enzyme. The reaction catalyzed by this enzyme is: arginine + H2O → ornithine + urea. It is the final enzyme of the urea cycle.- Structure and function :Arginase belong to the ureohydrolase family of enzymes....

Iron Catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...


Hydrogenase
Hydrogenase
A hydrogenase is an enzyme that catalyses the reversible oxidation of molecular hydrogen . Hydrogenases play a vital role in anaerobic metabolism....


IRE-BP
Aconitase
Aconitase
Aconitase is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid cycle, a non-redox-active process.- Function :...

Nickel Urease
Urease
Urease is an enzyme that catalyzes the hydrolysis of urea into carbon dioxide and ammonia. The reaction occurs as follows:In 1926, James Sumner showed that urease is a protein. Urease is found in bacteria, yeast, and several higher plants. The structure of urease was first solved by P.A...


Hydrogenase
Hydrogenase
A hydrogenase is an enzyme that catalyses the reversible oxidation of molecular hydrogen . Hydrogenases play a vital role in anaerobic metabolism....

Copper Cytochrome oxidase
Laccase
Laccase
Laccases are copper-containing oxidase enzymes that are found in many plants, fungi, and microorganisms. The copper is bound in several sites; Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster . Type 1 copper is available to action of solvents,...

Zinc Alcohol dehydrogenase
Alcohol dehydrogenase
Alcohol dehydrogenases are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide...


Carboxypeptidase
Carboxypeptidase
A carboxypeptidase is a protease enzyme that hydrolyzes the peptide bond of an amino acid residue at the carboxy-terminal end...


Aminopeptidase
Aminopeptidase
Aminopeptidase is a zinc-dependent enzyme produced and secreted by glands of the small intestine. It helps the enzymatic digestion of proteins. Additional digestive enzymes produced by these glands include dipeptidases, maltase, sucrase, lactase, and enterokinase.Aminopeptidases catalyze the...


Beta amyloid
Molybdenum Nitrate reductase
Nitrate reductase
Nitrate reductases are molybdoenzymes that reduce nitrate to nitrite .* Eukaryotic nitrate reductases are part of the sulfite oxidase family of molybdoenzymes....

Selenium Glutathione peroxidase
Glutathione peroxidase
Glutathione peroxidase is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage...

various Metallothionein
Metallothionein
Metallothionein is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus...


Phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...


See also

  • Bioinorganic chemistry
    Bioinorganic chemistry
    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 artificially introduced metals, including those that are non-essential, in medicine and toxicology...

  • Coenzyme
  • Cofactor
    Cofactor (biochemistry)
    A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....

  • Hemoproteins
  • Metal Ions in Life Sciences
    Metal Ions in Life Sciences
    Metal Ions in Life Sciences is a series of books edited by Astrid, Helmut and Roland Sigel, now published by the Royal Society of Chemistry which reflects the interdisciplinary nature of biological inorganic chemistry. Six volumes have been produced, a seventh volume is in the press and two more...

  • Siderophore
    Siderophore
    Siderophores are small, high-affinity iron chelating compounds secreted by grasses and microorganisms such as bacteria and fungi...

  • Prosthetic group
  • QPNC-PAGE
    QPNC-PAGE
    QPNC-PAGE, or quantitative preparative native continuous polyacrylamide gel electrophoresis, is a high-resolution technique applied in biochemistry and bioinorganic chemistry to separate proteins by isoelectric point...

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