Metalloprotein is a generic term for a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that contains a metal ion
cofactor.
A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding
protein domain
In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...
s although there may be up to 3000 human zinc metalloproteins.
Abundance
It is estimated that approximately half of all
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s contain a
metal
A metal () is a material that, when polished or fractured, shows a lustrous appearance, and conducts electrical resistivity and conductivity, electricity and thermal conductivity, heat relatively well. These properties are all associated wit ...
. In another estimate, about one quarter to one third of all proteins are proposed to require metals to carry out their functions. Thus, metalloproteins have many different functions in
cells, such as storage and transport of proteins,
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s and
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
proteins, or infectious diseases. The abundance of metal binding proteins may be inherent to the amino acids that proteins use, as even artificial proteins without evolutionary history will readily bind metals.
Most metals in the
human
Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
body are bound to proteins. For instance, the relatively high concentration of iron in the human body is mostly due to the iron in
hemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
.
Coordination chemistry principles
In metalloproteins, metal ions are usually coordinated by
nitrogen
Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...
,
oxygen
Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...
or
sulfur
Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...
centers belonging to
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
residues of the protein. These donor groups are often provided by side-chains on the amino acid residues. Especially important are the
imidazole
Imidazole (ImH) is an organic compound with the formula . It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. It can be classified as a heterocycle, specifically as a diazole.
Many natural products, ...
substituent in
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
residues,
thiolate
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...
substituents in
cysteine
Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
residues, and
carboxylate
In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an anion, an ion with negative charge.
Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,... ...
groups provided by
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...
. Given the diversity of the metallo
proteome
A proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell or organism, at a given time, under defined conditions. P ...
, virtually all amino acid residues have been shown to bind metal centers. The peptide backbone also provides donor groups; these include deprotonated
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...
s and the amide
carbonyl
In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
oxygen centers. Lead(II) binding in natural and artificial proteins has been reviewed.
In addition to donor groups that are provided by amino acid residues, many organic
cofactors function as ligands. Perhaps most famous are the tetradentate N
4 macrocyclic ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
s incorporated into the
heme
Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
protein. Inorganic ligands such as sulfide and oxide are also common.
Storage and transport metalloproteins
These are the second stage product of protein hydrolysis obtained by treatment with slightly stronger acids and alkalies.
Oxygen carriers
Hemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
, which is the principal oxygen-carrier in humans, has four subunits in which the
iron
Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
(II) ion is coordinated by the planar
macrocyclic ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
protoporphyrin IX (PIX) and the
imidazole
Imidazole (ImH) is an organic compound with the formula . It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. It can be classified as a heterocycle, specifically as a diazole.
Many natural products, ...
nitrogen atom of a
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
residue. The sixth coordination site contains a
water
Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...
molecule or a
dioxygen
There are several known allotropes of oxygen. The most familiar is molecular oxygen (), present at significant levels in Earth's atmosphere and also known as dioxygen or triplet oxygen. Another is the highly reactive ozone (). Others are:
* Ato ...
molecule. By contrast the protein
myoglobin
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle, skeletal Muscle, muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compar ...
, found in
muscle cell
A muscle cell, also known as a myocyte, is a mature contractile Cell (biology), cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal muscle, skeletal, smooth muscle, smooth, and Cardiac muscle, cardiac ...
s, has only one such unit. The active site is located in a
hydrophobic
In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, thu ...
pocket. This is important as without it the iron(II) would be irreversibly
oxidized
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
to iron(III). The
equilibrium constant
The equilibrium constant of a chemical reaction is the value of its reaction quotient at chemical equilibrium, a state approached by a dynamic chemical system after sufficient time has elapsed at which its composition has no measurable tendency ...
for the formation of HbO
2 is such that oxygen is taken up or released depending on the
partial pressure
In a mixture of gases, each constituent gas has a partial pressure which is the notional pressure of that constituent gas as if it alone occupied the entire volume of the original mixture at the same temperature. The total pressure of an ideal g ...
of oxygen in the
lung
The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
s or in muscle. In hemoglobin the four subunits show a cooperativity effect that allows for easy oxygen transfer from hemoglobin to myoglobin.
[
In both ]hemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
and myoglobin
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle, skeletal Muscle, muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compar ...
it is sometimes incorrectly stated that the oxygenated species contains iron(III). It is now known that the diamagnetic
Diamagnetism is the property of materials that are repelled by a magnetic field; an applied magnetic field creates an induced magnetic field in them in the opposite direction, causing a repulsive force. In contrast, paramagnetic and ferromagn ...
nature of these species is because the iron(II) atom is in the low-spin state. In oxyhemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglob ...
the iron atom is located in the plane of the porphyrin ring, but in the paramagnetic
Paramagnetism is a form of magnetism whereby some materials are weakly attracted by an externally applied magnetic field, and form internal, induced magnetic fields in the direction of the applied magnetic field. In contrast with this behavior, ...
deoxyhemoglobin the iron atom lies above the plane of the ring.[ Fig.25.7, p 1100 illustrates the structure of deoxyhemoglobin] This change in spin state is a cooperative effect due to the higher crystal field splitting and smaller ionic radius
Ionic radius, ''r''ion, is the radius of a monatomic ion in an ionic crystal structure. Although neither atoms nor ions have sharp boundaries, they are treated as if they were hard spheres with radii such that the sum of ionic radii of the cati ...
of Fe2+ in the oxyhemoglobin moiety.
Hemerythrin
Hemerythrin (also spelled haemerythrin; , ) is an oligomeric protein responsible for oxygen (O2) transport in the marine invertebrate phyla of sipunculids, priapulids, brachiopods, and in a single annelid worm genus, '' Magelona''. Myohemeryth ...
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
In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an anion, an ion with negative charge.
Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,... ...
side chains of a glutamate
Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
and aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...
and five histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
residues. The uptake of O2 by hemerythrin is accompanied by two-electron oxidation of the reduced binuclear center to produce bound peroxide
In chemistry, peroxides are a group of Chemical compound, compounds with the structure , where the R's represent a radical (a portion of a complete molecule; not necessarily a free radical) and O's are single oxygen atoms. Oxygen atoms are joined ...
(OOH−). The mechanism of oxygen uptake and release have been worked out in detail.
Hemocyanin
Hemocyanins (also spelled haemocyanins and abbreviated Hc) are proteins that transport oxygen throughout the bodies of some invertebrate animals. These metalloproteins contain two copper atoms that reversibly bind a single oxygen molecule (O2 ...
s carry oxygen in the blood of most mollusk
Mollusca is a phylum of protostomic invertebrate animals, whose members are known as molluscs or mollusks (). Around 76,000 extant species of molluscs are recognized, making it the second-largest animal phylum after Arthropoda. The ...
s, and some arthropod
Arthropods ( ) are invertebrates in the phylum Arthropoda. They possess an arthropod exoskeleton, exoskeleton with a cuticle made of chitin, often Mineralization (biology), mineralised with calcium carbonate, a body with differentiated (Metam ...
s such as the horseshoe crab
Horseshoe crabs are arthropods of the family Limulidae and the only surviving xiphosurans. Despite their name, they are not true crabs or even crustaceans; they are chelicerates, more closely related to arachnids like spiders, ticks, and scor ...
. They are second only to hemoglobin in biological popularity of use in oxygen transport. On oxygenation the two copper
Copper is a chemical element; it has symbol Cu (from Latin ) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkish-orang ...
(I) atoms at the active site are oxidized to copper(II) and the dioxygen molecules are reduced to peroxide, .
Chlorocruorin (as the larger carrier erythrocruorin
Erythrocruorin (from Greek ''eruthros'' "red" + Latin ''cruor'' "blood"), and the similar chlorocruorin (from Greek ''khlōros'' "green" + Latin ''cruor'' "blood"), are large oxygen-carrying hemeprotein protein complex, complexes, which have a mo ...
) is an oxygen-binding hemeprotein present in the blood plasma
Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
of many annelid
The annelids (), also known as the segmented worms, are animals that comprise the phylum Annelida (; ). The phylum contains over 22,000 extant species, including ragworms, earthworms, and leeches. The species exist in and have adapted to vario ...
s, particularly certain marine polychaete
Polychaeta () is a paraphyletic class of generally marine Annelid, annelid worms, common name, commonly called bristle worms or polychaetes (). Each body segment has a pair of fleshy protrusions called parapodia that bear many bristles, called c ...
s.
Cytochromes
Oxidation
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
and reduction reactions are not common in organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
as few organic molecules can act as oxidizing
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
or reducing agent
In chemistry, a reducing agent (also known as a reductant, reducer, or electron donor) is a chemical species that "donates" an electron to an (called the , , , or ).
Examples of substances that are common reducing agents include hydrogen, carbon ...
s. Iron
Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
(II), on the other hand, can easily be oxidized to iron(III). This functionality is used in cytochrome
Cytochromes are redox-active proteins containing a heme, with a central iron (Fe) atom at its core, as a cofactor. They are involved in the electron transport chain and redox catalysis. They are classified according to the type of heme and its ...
s, which function as electron-transfer vectors. The presence of the metal ion allows metalloenzyme
Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains al ...
s to perform functions such as redox reaction
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
s that cannot easily be performed by the limited set of functional group
In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...
s found in amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s. The iron atom in most cytochromes is contained in a heme
Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
group. The differences between those cytochromes lies in the different side-chains. For instance cytochrome a has a heme a prosthetic group and cytochrome b has a heme b prosthetic group. These differences result in different Fe2+/Fe3+ redox potential
Redox potential (also known as oxidation / reduction potential, ''ORP'', ''pe'', ''E_'', or E_) is a measure of the tendency of a chemical species to acquire electrons from or lose electrons to an electrode and thereby be reduced or oxidised respe ...
s such that various cytochromes are involved in the mitochondrial
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
electron transport chain.
Cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
enzymes perform the function of inserting an oxygen atom into a C−H bond, an oxidation reaction.
Rubredoxin
Rubredoxin is an electron-carrier found in sulfur
Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...
-metabolizing bacteria
Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
and archaea
Archaea ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...
. The active site contains an iron ion coordinated by the sulfur atoms of four cysteine
Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
residues forming an almost regular tetrahedron
In geometry, a tetrahedron (: tetrahedra or tetrahedrons), also known as a triangular pyramid, is a polyhedron composed of four triangular Face (geometry), faces, six straight Edge (geometry), edges, and four vertex (geometry), vertices. The tet ...
. Rubredoxins perform one-electron transfer processes. The oxidation state
In chemistry, the oxidation state, or oxidation number, is the hypothetical Electrical charge, charge of an atom if all of its Chemical bond, bonds to other atoms are fully Ionic bond, ionic. It describes the degree of oxidation (loss of electrons ...
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
200px, The copper site in ">plastocyanin
Plastocyanin is one of the family of blue copper proteins that are involved in electron transfer
Electron transfer (ET) occurs when an electron relocates from an atom, ion, or molecule, to another such chemical entity. ET describes the mechanism by which electrons are transferred in redox reactions.
Electrochemical processes are ET reactio ...
reactions. The copper
Copper is a chemical element; it has symbol Cu (from Latin ) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkish-orang ...
-binding site is described as 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 pm) than Cu−S2 (282 pm).
The elongated Cu−S2 bonding destabilizes the Cu(II) form and increases the redox potential
Redox potential (also known as oxidation / reduction potential, ''ORP'', ''pe'', ''E_'', or E_) is a measure of the tendency of a chemical species to acquire electrons from or lose electrons to an electrode and thereby be reduced or oxidised respe ...
of the protein. The blue color (597 nm peak absorption) is due to the Cu−S1 bond where S(pπ) to Cu(d''x''2−''y''2) charge transfer occurs.
In the reduced form of plastocyanin, His
His or HIS may refer to:
Computing
* Hightech Information System, a Hong Kong graphics card company
* Honeywell Information Systems
* Hybrid intelligent system
* Microsoft Host Integration Server
Education
* Hangzhou International School, ...
-87 will become protonated with a p''K''a of 4.4. Protonation
In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), usually denoted by H+, to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brø ...
prevents it acting as a ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
and the copper site geometry becomes trigonal planar.
Metal-ion storage and transfer
Iron
Iron
Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
is stored as iron(III) in ferritin
Ferritin is a universal intracellular and extracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. ...
. The exact nature of the binding site has not yet been determined. The iron appears to be present as a hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
product such as FeO(OH). Iron is transported by transferrin
Transferrins are glycoproteins found in vertebrates which bind and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Iron(III), Fe3+ ions. Human transferrin is ...
whose binding site consists of two tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
s, one aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...
and one histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
. The human body has no controlled mechanism for excretion of iron. This can lead to iron overload
Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the ...
problems in patients treated with blood transfusion
Blood transfusion is the process of transferring blood products into a person's Circulatory system, circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used ...
s, as, for instance, with β-thalassemia
Thalassemias are a group of Genetic disorder, inherited blood disorders that manifest as the production of reduced hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe, including death. Often there is mild to ...
. Iron is actually excreted in urine and is also concentrated in bile which is excreted in feces.
Copper
Ceruloplasmin is the major copper
Copper is a chemical element; it has symbol Cu (from Latin ) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkish-orang ...
-carrying protein in the blood. Ceruloplasmin exhibits oxidase activity, which is associated with possible oxidation of Fe(II) into Fe(III), therefore assisting in its transport in the blood plasma
Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
in association with transferrin, which can carry iron only in the Fe(III) state.
Calcium
Osteopontin is involved in mineralization in the extracellular matrices of bones and teeth.
Metalloenzymes
Metalloenzymes all have one feature in common, namely that the metal ion is bound to the protein with one labile
Lability refers to the degree that something is likely to undergo change. It is the opposite ( antonym) of stability.
Biochemistry
In reference to biochemistry, this is an important concept as far as kinetics is concerned in metalloprotein ...
coordination
Coordination may refer to:
* Coordination (linguistics), a compound grammatical construction
* Coordination complex, consisting of a central atom or ion and a surrounding array of bound molecules or ions
** A chemical reaction to form a coordinati ...
site. As with all enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s, the shape of the active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...
is crucial. The metal ion is usually located in a pocket whose shape fits the substrate. The metal ion catalyzes
Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...
reactions that are difficult to achieve in organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
.
Carbonic anhydrase
In aqueous solution
An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, also known as sodium chloride (NaCl), in water ...
, carbon dioxide
Carbon dioxide is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...
forms carbonic acid
Carbonic acid is a chemical compound with the chemical formula . The molecule rapidly converts to water and carbon dioxide in the presence of water. However, in the absence of water, it is quite stable at room temperature. The interconversion ...
:CO2 + H2O H2CO3
This reaction is very slow in the absence of a catalyst, but quite fast in the presence of the hydroxide
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and hydrogen atom held together by a single covalent bond, and carries a negative electric charge. It is an important but usually minor constituent of water. It ...
ion
:CO2 + OH−
A reaction similar to this is almost instantaneous with carbonic anhydrase. The structure of the active site in carbonic anhydrases is well known from a number of crystal structures. It consists of a zinc
Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
ion coordinated by three imidazole
Imidazole (ImH) is an organic compound with the formula . It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. It can be classified as a heterocycle, specifically as a diazole.
Many natural products, ...
nitrogen atoms from three histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
units. The fourth coordination site is occupied by a water molecule. The coordination sphere of the zinc ion is approximately tetrahedral
In geometry, a tetrahedron (: tetrahedra or tetrahedrons), also known as a triangular pyramid, is a polyhedron composed of four triangular Face (geometry), faces, six straight Edge (geometry), edges, and four vertex (geometry), vertices. The tet ...
. The positively-charged zinc ion polarizes the coordinated water molecule, and nucleophilic attack by the negatively-charged hydroxide portion on carbon dioxide proceeds rapidly. The catalytic cycle produces the bicarbonate ion and the hydrogen ion[ as the equilibrium:
:H2CO3 + H+
favouring dissociation of ]carbonic acid
Carbonic acid is a chemical compound with the chemical formula . The molecule rapidly converts to water and carbon dioxide in the presence of water. However, in the absence of water, it is quite stable at room temperature. The interconversion ...
at biological pH values.
Vitamin B12-dependent enzymes
The cobalt
Cobalt is a chemical element; it has Symbol (chemistry), symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. ...
-containing Vitamin B12 (also known as cobalamin) catalyzes the transfer of methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...
(−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
In the Arrhenius model of reaction rates, activation energy is the minimum amount of energy that must be available to reactants for a chemical reaction to occur. The activation energy (''E''a) of a reaction is measured in kilojoules per mole (k ...
for the process by forming a transient Co−CH3 bond. The structure of the coenzyme
A cofactor is a non-protein chemical compound or Metal ions in aqueous solution, metallic ion that is required for an enzyme's role as a catalysis, catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can ...
was famously determined by Dorothy Hodgkin
Dorothy Mary Crowfoot Hodgkin (née Crowfoot; 12 May 1910 – 29 July 1994) was a Nobel Prize-winning English chemist who advanced the technique of X-ray crystallography to determine the structure of biomolecules, which became essential for ...
and co-workers, for which she received a Nobel Prize in Chemistry
The Nobel Prize in Chemistry () is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outst ...
. It consists of a cobalt(II) ion coordinated to four nitrogen atoms of a corrin ring and a fifth nitrogen atom from an imidazole
Imidazole (ImH) is an organic compound with the formula . It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. It can be classified as a heterocycle, specifically as a diazole.
Many natural products, ...
group. In the resting state there is a Co−C sigma bond
In chemistry, sigma bonds (σ bonds) or sigma overlap are the strongest type of covalent chemical bond. They are formed by head-on overlapping between atomic orbitals along the internuclear axis. Sigma bonding is most simply defined for diat ...
with the 5′ carbon atom of adenosine
Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...
. This is a naturally occurring organometallic
Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and so ...
compound, which explains its function in ''trans''-methylation reactions, such as the reaction carried out by methionine synthase.
Nitrogenase (nitrogen fixation)
The fixation of atmospheric nitrogen is an energy-intensive process, as it involves breaking the very stable triple bond
A triple bond in chemistry is a chemical bond between two atoms involving six Electron pair bond, bonding electrons instead of the usual two in a covalent bond, covalent single bond. Triple bonds are stronger than the equivalent covalent bond, sin ...
between the nitrogen atoms. The nitrogenases catalyze the process. One such enzyme occurs in ''Rhizobium'' bacteria
Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
. There are three components to its action: a molybdenum
Molybdenum is a chemical element; it has Symbol (chemistry), symbol Mo (from Neo-Latin ''molybdaenum'') and atomic number 42. The name derived from Ancient Greek ', meaning lead, since its ores were confused with lead ores. Molybdenum minerals hav ...
atom at the active site, iron–sulfur clusters that are involved in transporting the electrons needed to reduce the nitrogen, and an abundant energy source in the form of magnesium
Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
ATP. This last is provided by a mutualistic symbiosis between the bacteria and a host plant, often a legume
Legumes are plants in the pea family Fabaceae (or Leguminosae), or the fruit or seeds of such plants. When used as a dry grain for human consumption, the seeds are also called pulses. Legumes are grown agriculturally, primarily for human consum ...
. The reaction may be written symbolically as
:N2 + 16 Mg ATP + 8 e− → 2 NH3 + 16 Mg ADP +16 Pi + H2
where Pi stands for inorganic phosphate
Phosphates are the naturally occurring form of the element phosphorus.
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...
. The precise structure of the active site has been difficult to determine. It appears to contain a MoFe7S8 cluster that 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 sulfur bridges.
Superoxide dismutase
The superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of t ...
ion, is generated in biological systems by reduction of molecular oxygen
Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...
. It has an unpaired electron
The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...
, so it behaves as a free radical
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. It is a powerful oxidizing agent
An oxidizing agent (also known as an oxidant, oxidizer, electron recipient, or electron acceptor) is a substance in a redox chemical reaction that gains or " accepts"/"receives" an electron from a (called the , , or ''electron donor''). In ot ...
. These properties render the superoxide ion very toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
and are deployed to advantage by phagocytes
Phagocytes are cell (biology), cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or Apoptosis, dying cells. Their name comes from the Greek language, Greek ', "to eat" or "devour", and "-cyte", the suffix in ...
to kill invading microorganism
A microorganism, or microbe, is an organism of microscopic scale, microscopic size, which may exist in its unicellular organism, single-celled form or as a Colony (biology)#Microbial colonies, colony of cells. The possible existence of unseen ...
s. Otherwise, the superoxide ion must be destroyed before it does unwanted damage in a cell. The superoxide dismutase
Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxy ...
enzymes perform this function very efficiently.
The formal oxidation state
In chemistry, the oxidation state, or oxidation number, is the hypothetical Electrical charge, charge of an atom if all of its Chemical bond, bonds to other atoms are fully Ionic bond, ionic. It describes the degree of oxidation (loss of electrons ...
of the oxygen atoms is −. In solutions at neutral pH, the superoxide ion Disproportionation, disproportionates to molecular oxygen and hydrogen peroxide.
:2 + 2 H+ → O2 + H2O2
In biology this type of reaction is called a dismutation reaction. It involves both oxidation and reduction of superoxide ions. The superoxide dismutase
Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxy ...
(SOD) group of enzymes 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 that can act either as an oxidizing agent or as a reducing agent.
:Oxidation: M(''n''+1)+ + → M''n''+ + O2
:Reduction: M''n''+ + + 2 H+ → M(''n''+1)+ + H2O2.
In human SOD, the active metal is copper
Copper is a chemical element; it has symbol Cu (from Latin ) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkish-orang ...
, as Cu(II) or Cu(I), coordinated tetrahedral molecular geometry, tetrahedrally by four histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
residues. This enzyme also contains zinc
Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
ions for stabilization and is activated by copper chaperone for superoxide dismutase (CCS (gene), CCS). Other isozymes may contain iron
Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
, manganese or nickel. The activity of Ni-SOD involves nickel(III), an unusual oxidation state for this element. The active site nickel geometry cycles from square planar molecular geometry, square planar Ni(II), with thiolate (Cys2 and Cys6) and backbone nitrogen (His1 and Cys2) ligands, to square pyramidal molecular geometry, square pyramidal Ni(III) with an added axial His1 side chain ligand.
Chlorophyll-containing proteins
Chlorophyll plays a crucial role in photosynthesis. It contains a magnesium
Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
enclosed in a chlorin 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 this purpose.
Initially, the absorption of a photon causes an electron
The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...
to be excited into a singlet state of the Q band. The excited state undergoes an intersystem crossing from the singlet state to a triplet state in which there are two electrons with parallel electron spin, spin. This species is, in effect, a free radical
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...
, and is very reactive and allows an electron to be transferred to acceptors that are adjacent to the chlorophyll in the chloroplast. In the process chlorophyll is oxidized. Later in the photosynthetic cycle, chlorophyll is reduced back again. This reduction ultimately draws electrons from water, yielding molecular oxygen as a final oxidation product.
Hydrogenase
Hydrogenases are subclassified into three different types based on the active site metal content: iron–iron hydrogenase, nickel–iron hydrogenase, and iron hydrogenase.
All hydrogenases catalyze reversible hydrogen, H2 uptake, but while the [FeFe] and [NiFe] hydrogenases are true redox catalysis, catalysts, driving H2 oxidation and H+ reduction
:H2 2 H+ + 2 e−
the [Fe] hydrogenases catalyze the reversible Heterolysis (chemistry), heterolytic cleavage of H2.
:H2 H+ + H−
Ribozyme and deoxyribozyme
Since discovery of ribozymes by Thomas Cech and Sidney Altman in the early 1980s, ribozymes have been shown to be a distinct class of metalloenzymes. Many ribozymes require metal ions in their active sites for chemical catalysis; hence they are called metalloenzymes. Additionally, metal ions are essential for structural stabilization of ribozymes. Group I catalytic intron, Group I intron is the most studied ribozyme which has three metals participating in catalysis. Other known ribozymes include group II intron, Ribonuclease P, RNase P, and several small viral ribozymes (such as Hammerhead ribozyme, hammerhead, Hairpin ribozyme, hairpin, Hepatitis delta virus ribozyme, HDV, and VS ribozyme, VS) and the large subunit of ribosomes. Several classes of ribozymes have been described.
Deoxyribozymes, also called DNAzymes or catalytic DNA, are artificial DNA-based catalysts that were first produced in 1994. Almost all DNAzymes require metal ions. Although ribozymes mostly catalyze cleavage of RNA substrates, a variety of reactions can be catalyzed by DNAzymes including RNA/DNA cleavage, RNA/DNA ligation, amino acid phosphorylation and dephosphorylation, and carbon–carbon bond formation. Yet, DNAzymes that catalyze RNA cleavage reaction are the most extensively explored ones. 10-23 DNAzyme, discovered in 1997, is one of the most studied catalytic DNAs with clinical applications as a therapeutic agent. Several metal-specific DNAzymes have been reported including the GR-5 DNAzyme (lead (metal), lead-specific), the CA1-3 DNAzymes (copper
Copper is a chemical element; it has symbol Cu (from Latin ) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkish-orang ...
-specific), the 39E DNAzyme (uranyl-specific) and the NaA43 DNAzyme (sodium-specific).
Signal-transduction metalloproteins
Calmodulin
file:EF hand.jpg, 300px, EF-hand motif
Calmodulin is an example of a signal-transduction protein. It is a small protein that contains four EF-hand motifs, each of which is able to bind a calcium, Ca2+ ion.
In an EF-hand loop protein domain, the calcium ion is coordinated in a pentagonal bipyramidal configuration. Six glutamic acid and aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...
residues involved in the binding are in positions 1, 3, 5, 7 and 9 of the polypeptide chain. At position 12, there is a glutamate or aspartate ligand that behaves as a Denticity, bidentate ligand, providing two oxygen atoms. The ninth residue in the loop is necessarily glycine 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 hsab, 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 cell signaling, intracellular signaling system by acting as a diffusible second messenger to the initial stimuli.
Troponin
In both cardiac muscle, cardiac and skeletal muscles, muscular force production is controlled primarily by changes in the intracellular calcium concentration (chemistry), concentration. In general, when calcium rises, the muscles contract and, when calcium falls, the muscles relax. Troponin, along with actin and tropomyosin, is the protein complex to which calcium binds to trigger the production of muscular force.
Transcription factors
Many transcription factors contain a structure known as a zinc finger, a structural module in which a region of protein folds around a zinc ion. The zinc does not directly contact the DNA 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
There are two types of carbon monoxide dehydrogenase: one contains iron and molybdenum, the other contains iron and nickel. Parallels and differences in catalytic strategies have been reviewed.
Pb2+ (lead) can replace Ca2+ (calcium) as, for example, with calmodulin or Zn2+ (zinc) as with metallocarboxypeptidases.
Some other metalloenzymes are given in the following table, according to the metal involved.
See also
References
External links
*
Catherine Drennan's Seminar: Snapshots of Metalloproteins
{{Authority control
Metalloproteins,
Medicinal inorganic chemistry
Bioinorganic chemistry