Metalloprotein

Source: Wikipedia, the free encyclopedia.

The structure of hemoglobin. The heme cofactor, containing the metal iron, shown in green.

Metalloprotein is a generic term for a protein that contains a metal ion cofactor.[1][2] 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[3] although there may be up to 3000 human zinc metalloproteins.[4]

Abundance

It is estimated that approximately half of all proteins contain a metal.[5] In another estimate, about one quarter to one third of all proteins are proposed to require metals to carry out their functions.[6] Thus, metalloproteins have many different functions in cells, such as storage and transport of proteins, enzymes and signal transduction proteins, or infectious diseases.[7] 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.[8]

Most metals in the human 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.

Metal concentrations in humans organs (ppm = μg/g ash)[9]
Liver Kidney Lung Heart Brain Muscle
Mn (manganese) 138 79 29 27 22 <4-40
Fe (iron) 16,769 7,168 24,967 5,530 4,100 3,500
Co (cobalt) <2-13 <2 <2-8 --- <2 150 (?)
Ni (nickel) <5 <5-12 <5 <5 <5 <15
Cu (copper) 882 379 220 350 401 85-305
Zn (zinc) 5,543 5,018 1,470 2,772 915 4,688

Coordination chemistry principles

In metalloproteins, metal ions are usually coordinated by

carbonyl oxygen centers. Lead(II) binding in natural and artificial proteins has been reviewed.[10]

In addition to donor groups that are provided by amino acid residues, many organic

macrocyclic ligands incorporated into the heme
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

oxidized to iron(III). The equilibrium constant for the formation of HbO2 is such that oxygen is taken up or released depending on the partial pressure of oxygen in the lungs or in muscle. In hemoglobin the four subunits show a cooperativity effect that allows for easy oxygen transfer from hemoglobin to myoglobin.[11]

In both

deoxyhemoglobin the iron atom lies above the plane of the ring.[11] This change in spin state is a cooperative effect due to the higher crystal field splitting and smaller ionic radius
of Fe2+ in the oxyhemoglobin moiety.

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.[12][13]

mollusks, and some arthropods such as the horseshoe crab. 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 oxidized to copper(II) and the dioxygen molecules are reduced to peroxide, O2−
2.[14][15]

Chlorocruorin (as the larger carrier erythrocruorin) is an oxygen-binding hemeprotein present in the blood plasma of many annelids, particularly certain marine polychaetes
.

Cytochromes

Main article: cytochrome

mitochondrial electron transport chain.[17]

Cytochrome P450 enzymes perform the function of inserting an oxygen atom into a C−H bond, an oxidation reaction.[18][19]

Rubredoxin

Rubredoxin active site.
Main article:
Iron–sulfur protein

high spin
, which helps to minimize structural changes.

Plastocyanin

Main article: Plastocyanin
The copper site in plastocyanin

Plastocyanin is one of the family of blue

pm
) than Cu−S2 (282 pm). The elongated Cu−S2 bonding destabilizes the Cu(II) form and increases the
nm peak absorption) is due to the Cu−S1 bond where S(pπ) to Cu(dx2−y2) charge transfer occurs.[21]

In the reduced form of plastocyanin, His-87 will become protonated with a pKa of 4.4. Protonation prevents it acting as a ligand and the copper site geometry becomes trigonal planar.

Metal-ion storage and transfer

Iron

Iron is stored as iron(III) in ferritin. The exact nature of the binding site has not yet been determined. The iron appears to be present as a hydrolysis product such as FeO(OH). Iron is transported by transferrin whose binding site consists of two tyrosines, one aspartic acid and one histidine.[22] The human body has no mechanism for iron excretion.[citation needed] This can lead to iron overload problems in patients treated with blood transfusions, as, for instance, with β-thalassemia. Iron is actually excreted in urine[23] and is also concentrated in bile[24] which is excreted in feces.[25]

Copper

Main article: Ceruloplasmin

Ceruloplasmin is the major copper-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 in association with transferrin, which can carry iron only in the Fe(III) state.

Calcium

Main article: Osteopontin

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

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 that are difficult to achieve in organic chemistry
.

Carbonic anhydrase

Active site of carbonic anhydrase. The three coordinating histidine residues are shown in green, hydroxide in red and white, and the zinc in gray.

In aqueous solution, carbon dioxide forms carbonic acid

CO2 + H2O ⇌ H2CO3

This reaction is very slow in the absence of a catalyst, but quite fast in the presence of the hydroxide ion

CO2 + OH− ⇌
HCO−
3

A reaction similar to this is almost instantaneous with

nucleophilic attack by the negatively-charged hydroxide portion on carbon dioxide proceeds rapidly. The catalytic cycle produces the bicarbonate ion and the hydrogen ion[2] as the equilibrium

H2CO3 ⇌ HCO−
3 + H+

favours dissociation of carbonic acid at biological pH values.[26]

Vitamin B12-dependent enzymes

The

methionine synthase
.

Nitrogenase (nitrogen fixation)

The

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 ATP. This last is provided by a mutualistic symbiosis between the bacteria and a host plant, often a legume
. The reaction may be written symbolically as

N2 + 16 MgATP + 8 e− → 2 NH3 + 16 MgADP +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 that is able to bind the dinitrogen molecule and, presumably, enable the reduction process to begin.[30] The electrons are transported by the associated "P" cluster, which contains two cubical Fe4S4 clusters joined by sulfur bridges.[31]

Superoxide dismutase

Structure of a human superoxide dismutase 2 tetramer

The

phagocytes to kill invading microorganisms. Otherwise, the superoxide ion must be destroyed before it does unwanted damage in a cell. The superoxide dismutase enzymes perform this function very efficiently.[32]

The formal oxidation state of the oxygen atoms is −1⁄2. In solutions at neutral pH, the superoxide ion disproportionates to molecular oxygen and hydrogen peroxide.

2 O−
2 + 2 H+ → O2 + H2O2

In biology this type of reaction is called a

rate of reaction to near the diffusion-limited rate.[33]
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)+ + O−
2 → Mn+ + O2
Reduction: Mn+ + O−
2 + 2 H+ → M(n+1)+ + H2O2.

In human SOD, the active metal is copper, as Cu(II) or Cu(I), coordinated tetrahedrally by four histidine residues. This enzyme also contains zinc ions for stabilization and is activated by copper chaperone for superoxide dismutase (CCS). Other isozymes may contain iron, 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 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.[34]

Chlorophyll-containing proteins

Main articles: chlorophyll and photosystem
Hemoglobin (left) and chlorophyll (right), two extremely different molecules when it comes to function, are quite similar when it comes to its atomic shape. There are only three major structural differences; a magnesium atom (Mg) in chlorophyll, as opposed to iron (Fe) in hemoglobin. Additionally, chlorophyll has an extended isoprenoid tail and an additional aliphatic cyclic structure off the macrocycle.

Chlorophyll plays a crucial role in photosynthesis. It contains a magnesium 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

free radical, 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

Main article: Hydrogenase

Hydrogenases are subclassified into three different types based on the active site metal content: iron–iron hydrogenase, nickel–iron hydrogenase, and iron hydrogenase.[35] All hydrogenases catalyze reversible H2 uptake, but while the [FeFe] and [NiFe] hydrogenases are true redox catalysts, driving H2 oxidation and H+ reduction

H2 ⇌ 2 H+ + 2 e−

the [Fe] hydrogenases catalyze the reversible heterolytic cleavage of H2.

H2 ⇌ H+ + H−
The active site structures of the three types of hydrogenase enzymes.

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.[36] 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 intron is the most studied ribozyme which has three metals participating in catalysis.[37] Other known ribozymes include group II intron, RNase P, and several small viral ribozymes (such as hammerhead, hairpin, HDV, and VS) and the large subunit of ribosomes. Several classes of ribozymes have been described.[38]

lead-specific),[42] the CA1-3 DNAzymes (copper-specific), the 39E DNAzyme (uranyl-specific)[43] and the NaA43 DNAzyme (sodium-specific).[44]

Signal-transduction metalloproteins

Calmodulin

EF-hand motif

EF-hand motifs, each of which is able to bind a Ca2+
ion.

In an

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 signaling system by acting as a diffusible second messenger to the initial stimuli.[45][46]

Troponin

In both

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

Zinc finger. The zinc ion (green) is coordinated by two histidine residues and two cysteine residues.

Many transcription factors contain a structure known as a zinc finger, this is a structural module where 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.[47] 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.[48]

Pb2+ (lead) can replace Ca2+ (calcium) as, for example, with

metallocarboxypeptidases[49]

Some other metalloenzymes are given in the following table, according to the metal involved.

Ion Examples of enzymes containing this ion
Magnesium[50] Glucose 6-phosphatase
Hexokinase
DNA polymerase

Poly(A) polymerase

Vanadium
vanabins
Manganese[51] Arginase
Oxygen-evolving complex
Iron[52]
IRE-BP
Aconitase
Cobalt[53] Nitrile hydratase
Methionyl aminopeptidase
Methylmalonyl-CoA mutase
Isobutyryl-CoA mutase
Nickel[54][55]
Methyl-coenzyme M reductase
(MCR)
Copper[56]
Cytochrome oxidase
Laccase
Nitrous-oxide reductase
Nitrite reductase
Zinc[57]
Beta amyloid
Cadmium[58][59]
Thiolate
proteins
Molybdenum[60] Nitrate reductase
Sulfite oxidase
Xanthine oxidase
DMSO reductase
Tungsten[61] Acetylene hydratase
various Metallothionein
Phosphatase

See also

References

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