Bioinorganic Chemistry
- Bioinorganic chemistry is a relatively new and still growing interdisciplinary field of chemistry which largely focuses on the roles of metal ions in living systems.
Metalloporphyrins
- The metaloporphyrins are the complexes in which a metal ion is coordinated to four nitrogen atoms inside the cavity of the porphyrin ring in a square planar geometry.
- The axial sites are available for other ligands.
- Some examples of metalloporphyrins are hemoglobin, myoglobin, cytochromes and chlorophylls.
The porphyrin rings are the derivatives of a macrocyclic ligand called porphine.
The porphine molecule consists of
- unsubstituted tetra pyrole connected by methylidyne (CH) bridges.
- These methylidyne carbon positions are labeled the alpha, beta, Gama, delta and 5, 10, 15, 20 positions in porphine and porphyrin rings respectively.
- The 5, 10, 15, 20-tetraphenyl derivatives (tpd) are readily available because of their ease of synthesis and purification.
- In porphyrin rings various groups are attached to the perimeter of porphine molecule.
- The porphyrin ring can accept two hydrogen ions to form the dication (ie,+ 2 diacid) or donate two protons to form dianion.
- In metalloporphyrin complexes the inner hydrogen atoms are replaced as protons by dipositive metal ions.
- Therefore, the metal free porphyrin ligand has -2 charges.
- Since, this macrocyclic ligand has a planar conjugated system of π bonds around its perimeter, it is much more rigid macrocyclic ligand than the crown ethers
- Therefore, the ligand is more selective for certain metal atoms than the crown ethers.
- It has a stronger preferences for the d8 Ni2+ ion.
- The other metal ions may add above or below the square plane.
- The structures of porphine molecule, metalloporphyrin and Fe-protoporphyrin IX or heme group are shown in Fig. 9.1.
Fig. 9.1 Structure of (a) Porphine (b) Metalioporphynin (c) Fe-protoporphyrn DX
The porphyrin rings are rigid because of the delocalization of the π-electrons around the perimeter.
The size of the cavity in the centre of porphyrin ring is ideal for accommodation of metal ions of the first transition series.
If the metal ion is too small such as Ni 2+, the ring becomes ruffled to allow closer approach of nitrogen atoms to the metal ion.
On the other hand, if the metal ion is too large, it can not fit into the cavity and occupies position above the ring which also becomes domed
Role of Iron in Living Systems
Iron is the most important transition metal involved in living systems, being vital for both plants and animals.
In the living systems, iron has three well characterized systems:
- (1) Proteins that contain one or more porphyrin rings such as hemoglobin, myoglobin and cytochrome P450
- (2) Proteins that contain non-heme iron such as iron-sulphur compounds (ruberdoxin, ferredoxins nitrogenase)
- (3) The non-heme diiron oxo-bridged compounds such as carboxylates (hemerythrin ribonucleotide reductase and methane monooxygenase)
Some important naturally occuring iron proteins and their functions in living systems are listed in Table 9.1.
Hemoglobin and Myoglobin
Hemoglobin contains two parts:
- heme groups and
- globin proteins.
A porphyrin ring containing an Fe atom is called a heme group.
Cellular respiration is the process of using oxygen to break down glucose to produce CO₂, water and energy for use by the cell.
It has molar mass of about 64500.
Hemoglobin is found in red blood cells that are called erythrocytes and is resposible for their characteristic colour.
Without hemoglobin the blood is either colourless or a different colour
Hemoglobin picks up the weak ligand dioxygen from the lungs or gills and carries dioxygen in arterial blood to the muscles, where the oxygen is transferred to another heme containing protein, myoglobin which stores it untill oxygen is required to decompose glucose to produce energy, CO, and water
Hemoglobin then uses certain amino and groups to bind CO, and carry it in venous blood back to the lungs
Each hemoglobin molecule is made up of four subunits, each of which consists of a globin protein in the form of folded helix or spiral.
The globin proteins are of two types:
- two are alpha and two are beta .
An alpha globin protein consists of 141 and an beta globin protein consists of 146 amino acids.
Each protein consists of one polar and one non-polar group.
In hemoglobin which has no dioxygen attached (and is therefore called as deoxyhemoglobin or reduced hemoglobin), the protein is attached to Fe(II) protoporphyrin IX through imidazole nitrogen of histidine residue in such a way that the polar groups of each protein are on the outside of the structure leaving a hydrophobic interier.
Therefore, the heme group is held in a water resistant protein pocket.
Perutz has suggested a "trigger" mechanism for the cooperativity of the four heme groups in a process of oxygenation in hemoglobin. According to him there is a comformational change of the beme group upon coordination of an oxygen molecule which triggers interconversion of the T and R conformations. In deoryhemoglobin, iron is coordinated to four nitrogen atoms of the planar protoporphynin IX and the fifth coordination site is occupied by nitrogen atom on imidazole of a proximal histidine of globin protein. The sixth vacant site trans to the imidazole nitrogen is vacat and reserved for dicaygen. In deoxybemoglobin iron present as high spin Fe(II) with one electron ocupying the d orbital that points directly toward the nitrogen atoms of protoporphyrin DC. The presence of this electron increases the size of Fe(II) in these directions by repelling the lone pair of electrons on nitrogen atoms. As a consequence, Fe(ID becomes too large to fit easily within the hole provide by the planar protoporphyrin IX ring. The Fe() ion is, therefore, lies about 40 pm out of the plane in the direction of the histidine group, and the hese group is slightly bent into a domed shape
(Fig.9.2) The imo atom in deoxyhemoglobin has square based pyramidal coordination. The steric interactions between the histidine residue, the associated globin chain and hene group inhibit the free movement of the imm atos into the porphyrin ring Although O, is not a strong ligand, the coordination of the dioxygen molecule trami to the
histidine group as a sixth ligand ahen the strength of the ligand field and causes the pairing of electrons on iron without affecting the oxidation state of iron. Therefore, Fe(l) becomes low spin and diamagnetic. In low spin Fe(II) che six delectrons occupy the d.d. and d ochals. The darbinals is now empty and the previous effects of an electron present in this orbital in repelling the porphyrin nitrogen atoms is diminished. Therefore, the size of low spin Fell) becomes about 17 pm smaller that high spin Feil). Thus, the Fe() slips in the hole of an approximately planar porphyrin ring. As the iron slips into the hole, the midsole side chain of histidine F, al moves toward Fe atom, and the complex has an octahedral geometry Recent X-ray studies show that dioxygen is bound in a bent fashion with an Fe-0-0 angle of approximately 130. There is strong evidence for hydrogen bonding between an imidanile N-H of a distal histidine and the bound dioxygen.
the four subunits of hemoglobin are linked with each other through salt bridges between the for polypeptide chains. These salt bridges are formed mainly due to electrostatic interaction between the-NH; and-C00 groups present on all the four polypeptide chains of hemoglobin. The protein structures in hemoglobin consists of a peptide backbone with various side chains. These tide chains consist of a variety of non-polar (hydrocarboni), cationic (such as-NH;) and anionic (such -C00) groups. These salt bridges between the polypeptide chains in hemoglobin are now believed to introduce strain in the molecule. Therefore, the deoxy form of hemoglobin is called tense
state (or T state). The movement of iron atom and imidazole side chain of histidine F, toward the porphyrin plane results in breaking of some of the salt bridges. The breaking of these salt bridges reduces the strain in hemoglobin molecule. Therefore, the oxyform of hemoglobin is called relaxed state (i.e., R state). The T form of deoxyhemoglobin discourages the addition of first dioxygen molecule.
The bonding of one dioxygen molecule to a subunit of hemoglobin reduces the steric hindrance in the other subunits (due to breaking of salt bridges) and therefore encourages the bonding of dionygen molecules to the iron atom of the second subunit which in turn encourages the third as well as fourth subunits. The binding of dioxygen molecule is the most difficult in first subunit and the easiest in the last subunit due to conformational change in the protein chain (or polypeptide chain). Initial addition of a dioxygen molecule to high spin Fe(II) triggers the oxygenation of deoxyhemoglobin. This is called cooperative effect.
The phenomenon where the addition of dioxygen to one heme subunit encourages addion of the
dotypen molecules to other heme subunits is known as cooperative effect."
The successive equilibrium constants for binding of dioxygen molecules to each of the four iron
woms follow the order:
K₁ < K₂ < K₂ <K4
The fourth equilibrium constant (K) is found to be much larger than the first (K). This indicates that last O, molecule bound much more readily and tightly than the first. In the absence of conformational changes, K, would be much smaller than Ky. As a result, as soon as one or two dioxygen molecules are bound to iron atoms, all the four iron atoms are readily oxygenated. Conversely, as one O, molecule is removed from oxyhemoglobin the reverse conformational changes occur and successively decrease its affinity for oxygen. Therefore, initial removal of O, molecule from deoxyhemoglobin triggers the removal of remaining O, molecules. This phenomenon is also called as cooperative effect.
Fig. 9.3:1-oxo dimer (hematin)
The naked heme, the tron-porphyrin complex without accompanying the polypeptide chains is oxidized to Fe(III) by dioxygen molecule in aqueous solution and is converted immediately into a stableu-oxo dimer (Fig. 9.3) known as hematin. In hematin iron is high spin Fe(III). The hemarin is unable to transport oxygen. The polypeptide chain can be removed by treatment with HCl/acetone. The polypeptide chain in hemoglobin and myoglobin prevents oxidation of Fe(II) because: (1) The hydrocarbon environment round the iron has a low dielectric constant and is
hydrophobic and therefore act as a non-polar and provides non-aqueous environment.
(2) It provides steric hindrance and does not allow the formation of hematin.
The mechanism of the formation of hematin is as follows:
The first step involves the binding of the O, molecule to Fe(II) of the heme group, PFe(II)
PFe +0₂ Pre-O
Second step involves the coordination of bound oxygen to second heme group forming u peroso
complex.
+PFe"
Pre-0-0-Fe p
O Third step involves the cleavage of the peroxo complex into two ferryl complexes in which iron is present in + 4 formal oxidation state.
0. 0-Fe P-2PF-0
In the last step, the ferryl complex combines with an another heme group resulting in the formation of hematin.
Pre-O+PFeFFe-0-Fe P
Myoglobin (Mb)
Myoglobin (or deoxy-myoglobin) is a protein which has only one heme group per molecule and serves as an oxygen storage molecule in the muscles. It has molar mass of about 17000 and binds
Baterpinic Chemistry
9-7
doxygen molecule more strongly than hemoglobin. The yoglobin molecule is sindur to a single vir of hemoglobin Myoglobin is a five coordinate high spin Fell) complex with four of the ordinating positions occupied by N-atoms of the porphyrin ring. The fifth position is occupied by an Naim of an unidazole group of a histidine residue (a globin protein). The protein consists of 153 acids. This protein restricts access to the Fell) by a second heme and reduces the formation of hematin like Fe (III) dimer. The result is that the Fe(1) porphyrin complex survives long enough to nd and release dioxygen molecule. Such five coordinate heme complexes of Feill) are always high pin te with one electron occupying the da, orbital that points directly toward the four the size of Fe(II) in these directions
prpbyzn nitrogen atoms. The presence of this electron increases by repelling the lone pair of electrons of the nitrogen atoms.
The size of Fe(II) is 92 pm in the square pyramidal arrangement which is considered to be peado octahedral environment with the sixth ligand removed. The size of Fe() ia solarge that it in not fit into the hole of the planar porphyrin ring and therefore it lies about 40 pm away from the plane of the ring (Fig. 9.2). Therefore, high spin Fell) porphyrin complexes (in Hb and Mh) involves packering and twisting of porphyrin ring.
When a dioxygen molecule binds to Fe(II) at sixth coordination site trans to imidazole group of hinde residue, the complex converts to low spin Fe(1) octahedral complex and the electronic configuration changes tori (e, the six d-electrons occupy the dg. d, and, orbish leading to and da orbitals empty). The previous effect of two electrons occupying the citals in repelling the N atoms on X, Y and Z axes diminishes. Therefore, the low spin Fellt) son is maller (75 pm) and slips into the hole in the planar pophyrin ring As the Fe(10 kon moves, it pulls
beidzale group of histidine residue. Therefore, all the nitrogen atoms (including that of
painal histidine) approach more closer to the Fe(II) ion.
Physiology of Hemoglobin and Myoglobin Hemoglobin has relatively high affinity for dioxygen at high partial presure of dixygen where
The
vertibiranes diosygen enters the blood in the lungs or gills where the partial pere of dioxygen go has relatively high affauty for dioxygen at lower partial pressure of dissygen. In natively high and hemoglobin is virtually saturated with dioxygen in hurtigs When hemoglobin ramties dinnypen to muscle tissues, it experiences the lower partial pressure of dicaygen and s way for dioxygen has fallen off rapidly and in this situation affany of myoglobin for disaygen is wively high. Therefore, in muscle tissues dioxygen is thermodynamically favourable transferred han hecsoglobin to myoglobin. The reactions occuring in lungs and muscles a
Hb40,
HNO₂)
The cyproation equilibrium for myoglobin is represented as
9-8
Organometallic and Binorganic Chemistry
Mh+ O₂ Mb(0₂)
K
Iff is the fraction of myoglobin bearing oxygen and Po, is the equilibrium partial
dioxygen, then
K
K PO 1+K Pos if
pressure of
to br
or
The equilibrium constant K is called the binding constant of myoglobin for 0₂.
This is the equation for the hyperbolic curve for myoglobin (Fig. 9.4).
100
80
aope w
de
stof
hat tow
avea at
1. Th
harth his
Bohr's
The c
60
Mb
HypH-7.6 Hb pH 6.8
40+
Partial pressure of O, in lungs
Partial pressure of O, in muscle
0
20
40
60
80
100
20
Percentage satuartion with O₂
120
pure d
be Lunge
yhtey
The 1
the w
Partial pressure of O₂ in mm Hg
Fig. 9.4 Oxygen Dissociation Curves for Hemoglobin and Myoglobin. Showing how Hemoglobin is Able to Absorb O, Efficiently in the Lungs yet Transfer it to Myoglobin in Muscle Tissue
The hemoglobin curve does not follow such an equation. Hemoglobin has more complex behaviour ms it has four heme subunits. It follows an emperically modified form with Por replaced by Po
K = [Mb(0₂).]
K M
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