Bioinorganic Chemistry

Principles of Structure and Reactivity

Prof. Halan Prakash

 Bioinorganic Chemistry

The chemistry of life processes

(i) Solar energy to drive chemical reactions that produce oxygen and reduced organic
compounds from carbon dioxide and water

(ii) Oxidation of the products from (i) to produce CO2, water and Energy

Ability to capture light, Ability to employ catalysts for the controlled release of energy
Enzyme catalysis- control the synthesis and degradation of biologically important
molecules

Many enzymes depend on the metal ions for their activity.

Metal containing compounds are also important

Energy Sources for Life

Most of the reactions for obtaining the energy for living systems are basically inorganic
Reactions are mediated and made possible by complete biochemical systems

Non photosynthetic processes

Many living organisms depend either directly (green plant) or indirectly (animals)
Upon photosynthesis to capture the energy of sun, there are few reactions
Utlise inorganic sources for energy
Non photosynthetic processes
Metalloproteins and respiration

The active Centre of the cytochrome is the heme. Porphyrin ring chelated to an iron atom

Macrocyclic pyrrole system with conjugated double bond

Various groups are attached to perimeter

Electronic donating and withdrawing ability they can tune the delocalised molecular
Orbitals of the complex and tune its redox properties

Porphyrin can accept two protons +2 diacid

Porhyrin can donate protons -2 dianion –metalloprohyrin complexes

The distance between the N and an atom of first row transition series should be
200 pm

RigidNickel 193-196 pm, Fe- 210 pm in high spin

If metal is too large , it cannot fit into the hole and sit above the ring -domed
Porphyrin importance- biologically accessible, changing the metal , metal ion oxidation
and nature of the substituents on the porphyrin ring

The evolution generally tends to proceed by modifying structures and functions that
are already present than producing new ones.

The oxidation state of Fe may be +2 or +3 , redox ability

Present in cytochromes, redox medators in electron transfer

Chloroplasts for photosynthesis but also in mitochondria to take part in

Respiration.
Heme group in cytochrome c – polypeptide chain, variable number of amino acids 103 in fish
and 104 in another fish, vertebrates , 112 in plants

Nitrogen atom from the histidine and Sulphur from methionine , coordinated
Fifth and sixth ligand iron atom

Saturated, must react indirectly by an electron transfer mechanism. Unlike hemoglobin and
myoglobin

It can reduce the dioxygen and transmit its oxidizing power towards the burning of food and
Release of energy in respiration ( the reverse process to complement photosynthesis

There are many cytochormes, cytochrome c is the most well characterised

Depending on the ligands present, the redox potential of a given cytochrome can be tailored
To meet the specific electron transfer , photosynthesis or in respiration.
Potentials are such that the electron flows from
b-c-a-O2

A type are capable of binding oxygen and reducing them. Cytochrome c oxidase. Five
coordinated in contrast to cytochrome c, and bind oxygen.
https://www.technologynetworks.com/applied-sciences/articles/essential-amino-acids-chart-
abbreviations-and-structure-324357
SOLUTION STRUCTURE OF OXIDIZED HORSE HEART 1AKK
CYTOCHROME C, NMR, MINIMIZED AVERAGE STRUCTURE
Cytochrome c oxidase- bind CN- strongly to the sixth position and stabilizes the
Fe(III) that it can no longer be readily reduced and take part in electron transfer

CN- is isoelectronic wit CO, and it might be thought it could bind to hemoglobin
as CO

However, CN- binds to Fe(III) of hemoglobin (methemoglobin) an aberrant form

usually present only in small quantities. Thus CN poisoning is not due to lack of the
Function of hemoglobin

amyl nitrite and sodium nitrite oxidizes hemoglobin to methemoglobin.

Methemoglobin binds cyanide tightly than hemoglobin or cytochrome oxidase
and remove it from the system.
The structure of cytochrome c oxidase is not known completely

It contains two heme types (a and a3) and two copper atoms ( Cua and Cub).
Dioxygen binding , Transport and Utilization

Hemoglobin picks up the dioxygen from lungs or gills and transport to tissues where it is
stored by myoglobin

Myoglobin Repository . Provide oxygen during increased metabolism or oxygen deprivation,

flow of oxygen in cell and buffering of partial pressure of oxygen in response to increase or
decrease of oxygen supply.

Dioxygen has some  bonding capacity, the tetrapyrrole ring facilitates the binding of oxygen

Heme group binds CO more tightly , CO poisoning.

A potential flaw in binding of oxygen by heme ,

irreversible oxidation,

Free heme in aqueous solution is exposed to dioxygen,

µ-oxo dimer hematin
PFe(II) +O2 PFe(II)O2 PFe(III)O2

PFe(II)O2 + PFe(II) PFe(III)---O-----O---FeIIIP

PFe(III)---O-----O---FeIIIP 2PFe(III)---O + 2PFeIV O

PFeIV O + PFe(II) PFe(III)---O---FeIIIP

Living systems have found a way to stop the above reactions

Steric hindrance, globin part of the prevents

Picket fence

Angular bent dioxygen coordination

1MBO
1MOA
Binding of dioxygen to myoglobin,

Molecular weight ~ 17000, protein chain folded about a single heme

No hematin like dimer

Similar to cytochrome c , but no sixth ligand methionine

Thus there is a site to bind dioxygen reversibly

In myoglobin and hemoglobin the redox behavior is retarded and binding of dioxygen takes
place without electron transfer.

Myoglobin contains Fe in Fe(II) state , d6 high spin has a radius of 92 pm in a

square pyramidal arrangement (may be considered as pseudo octahedron) , and iron atom
will not fit into the hole of porphyrin ring , lies about 42 pm above the plane of nitrogen
atoms of porphyrin ring

When oxygen binds, iron (II) becomes low spin d6 , ionic radius reduces to 75 pm.
High spin t2g4 eg2, eg will repel the ligands therefore have more radius , 92 pm compared to
lowspin 75 pm

In low spin, spin pairing occurs and the iron atom drops into the porphrying ring
42 pm above the plane of nitrogen atoms of
porphyrin ring
Dioxygen bending

Fe -----O bond is almost similar for oxymyglobin and oxyheamoglobin

However, Fe -----O --------O bond angles vary considerably
115 in myoglobin
153 in hemoglobin
131 in picket fence

The hydrogen bonding between the dioxygen and the NH of distal

Histidine could be important
1MBO
The physiology of Myoglobin and Hemoglobin

In vertebrates dioxygen enters the blood in the lungs or gills

Partial pressure is 0.2 x 1.01 x 105 Pa (160 mmHg)

It is then carried by red blood cells to the tissues where partial pressure is
considerably lower of the order of 2.5 x 103 Pa to 6.5 x 103 Pa , (20-50 mm Hg ).

Lungs /gills Hb + O2 Hb(O2)4

Tissues Hb(O2)4 + 4 Mb 4 Mb(O2) + Hb

Hb has ambivalent function, bind dioxygen tightly and carry as much as possible
to tissues .In tissues, it readily gives to myoglobin , Mb, which can store it for oxidation
Of food.

(i) Myoglobin has greater affinity for dioxygen than hemoglobin in order to effect the
Transfer of dioxygen in the cell

(ii) The equilibrium constant for the myoglobin –dioxygen complexation is given by

kMb = [MbO2]/[Mb][O2], if Mb and MbO2 i.e amount of Mb is constant, and

The partial pressure of oxygen is varied , the curve as shown in the following figure
Is obtained.
 Dioxygen binding curve

1 = myoglobin , 2-4 hemoglobin with different partial pressure of CO2

Myoglobin is largely converted to oxymyoglobin even at low partial pressure of oxygen
Such as in the cell
Hb is more
Complicated
kHb = [Hb(O2)4]/[Hb][O2]2.8

The 2.8 exponent for dioxygen results from the fact that a sing hemoglobin molecule
can accept four dioxygen , and the binding is not independent.

If they acted independently, they would give a curve identical to Mb

Cooperativity of the four heme groups –

At low dioxygen concentration, Hb is less oxygenated, tends to release O2

At high dioxygen concentation, Hb is oxygenated almost to the same extent as if the
Exponent is 1. Sigmoidal curve

High pressure in lungs , Hb is saturated with oxygen, low pressure in capillary Hb tends to
Deoxygenate i.e release oxygen

There is a pH dependence shown by Hb. This is known as Bohr effect. Hb binds one
H+ for every dioxygen molecule released. This favor CO2 conversion to Hydrogen
Carbonate , promoting the CO2 lungs.
Structure function of Hb

An approximate tetramer of myoglobin

64,500 M.W , four heme , bound to four chains

2 alpha chains , similar to myoglobin

2 beta chains , less like myoglobin

Upon oxygenation, two of the heme groups move about 100 ppm towards each other

While other two separate about 700 ppm.

One alpha and beta half of the molecule rotates 15 relative to each other half. Change
In the quaternary structure, and responsible for cooperative effects observed.
1NQP

3A0G
The interaction between the dioxygen molecule and heme affects the position of the
Protein chain attached to it, which in turn affects the tertiary and quaternary
Structure of the proteins- cooperative and/or Bohr effect.
T state- deoxygenated quaternary structure
R state- oxygenated quaternary structure

R form has oxygen affinity similar to isolated   chains but

T form has lower oxygen affinity. Structural difference, and slow start in binding curve.

The radius of Fe (II) high spin is too large to fit into the plane of four porphyrin nitrogen’s
42 pm above plane
92 pm in HS, and 75 pm in LS, , so radius of LS is about 17 pm less than HS.

The HS Fe(II) atom is forced to sit above the center of heme group
Fe ------N Porphyrin 206 ppm, Heme group is domed upwards towards proximal histidine

Coordination of oxygen causes spin pairing , low spin Fe(II) is smaller , it should fit into
Prophyrin, Fe ------N Porphyrin 198 ppm, Move about 20 pm towards porphyrin ring, but
not all the way into plane.
Steric interaction histidine, globin chain, and heme group. This results in strain on oxyheme
And tertiary structure within T state. Discourage the addition of first oxygen, or it pushes
The last oxygen. Addition of second oxygen takes places with similar result.
Bis(dioxygen) T state show little movement of iron and negligible movement of
Histidine

Addition of 3rd oxygen molecule results in interconversion to the R state.

Removes the tension, and allows iron atom to move into center of porphyrin ring

Ring flattens, and histidine follow iron 50-60 pm.

This change allow fourth oxygen to accept dioxygen without protein constraint
And accounts for high affinity for Hb(O2)3 to take the last oxygen.

Globin portion produces a constraint upon the iron atom ,

 partial movement of iron
Atom into porphyrin , oxy T

215
200
Proximal
H2O bound to distal His
In deoxy

210
 164 pm 183 pm

In myoglobin and sterically hindered 2-methyimidazole complex , the iron atom

Does not move into the plane of the porphyrin , however in 1 methylimidazole
The iron fits
Genetic mutation , Glutamic acid at position 6 in the beta chain
With valine – Hemoglobin S, Sickle cell

Globular protein prevents oxidation

Fe (III) will not bind oxygen

Small amount may be oxidized, Heme is susceptible to oxidation

3% of Hb is in oxidized state, methemoglobon. Methemoglobin reductase

Returns the oxidized form to +2

Nitrite/nitrate intoxication , oxidation

utswmed
Other biological dioxygen carriers

Hemerythrin is a non heme dioxygen carrier- marine vertebrates.

Contains iron in +2 state, which binds oxygen reversibly, but when oxidisded to +3
It does not bind, similar to heme in myoglobin and heamoglobin

Octameric form, eight subunits

A major difference in binding dioxygen with respect to hemoglobin is

Each dioxygen binding site contains two Fe(II) atoms, and the reaction
Takes place via a redox reaction to form Fe(III) and peroxide.

Oxyhemerthrin is diamagnetic , spin coupling of the odd electron on two iron (III)
Atoms.

Mossbauer date reveals two Fe(III) atoms are in different environments

One has peroxide ion coordinating , and differences in the ligands

STRUCTURE OF DEOXY AND OXY HEMERYTHRIN AT 2.0 ANGSTROMS
RESOLUTION 1HMO
Hemocyanin
1NOL
Ferredoxins and Rubredoxins

Rubredoxins , Fe1S0 Ferredoxins, Fe2S

Iron Sulphur Clustes

Iron and cysteine sulfhydrl

and labile sulphide ions
Fe4S4

(RS)4Fe4S4 + 8H+ (RS)4Fe48+ + 4H4S

 Blue Copper Proteins

Electron transfer
1. HS, Tet, Fe(II)/Fe(III) in rubredoxin, Ferrodoxin 2. LS, Oct, Fe(II)/Fe(III) in cytochormes
3. Pseudotetrahedral Cu(I)/Cu(II) in blue copper proteins – stellacyanin, plastocyanin azurin

Plastocyanin

Cu(I), d10, no LFSE in any geometry

Tetrahedral,

In contrast,

Cu(II) d9, octahedrally coordinated

Jahn Teller distortion, to Square

Plastocyanin ,flattened tetrahedral

His, His, Cys, Met

1JXD
Cu(II) oxidizes , to couple two sulfhydryl

2RSH Cu2+ RSSR + 2H+

N4 macrocyclic complex

[N4Cu(II)]2+ + HSCH2CH2COO- [N4CuSCH2CH2COO] + H+

[N4Cu(II)]2+ + [HSCH2CH(CO2CH3)NHCH2]2
Photosynthesis

Splitting of water and reduction of carbon dioxide

2H2O 4H + O2

xCO2 + x/ 2 .{4H] (CH2O)x + x/2.O2

Broad outlines , PSI and PSII

chlorophyll present and in accessory chemicals for processing

Trapped energy of photon

PSI product is reduced Carbon

PSII produces O2.

The energy of an absorbed photon in sytem 1 produces a strong reducing species RED1
And strong oxidizing species OX1

System II produces a stronger oxidizing agent OXII but a weaker reducing agent

OXII is responsible for molecular oxygen

A Mn complex, probably 4 atoms of Mn is present. It reduces OXII

Mn Cubane like and adamantane like configuration.

 carboxypeptidase A

Pancreatic enzyme, carboxyl terminal amino acid is cleaved , hydrolysis amide linkage

Pro-Leu-Glu-Phe H2O/caroboxypeptidase A Pro-Leu-Glu + Phenylalanine

307 amino acids , One Zn2+, 34600

Egg shaped , cleft contains zinc ion

Tetrahedrally , His 69, Glu 72, His 169

4th site accepts a pair of electrons from

The substrate to be cleaved

Arginine side chain moves about 200 pm

Closer to carboxylate group of the substrate

Phenolic group of Tyrosine –hydrogen bond with imido group of C terminal amino acid
STRUCTURE OF CARBOXYPEPTIDASE
1YME
 CARBONIC ANHYDRASE

Catalyse interconversion of CO2 and caronates, One Zn2+

30000 , 3 His , Water /OH

CARBONIC ANHYDRASE

1THJ