Bioinorganic Chemistry

Study of metal species in biological systems

•metal ion transport and storage,

•Metallohydrolase enzymes,

•metal-containing electron transfer proteins,

•oxygen transport and activation proteins,

•bioorganometallic systems such as hydrogenases and alkyltransferases,

•enzymes involved in nitrogen metabolism pathways.

Biological functions of selected metal ions

Metal Function
Na, K Charge carrier, osmotic balance

Mg, Zn Structural, hydrolase, isomerase

Ca Structural, charge carrier

V, Mo Nitrogen fixation, oxidase

Mn Photosynthesis, structural, oxidase

Fe, Cu Dioxygen transport and storage,

electron transfer, oxidase
Ni hydrogenase, hydrolase
Na Mg

K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn

Y Zr Nb Mo Tc Ru Rh Pd Ag Cd

La Hf Ta W Re Os Ir Pt Au Hg

Naturally occurring in biology

Used as probes
Chemical elements essential to life forms can be divided into the following

(i) Bulk elements: C, H, N, O, P, S

(ii) Macrominerals and ions: Na, K, Mg, Ca, Cl, PO43-, SO42-

(iii) Trace elements: Fe, Zn, Cu

(iv) Ultratrace elements comprises of

(a) non-metals: F, I, Se, Si, As, B

(b) metals: Mn, Mo, Co, Cr, V, Ni, Cd, Sn, Pb, Li
 Essentiality of elements is defined by

(1) A physiological deficiency appears when the element is

removed from the diet

(2) The deficiency is relieved by the addition of that element

to the diet

(3) A specific biological function is associated with the element

Every essential element follows a dose-response curve
 At lowest dosages organism does not survive

In deficiency regions, the organism exists with less than

optimal functions

After optimal dosage (plateau region), higher dosage cause

toxic effects in the organism eventually leading to lethality
 Active Site and Enzyme Substrate Complex

The active site of an enzyme is the region that binds the substrate
and contributes the amino acid residues that directly participates
in the making and breaking of chemical bonds

Generalizations

1) Enzymes are usually very large compared to the substrate

Only a small portion is involved in ES complex

Rest portion is involved in control and maintaining of structure

 2) The substrate is bound by relatively weak forces

ΔG E-S complex = (12 to 36) KJ mol-1

(strength of a covalent bond is upto ~ 450 KJ mol-1)

3) Active sites are designed to exclude H2O

Surrounded with non-polar amino acids to create a hydrophobic environment

Essential for substrate binding and product formation (Catalysis)

 Specificity
Active site provides specificity for its particular substrate

Substrate has a matching shape to fit into the active site

(Lock and Key mechanism)

Formation of Enzyme-Substrate Complex is thus crucial to the

product formation
 Evidence for Enzyme-Substrate Complex
(1) At constant [E], increasing the [S] will increase the reaction rate until a
maximum velocity is reached,

(2) Isolation of E-S complex

(3) X-ray diffraction studies of E-S complex

(4) Spectroscopic studies of E-S complex

 Active sites of Enzymes
His(N)
peptide hydrolysis
Zn OH 2 (removes terminal amino
Glu(O) acids f rom proteins)
His(N)

Carboxy peptidase

His(N)

Zn OH2 H 2O + CO H 2CO 3 H + + HCO 3-

His (N)
His(N)
Carboxy anhydrase

Cys(S) NAD+ NADH

Zn OH2
Cys(S)
CH 3CH 2OH CH 3CHO
His(N)
Liver Alcohol dehydrogenase
 Active-Sites of Enzymes
O
O
Hemoglobin CO 2-
CO 2-

N
N CO 2-
CO 2- O2 II
II N Fe N
N Fe N
N
N

Hemocyanin NH
NH HN H Nh
N N
N N N
N
O2 O
CuI CuI
CuII CuII
N O
N N N
N N
HN N
NH N N
N NH H
H H
N
H

Hemerythyrin H
H N
N H O
O NH
H N O N
N O NH
N HN
HN N FeII FeIII
N Fe II
Fe II
O2
N O N
N O
N O O HN
O O
HN N
O O
N H
H
 Porphyrins

Porphyrins are tetrapyrrole macrocycles with conjugated double

bonds and various groups attached to the perimeter

R R

N
R R
NH HN
R R
N

R R

variation of substituents facilitates the tuning of electron-donating and

electron-withdrawing ability of the ligand
The porphyrins can accept two hydrogen ions to form+2 diacids or donate
two protons to form -2 dianions

Porphyrins are found in many metalloenzyme

Enzyme Function

Fe-porphyrin Cytochrome electron transfer

Fe-porphyrin Hemoglobin dioxygen carrier

Myoglobin

Mg-porphyrin Chlorophyll photosynthesis

 Cytochromes
Cytochromes are electron transfer proteins

There are three types of cytochromes depending upon the porphyrin types

cytochrome a, cytochrome b, cytochrome c

s-cys protein s-cys protein

HO HO

N N N
N N N
Fe Fe
Fe
N N N
N N N
O

OH HO OH
HO OH HO O
O O O
O O

a b c
The prosthetic group in all cytochromes comprises of four heme units

They have a molecular weight of about 12,400

Active site differences between Hemoglobin and Cytochrome

O
O S (cys)

N N N N
Fe Fe
N N N N

N N
(His) (His)

Hemoglobin Cytochromes
Depending upon the ligand, the redox potential of a given cytochrome
can be tailored to meet specific need in electron transfer schemes
(photosynthetic versus respiration)

The potentials are such that the electron flow is from

b c a O2

Cytochrome a is capable of binding O2 and reducing them

Cytochrome a is responsible for severe toxicity of CN-

CN- binds to the 6th site and stabilize FeIII to such an extent that it
cannot participate in electron transfer schuttle
 Hemoglobin
O
O

N N N N
Fe II Fe II
N N N N

N N
(His) (His)
High Spin Low Spin
paramagnetic diamagnetic
t2g4 eg2 t2g6 eg0
Deoxyhemoglobin Oxyhemoglobin

Deoxyhemoglobin is the form of hemoglobin without the bound oxygen.

The oxyhemoglobin has significantly lower absorption (660 nm) than
deoxyhemoglobin (940 nm). This difference is used for measurement of
the amount of oxygen in patient's blood by pulse oximeter.
 The size of Fe2+ increase by 28% on going from

Low spin (oxyhemoglobin) (0.61 Å)

to

High spin (Deoxyhemoglobin) (0.78 Å)

The Fe2+ in deoxyhemoglobin is too large to fit in the ring and is

situated (0.7-0.8)Ao above the ring

Thus, presence of O2 changes the electronic arrangement of Fe2+ and

distorts the shape of the complex

The globular protein prevents the irreversible oxidation of Fe(II) to Fe(III)

 Cooperativity
When O2 binds to Fe2+ contracts, moves into plane
one sub-unit of porphyrin ring

triggers conformational
moves the histidine attached to it
changes in the globin chain

translated through Enhances the ability of other

H-bond network three units to bind O2

This phenomenon is
called cooperative effect
In a similar way when the blood reaches the muscle, only one O2 is released,
the others are released even more easily due to the cooperative effect in reverse
picket fence porphyrin