Bioinorg

anic Toxic Elements

Chemist E.g. arsenic, lead, cadmium, mercury

These are also present in the human body

ry (mostly lead) – their toxicity derives from

Classification of the elements in living
systems
Bulk elements (‘organic’) – O, H, C, N, S, P
– these are essential for all organisms and
normally considered the domain of
‘organic” chemistry. They form the
building blocks of proteins, nucleic acids
and carbohydrates. The human body is
mainly water.
Ionic elements – Na+, K+, Mg2+, Ca2+, Cl- -
these are elements normally present as
ions whose roles involved charge
neutralisation. Ca2+ is also structural, in
bone, as the mineral hydroxyapatite.
their ability to replace or destroy the
activity of essential elements.
e.g. mercury binds strongly to sulfur
atoms in proteins and therefore poisons
many enzymes.
Metals in Medicine
e.g. Platinum in cancer chemo, gold for
arthritis.
Proteins and their metal binding
properties
1. Primary structure

Trace elements – those present in small

quantities whose roles are e.g. catalytic or
otherwise specialised.
2. Secondary structure
Main essential roles of metals in humans Helices and Sheets

1. Charge carriers - Na+, K+, Mg2+, Ca2+, 3. Tertiary structure

Cl- The protein fold.
2. Structural e.g. Ca in bone
3. Lewis acid catalysis e.g. Zn2+ in 4. Quaternary structure
enzymes. Larger assemblies
4. Redox catalysis e.g. Fe2+/3+ and
Cu+/2+. Amino Acids and Nucleic Acids
5. Electron transport e.g in Fe-S
clusters 20 naturally occurring amino acids.
6. Gas transport and reactions e.g.
haemoglobin and myoglobin.
A protein chain consists of a single chain
of amino acids linked by peptide bonds,
numbered from the N-terminus.
All natural amino acids are left handed.
These are well known effects of sequence
on structure; homology modelling can be
used to make structure predictions.
4 naturally occurring DNA basis + uracil in
RNA.
A nucleotide chain consists of a single
chain with a phosphate sugar backbone
(polymeric repeat), with the sequence
determined by the order of the four
bases. There are well-known effects of
sequence on structure, as with proteins.
The DNA duplex is right-handed, but there
is also a left-handed double helix.
Alpha helix – creates rods. These can be
joined together by flexible linkers as in the
globin fold, or (for example) packed
together in bundles with the hydrophobic
groups in the interior of the bundle and
hydrophilic groups on the outside.
Tertiary Structure – Protein Folding
The secondary structures of beta-sheet
and alpha-helix are the building blocks of
a typical domain, in which these elements
are found linked by loop regions. A large
protein typically has several such
domains.
The prediction of 3º structure is generally
not possible.
Character of amino acids
Behaviour in water classified by the
properties of the sidechain.
Zinc
Nature’s lewis acid.
A subtle regulatory switch.
Typically, 4 or 5 coordinate, typically
bound by glutamate, histidine or cysteine
ligands. Wider variety of amino acid
ligands (in the hard/soft sense) than e.g.
copper.
Typically, tetrahedral coordination.
Function doesn’t involve more than one
oxidation state.
Carbonic anhydrase is an example of a
zinc containing enzyme.
Iron
Fe(II) and Fe(III)
Essential for almost all species. Deficiency
causes anaemia, excess causes heart
disease.
Has to be tightly controlled as high spin
Fe(II) + 3O2 -> Fe(III) + O2-. Life evolved in
the absence of O2: living systems make
use of Fe(II), the much more soluble form
of iron than Fe(III).
Ferritin
The major iron storage protein in humans.
Mw 444 kDa
13% of body iron (haemoglobin is 65%).
Up to 4500 iron atoms in one ferritin
particle, an example of biomineralization.
Iron is stored as hydrated iron oxide. The
chemical synthesis of iron-oxo metal
clusters has been used to make chemical
models for the storage of iron in the
natural system.
EXAFS shows double layers of
approximately close packed O2- and [OH]-
ions.
Interstitial sites between the layers are
occupied by Fe3+ ions.
Phosphates link the protein shell and this
iron oxide core.
Iron likely goes in and out as Fe2+.
Ferritin Crystals
Converts soluble Fe2+ to Fe3+ for storage,
and reverses this to release the iron. Easy
to crystallise apoferritin (the iron-free
form).
The iron inside is not perfectly crystalline,
unlike the protein.
The outer coat of ferritin, which has 24
identical subunits around a central core of
iron oxide about 75 Å, overall diameter
about 120 Å. There are 2 sorts of channels
in this structure. It seems more likely that
the carboxylate ions of asp and glu are
involved in iron transport than the
hydrophobic leu.
Transferrins transfer iron
Binding of tyrosyl(x2), histidine, aspartate
and a bidentate CO32- ion by a member of
the iron transport protein transferrin
family.
They are glycoproteins, can have serum
transferrins, milk transferrins and egg
white transferrins.
Serum transferrin is a blood plasma
protein, and CO32- is the pH buffering ion
in plasma.
The human serum protein has two
domains and is hinged, binds 2 Fe3+. This is
a ‘hard’ metal centre. Very high stability
constant for bound iron. Release
mechanism must involve the hinge.
Functions of Iron
- Redox Catalysis
- Electron transport
- Gas transport and reactions e.g.
haemoglobin and myoglobin.
Oxygen binding by haemoglobin and
myoglobin
In humans – oxygen transport is by
haemoglobin, and storage in muscle is by
myoglobin.
Reduction of the oxygen molecule takes
place through a series of single electron
steps, as electrons are added to the π*
orbital.
O2- is the superoxide ion – bond order 1.5
O22- is the peroxide ion – bond order 1
2O2- + 2H+ -> H2O2 + O2
Superoxide is a dangerous free radical and
is destroyed in the body by
disproportionation catalysed by
superoxide dismutases (SODs).
Characteristics of haemoglobin and
myoglobin
Myoglobin – the oxygen acceptor in
muscle, a single protein chain, Mw ~
17,500, 151 amino acids.
Hemoglobin – the link between gaseous
oxygen in the lungs and oxygen storage in
muscle, 4 protein chains (2 alpha and 2
beta), total Mw ~64,500. 141 (alpha) and
146 (beta) amino acids.
Each chain binds one heme unit and
therefore one O2 molecule.
Since oxygen is transferred to myoglobin
in the lungs, myoglobin must have a
higher oxygen affinity than haemoglobin.
Both proteins contain the heme unit.
Heme has a fixed diameter and is a rigid
planar tetra-coordinating ligand.
In deoxyhemoglobin, the iron is 5-
coordinate with a 6th vacant site, and the
iron is high spin (+2), with 4 unpaired
electrons. In this spin state, it is too large
to fit perfectly in the heme ligand. The
fifth ligand, histidine, connects to a helix
in the protein.
When oxygen binds, to give
oxyhemoglobin, it remains essentially as
an O2 molecule, it is not reduced.
However, the iron becomes smaller and
fits perfectly into the heme ligand. It is
now (+2) low spin iron which is smaller
because no electrons point directly at the
ligands. The histidine ligand therefore
moves, taking it with the helix, and
triggering a series of movements in the
globin protein which ultimately lowers the
O2 affinity.
The iron-sulfur proteins
Ubiquitous small proteins – found in
everything from humans to primitive
microorganisms.
Key biological reducing agents.
Building blocks – tetrahedral iron, S2-.
Mixed oxidation state iron – typically as
2Fe or 4Fe clusters.
Similar molybdenum-containing system in
nitrogenase (without which, biological
nitrogen fixation would be impossible).
Copper
Both oxidation states good for binding to
organic molecules.
Redox potential between Cu(1+) and
Cu(2+) is in the right range. A good fit to
biological systems.
Cu(+1) can also π-bond e.g. to oxygen.
Copper protein functions
1. Electron transfer with either an
outer sphere mechanism, or
functioning as an inner-sphere
reductase, both involving the
Cu(I)/Cu(II) couple.
2. Mono- terminal-oxidases which
form either water or hydrogen
peroxide from dioxygen.
3. Oxygenases, which incorporate an
oxygen atom into a substrate.
4. Superoxide degradation to form
dioxygen and peroxide.
5. Oxygen transport in some lower
organisms.
Platinum in Medicine
- Still one of the most important
drugs in the clinic.
- Discovered by accident.
- Now known that Pt bends DNA
and changes binding affinity of
proteins in the minor groove.
- Main binding site is the adjacent
N7 atoms of 2 adjacent guanine
bases, which forces bending.
Kinetically stable once bound.