Download Inorganic elements of interest in biology and medecine

Inorganic elements of interest in biology and medecine
(respiration, metabolism, photosynthesis,, nerve transmission, muscle contraction….)
Na
Mg
K
Ca
V
Y
Cr
Mn
Mo
Tc
Fe
Co
W
Yellow: naturally occurring metals
Blue: metals introduced as drugs and diagnostic probes
Ni
Pt
Cu
Zn
Ag
Cd
Au
Hg
Biological functions of inorganic elements
Inorganic elements carry out important and otherwise not
guaranteed functions. They are listed below:
structural function (Ca2+ and Mg2+ for DNA polyanion)
charge carriers for fast information transfer (Na+, K+, Ca2+ for
electrical impulses in nerves, muscles contraction)
formation, metabolism and degradation of organic compounds.
These functions often require Lewis acid/base catalysis (Zn2+ in
hydrolytic enzymes)
electron transfer for energy conversion. This function requires
redox active metal centers (FeII/FeIII/FeIV, CuI/CuII, CoI/CoII)
Coordination complexes constituted by metal ions and bioligands are often
biologically relevant: metal ions are Lewis acid sites able to accept lone pairs
coming from the ligand which acts as a Lewis base.
Biological ligands for metal ions
Bioligands can be grouped in three main classes:
1) Peptides (proteins) with amino acid side chains
for coordination
2) Macrocyclic chelate ligands
3) Nucleobases (nucleic acids)
Biological ligands for metal ions: 1) proteins
Aminoacid
R
Aminoacid
N
histidine
methionine
cysteine
R
tyrosine
CH2
CH2CH2SCH3
aspartate
CH2COO
CH2SH
glutamate
CH2CH2COO
CH2
OH
N
-
-
Typical coordination numbers are 4 and 6: it often occurs that coordination with
aminoacidic residues is not complete. This is fundamental for the catalytic activity of
enzymes because an open site remains available for coordination of the substrate.
On the contrary, this situation does not occur if the protein function is exclusively that
of transferring electrons.
Biological ligands for metal ions: 1) proteins
The role of proteins are numerous:
-Act as multidentate chelate ligand (via amino acid side chains)
-Provide spatial fixation
-Serve as a medium with defined dielectrical properties
Biological ligands for metal ions: 2) tetradentate macrocycles
Ring is planar (sp2 ibridation)
N H
N
H
N
N H
N
N
porphyrin
N
N
H
N
N
chlorin
(2,3 dihydroporphyrin)
N
Tetrapyrrol macrocycles are
selective with regard to size of
metal ion
They are the “pigments of life” with
intense absorption bands in the
visible region.
Two axial positions remain
available: e.g. heme group
N
M
NH
N
N
X
N
N
corrin
metalloporphyrin complex
N
M
N
N
Y
Biological ligands for metal ions: 2) multidentate macrocycles
Coordination of Na+, K+,
Mg2+, Ca2+
Multiple heteroatoms are
strategically positioned for
bonding metal ions
ring size is tailored to fit
metal ionic radius
Dissociation is possible but
very unlikely
Inner cavity is polar,
outside is lipophile. So these
complexes can be
transported through
biological membranes.
Biological ligands for metal ions: 3) nucleobases
amino
amido
NH2
N
N
imine
N
HN
N
N
NH2
O
R
N
O
R
adenine
guanine
O
cytosine
HO
hydroxo
HN
N
N
R
O
R' = CH3 thymine
R' = H uracil
NH
NH2
N
N
R
R
R = ribose or deoxyribose
NH
R'
HN
N
N
N
H2N
O
N
R
O
N
R
oxo
Nucleobases can exist in different tautomeric forms and can be mono or multidentate ligands.
Positively charged metal ions can affect the normal hydrogen-bond interactions that are the basis of
base pairing in DNA. This can be exploited for the development of chemotherapic drugs
Thermodynamic aspects: 1) hard-soft concept
Metals (acids)
Hard
H+
Cr3+
Na+
Co3+
K+
Mg2+
Mn2+
Ca2+
Al3+
Fe3+
Ligands (bases)
Hard
H2O
CO32OHNO3RNH2
CH3CO2ROH
PO43Cl-
Borderline
Fe2+
Ni2+
Zn2+
Co2+
Cu2+
Borderline
NO2SO32Imidazole
Soft
Cu+
Pt4+
Hg2+
Pb2+
Soft
R2S
RSH
RNC
SCN-
Pt2+
Au+
Cd2+
RSCNCO
NH3
Hard metal is small and not
easily polarized. Fe3+ is
harder than Fe2+.
RO-
Br-
R3P
Soft metal is large and
easily polarizable.
The general rule is
that hard metals bind
preferentially hard
ligands and soft
metals to soft
ligands.
Hard-soft concept: metallothioneins
30-35% of aminoacids are
cysteins with soft –SH
groups
coordination of soft heavy
metal ions such as Cd2+,
Hg2+, Pb2+, Zn2+.
biological function of
metallothioneins is to protect
cells from toxic heavy metals
Thermodynamic aspects: 2) chelate effect
[Co(H2O)6 ]3+ + EDTA4COO-OOC
N
N
COO-
-OOC
EDTA
DG° = DH - TDS°
DG° = - RT lnK
Metal chelate complexes are very
stable, because there is a favourable
entropic factor accompanying the
release of non chelating ligands
[Co(EDTA)] - + 6H2O
Examples
of
chelates
Thermodynamic aspects: 3) pKa values of coordinated ligands
Reaction
H2O + M2+
[M-OH]+ + H+
Metal ion
water pKa
none
14.0
Ca2+
13.4
Mn2+
11.1
Cu2+
10.7
Zn2+
10.0
When coordinated to Zn2+, water is 10.000 times more acid than when it is free!!!!
Zinc enzymes: the example of carbonic anhydrase
in an enzymatic system, deprotonation of a coordinated water to form an hydroxo
ligand is a fundamental step of many hydrolytic mechanisms. The pKa value drops
to 7!!!
2+
Zn
2+
OH2
2+
Zn
+
OH
+ H+
pKa = 7
The role of zinc in carbonic anhydrase
zinc has a d10 configuration (non redox)
it has strong Lewis acidic properties
it binds water in a very labile way.
Carbonic anhydrase accelerates the following reaction of a factor of 107
H2O + CO2
HCO3- + H+
Carbonic anhydrase: mechanism
Zinc is coordinated
to three histidine
residues and H2O.
His 96
+
Zn
His64 has an
important role in the
polarization of the
O-H bond and in the
formation of Znhydroxide species
His 96
+ CO2
O
- CO2
His 94
Geometry is
distorted tetrahedral
Deprotonation of
water molecule is
essential for the
nucleophilic attack
to CO2.
H
His119
His 94
His119
N
N
H
BH+
+
Zn
H
O
O=C=O
His64
Thr 199
B
His 96
His 96
+
Zn
His 94
His119
H
His 94
O
O
O
O
His119
+
HN
N
H
+
Zn
H
His64
H2O
HCO3-
His 96
2+
Zn
His 94
H
O
H
His119
His64
N
N
H
Thermodynamic aspects: 4) tuning of redox potentials
Compound
name
E1/2, V
(Cu2+/Cu+)
R
O
N
Cu
O
N
Cu(O-sal)2en
-1.21
R
Cu(R-sal)2
Cu(Me-sal)2
-0.90
Cu(Et-sal)2
-0.86
-0.83
Cu(i-Pr-sal)2
-0.74
Cu(t-Bu-sal)2
-0.66
Cu+ prefers
tetrahedral fourcoordinate
geometries.
High redox potentials are achieved by the proteins
containing copper through distortion of the coordination
geometry
X
X
Cu(S-sal)2en
Cu2+ is typically
square-planar.
Cu
N
N
Cu+ is softer
than Cu2+
Cu(X-sal)2en
X = O or S
High redox potentials are achieved by the
proteins containing copper through the use of soft
donor ligands.
Thermodynamic aspects: 5) biopolymer effects
Biopolymer affects the thermodynamic stability of a
metal center, since it can control, through its three
dimensional structure,
-Stereochemistry
-Ligands available for coordination
-Local hydrophilicity and hydrophobicity
-Steric blockage of coordination sites
-Hydrogen bonding formation
These considerations are very important in order to
understand how metals function in biology