a snapshot of bioinorganic...
TRANSCRIPT
![Page 1: A snapshot of bioinorganic chemistryweb.chemistry.gatech.edu/~barefield/1311/bioinorganic_s09.pdf · of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994. 2 αchains](https://reader030.vdocuments.us/reader030/viewer/2022040414/5f25db028b62640d4177b35f/html5/thumbnails/1.jpg)
A snapshot of bioinorganic chemistry
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Biological periodic table
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The diverse coordination chemistry of the d block elements allows metallobiomolecules to be tuned for a wide array of biological functions.
Metallobiomolecules
Fe
CuMgCa, SiZn, Hg
Adapted from Fenton, D.E. Biocoordination Chemistry, Oxford Univ. Press, Oxford, UK, 1995, p. 4
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Metalloenzymes
Enzymes are proteins that catalyze chemical reactions.
Fe, CuFe, Cu, Mo
Fe, Cu, Mn
Fe, Mo, VFe, NiFe, Cu Fe
Co
Zn, MgZn, Cu, MgZn
Adapted from Fenton, D.E. Biocoordination Chemistry, Oxford Univ. Press, Oxford, UK, 1995, p. 4
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Heme-based oxygen carriers: hemoglobin and myoglobin
N
NN
N
Fe
CO2-
CO2-
iron protoporphyrin IX
N
N CO2H
NH2
H
histidine
Adapted from Lippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.
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Comparison of crystal field splittings for octahedral, square planar and tetrahedral
ligand fields
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Crystal field splittings in lower symmetries
eg
t2g dxydxz dyz
dx -y 2 2
dz2
L
M
L
L L
LL
X
M
X
L L
LLM
L L
LL
Octahedral Square planarTetragonal
dx -y 2 2
dz2
dxydxz dyz
Square-pyramidal
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Schematic structure of myoglobin• Hemoglobin consists of 4 similar
subunits
• Hemoglobin takes dioxygen from the air (lungs) and transports it via blood to myoglobin in tissue
• In resting state the iron atom is five-coordinate and is located ca. 0.4 D above the plane of the macrocyclic ligand
• In the oxy-form the iron is in the plane; O2 is end bound with an Fe-O-O angle of ca. 115E
• Free heme complexes CO 2x104
more tightly than O2; only 2x102
in proteinAdapted in part from Lippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.
2 α chains – 141 aa
2 β chains – 146 aa
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Sickle cell anemia – genetic disorder in which the sixth amino acid in the β chain of the normal protein, glutamate, is substituted by valine. This results in severe distortion of the red blood cells under conditions of oxygen stress. Imparts malaria resistant to carriers.
HO OH
OO
NH2
OH
NH2
O
Bottom images fromhttp://en.wikipedia.org/wiki/Sickle-cell_diseaseand Blood, 1973, 41,653
Genetic defects in hemoglobin synthesis
normal blood cell
“sickled” blood cell
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Thalassemia (Cooley's anemia) – genetic disorder that results in reduced or even no production of the β protein chain in hemoglobin, which means limited production of functional adult hemoglobin. This results in severe distortion of the red blood cells under conditions of oxygen stress.
Genetic defects in hemoglobin synthesis
• Those afflicted are dependent on blood transfusions which create problems with iron overload.
• Chelation therapy with siderophoreanalogs help to reduce the problem.
• There is currently no cure, only treatment.
Graphic fromhttp://en.wikipedia.org/wiki/Sickle-cell_disease
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Non-heme oxygen carriers
hemocyanin(mollusks & anthropods)
hemerythrin(sea worms)
Adapted from Lippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.
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Ferredoxins: Fe-S proteins for e- transport
2-, 1-
3-, 2-
3-, 2-, 1-
3-, 2-
Adapted from Wilkins and Wilkins. Inorganic Chemistry in Biology, Oxford Univ. Press, Oxford, UK, 1997, p. 41
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Respiratory electron transport chainADP + HOPO3
2- ADP + HOPO32- ADP + HOPO3
2-
e- e-
Figures from Shriver & Atkins, Inorganic Chemistry, 3rd and 4th editions
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Vitamin B12 coenzyme: a naturally occurring organometallic compound
HO SR
O O
CH3
HOS
R
O
O
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Ligands for treatment of disease
Desferrioxamine BThalassemia (Cooley’s anemia)(excess iron)
H3N+ NN
O
OOH
H
NHOONN
O
OH
O
H
Structure from “Coordination chemistry and biology of chelators for the treatment of iron overload disorders”Bernhardt, P.V. Dalton Trans. 2007, 3214
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Ligands for treatment of disease
Deferasirox (Cooley’s anemia)
Exjade® (Norvatis)
FDA approved 2005
HS OH
NH2
O
D-penicillamineWilson’s disease(excess copper)
Structure from “Coordination chemistry and biology of chelators for the treatment of iron overload disorders”Bernhardt, P.V. Dalton Trans. 2007, 3214
Structure of iron complex of analog of A) without the carboxyl group
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“A considerable part of O2 metabolized by the human organism is converted by one-electron reduction to the highly reactive superoxideradical anion, O2
.-. Sources of superoxide include leaks in the cytochrome c oxidase mediated O2-to-H2O transformation pathway in mitochondria, various autooxidation reactions (e.g. of glutathione in red blood cells) but also the controlled production of O2
.- by membrane-bound NAD(P)H oxidase in phagocytes to support immune defense against bacterial and fungal infections.”
“The Pharmaceutical Potential of Manganese-Based SuperoxideDismutase” Mimics Roland Krämer Angew. Chem Int. Ed. 2000, 39,4469.
The enzyme superoxide dismutase has been used to treat arthritis, inflammation and the side-effects of radiation treatment. Superoxide dismutase mimics have been developed for the treatment of many diseases which involve an excess of superoxide.
Metal compounds for treatment of disease
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Metal compounds for treatment of disease
PtH3N Cl
ClH3N
cis-Platin(anticancer)
O
Ti
O
O O
OO
Ph
Ph
O
Ti
O
O O
OO
Ph
Ph
O
Ti
O
O O
OO
Ph
Ph
19% 21% 60%Budotitane(anticancer)
Au P(CH2CH3)3
O S
OO
O
O
O
OO
O
Auranofin (antiarthritis)
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Diagnostic nuclear medicine (radiopharmaceuticals)
N
N N
N
O H O
TcO
N
N
N
O
O-
O-O O O-O-O O -O
DTPA Tc(O)HAMO
99mTcO4- 99TcO4
- (β, t1/2 = 2.1 x 105 y)γ (140 keV)
t1/2 = 6 h
{Tc[CNCH(CH3)2OCH3]6}+
Tc99mMIBI
brain blood flowrenal function myocardium imaging
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HOMO’s and LUMO’s for CH3CN, methylcyanide, and CH3NC, methylisocyanide
CH3CN
CH3NC
HOMO LUMO