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Bioinorganic and Environmental Chemistry16
26 main players in biological systems
What are the roles of these guys?
92 players in the nature (Earth)
Key roles of metal ions in biology
Metal Ions Roles
Na+, K+ charge carriers, osmotic and electrochemical balance across cell
membranes
Mg2+, Ca2+ enzyme activators, act as structure promoters and Lewis acids.
Fe, Cu, Mo redox (electron-transfer) proteins and enzymes involving Fe(III)/Fe(II),
Cu(II)/Cu(I), Mo(VI)/Mo(V)/Mo(IV). Oxygen carrying proteins of iron
and copper. Nitrogen fixation by Fe/Mo (V) containing nitrogenase
enzymes
Zn structure promoter, Lewis acid
:
Basics – Characteristics of life
살아있는기관의특성
• 구조적으로복잡하고, 고도로정리조직되어있다.
• 주위환경으로부터에너지를추출, 변환, 사용한다.
• 정밀하게자기복제와자기조립하는능력을가지고있다.
생명현상의분자적논리
• 다양한기관들은공통의화학적특성을갖는다.
• 같은구조적기본단위를가지고있다.(세포)
• 같은종류의고분자를가지고있다.(DNA, RNA, 단백질)
• 고분자들은같은종류의단분자단위로만들어져있다.(nucleotide,
amino acid)
Basics – Cell
단백질(protein)
The players of life
탄수화물 핵산(nucleaic acids)
The playground
Basics – Proteins
일차구조(primary structure):
단백질사슬의아미노산순서
이차구조(secondary structure): 단백질안의부분적구조로서아미노산이규칙으로배열되어있는인a-helix 와 b-sheet 등의구조
삼차구조(tertiary structure):
단백질의전체모양
사차구조(quaternary structure):
여러단백질의집합체
Basics – Nucleic acids
DNA (deoxyribonucleic acid): 유전정보를저장, 전달. 단백질합성(RNA와함께)에관여 (분자량 = 수백만)
RNA (ribonucleic acid): 단백질합성에관여 (분자량 = 20,000 ~ 40,000)
핵산의단위체: 뉴클레오타이드(nucleotide)
3. 인산(H3PO4)
Ribose (a pentose)
1. Deoxyribose for DNA and ribose for RNA
2. N을포함하는유기염기
Basics – Nucleic acids
nucleoside
nucleotide
CH2
CH2
Base
O
HO
HH
HH
O
PO
OH
OH
Base
O
HOH
HH
HH
O
PO
OH
OH
H
Dimerization
H2O
Base
O
HO
HH
H
CH2
H
O
PO
OH
OH
Base
O
HOH
HH
H
CH2
H
O
PO OH
뉴클레오타이드
의형성
Polymerization
Porphyrin and related – Heme
metalloporphyrine
heme
Cytochrome c
Hemeproteins
Oxygen transport – hemoglobin, myoglobin, neuroglobin,
cytoglobin, leghemoglobin
Catalysis - cytochrome P450s, cytochrome c oxidase,
ligninases, peroxidases
Electron transfer/transport - cyctochrome a, cytochrome b,
cytochrome c
Defense -catalase
Porphyrin and related – Hemoglobin, Myoglobn
heme
Hemoglobin (a2b2)
[oxygen transport]
Myoglobin
[oxygen storage]
Porphyrin and related – Hemoglobin, Myoglobn
O2 binding to heme (structure and spin)
high spin Fe(II) low spin Fe(II)
Porphyrin and related – Hemoglobin, Myoglobn
O2 binding to hemoglobin (corperative)
Hb + O2 ←←HbO2
HbO2 + O2 ←←Hb(O2)2
Hb(O2)2 + O2 ←←Hb(O2)3
Hb(O2)3 + O2 ←←Hb(O2)4
K1 = 5 to 60
K4 = 3000 to 6000
D. E. Benson, Wayne State
University
Mb + O2 ←←MbO2
Porphyrin and related – Hemoglobin, Myoglobn
O2 binding to hemoglobin (allosteric, Bohr effect)
CO2 + 2H2O → HCO3- + H3O
+←←
Relation of hemoglobin's oxygen binding affinity – acidity and carbon dioxide concentration
pH ↑
Porphyrin and related – Catalases
Catalase (a4)
2 H2O2 → 2 H2O + O2
H2O2 + Fe(III)-E → H2O + O=Fe(IV)-E(.+)
H2O2 + O=Fe(IV)-E(.+) → H2O + Fe(III)-E + O2
Proposed mechanism J. AM. CHEM. SOC. 2009, 131, 11751–11761
Porphyrin and related – Peroxidases
H2O2 + 2SH → 2 H2O + 2S
Glutathione peroxidase
Haloperoxidase
Myeloperoxidase (MPO)
Catalase
Thyroid peroxidase
Vanadium bromoperoxidase
Lactoperoxidase
Reaction cycle of peroxidase. (a) Classical
peroxidase chemistry. (b) Oxygen-transfer rection. S
represents the substrate
Porphyrin and related – Peroxidases
Glutathione peroxidase
Haloperoxidase
Myeloperoxidase (MPO)
Catalase
Thyroid peroxidase
Vanadium bromoperoxidase
Lactoperoxidase
H2O2 + 2SH → 2 H2O + 2S
Porphyrin and related – Cytochromes
Membrane-bound (i.e. inner mitochondrial membrane) hemeproteins containing heme groups.
Primarily responsible for the generation of ATP via electron transport.
Cytochrome a – heme a
Cytochrome b – heme b
Cytochrome c
Cytochrome P450 – strong absorption at 450 nm
detoxification in liver
:
Human Cytochrome P450 2E1
R-H + O2 + 2e- + 2H+ R-OH + H2O
Chem. Rev. 2004, 104, 3947-3980
Porphyrin and related – Photosystems
Chloroplast
Chloroplast ultrastructure:
1. outer membrane
2. intermembrane space
3. inner membrane (1+2+3: envelope)
4. stroma (aqueous fluid)
5. thylakoid lumen (inside of thylakoid)
6. thylakoid membrane
7. granum (stack of thylakoids)
8. thylakoid (lamella)
9. starch
10. ribosome
11. plastidial DNA
12. plastoglobule (drop of lipids)
Porphyrin and related – Photosystems
Z-Scheme
2 H2O + 2 NADP+ + 3 ADP + 3 Pi + light → 2 NADPH + 2 H+ + 3 ATP + O2
Other Fe Proteins - Ferredoxins ([Fe-S] proteins)
acidic, low molecular weight, soluble iron-sulfur proteins found in various organisms, and act as
multifunctional electron carriers in diverse redox systems
Rieske FeS
Low-potential FdsHiPiP Fds
Other Fe Proteins – Ferritin
Ferritin: intracellular iron-storage protein
– up to 4,500 Fe atoms
a24
Storage: Fe3+ forms
Removal: reduction to Fe2+ and chelation
Transferrin: transports iron through the blood to the
liver, spleen and bone marrow.
two specific high-affinity
Fe(III) binding sites
Zn Proteins – Carboxypetidase
hydrolyzes a peptide bond at the
carboxy-terminal (C-terminal) end of a
protein or peptide
Cu Proteins
Type-1 Type-2
• “blue copper protein”
• electron transfer
• “normal copper protein”
• tetragonal Cu(II)
• less intense than T1
• 600 nm: Cu(II) d-d transition
• catalysis
Cu Proteins
Type-3 Type-4 (T2/T3) CuA
CuB
• reversible binding of O2
• Oxy form: Cu(II)-Cu(II)
Mixed-valence Cu(II)-Cu(I) in oxidized state
CuZ
Cu Proteins - Ceruloplasmin
• copper-carrying protein in the blood, and in addition plays a role in iron metabolism
• carries more than 95% of the total copper in healthy human plasma
a2 T4 copper center
Nitrogen Cycle - Nitrogenase
2
3
4
Fe1 X
7
6
5
Mo
a-442His
a-275Cys
R-homocitrate
2
3
4
Fe1 X
7
6
5
Mo
a-442His
a-275Cys
2
3
4
Fe1 X
7
6
5
Mo
a-442His
a-275Cys
R-homocitrateN2 + 8H+ + 8e- + 16ATP
→ 2NH3 + H2 + 16ADP + 16 Pi
Nitrogen Cycle - Nitrogenase
M
N
N
M
N
NH
M
N
NH2
M
N
M
NH
M
NH
NH
M
NH
NH2
M
NH2M
NH2
NH2
M
NH3
NH3
NH3
NH3
D A11
55
33
Nitrogen Cycle – Nitrite Reductase
NO2- → NO → N2O → N2
Cu-containing Nitrite reductase
Fe-containing Nitrite reductase
Cu-containing Nitrite reductase
a3
Nitrogen Cycle – Nitrite Reductase
Cytochrome cd1 Nitrite reductase
a2
Heme c Heme d1
Heme b
Containing c-type cytochrome (for electron transfer)
and d1-type cytochrome (for substrate reduction)
Nitrogen Cycle – Nitrite Reductase
Cytochrome cd1 Nitrite reductase
Dalton Trans. , 2005, 3410–3418
Proposed mechanism
NO2- → NO
Nitrogen Cycle – Nitrite Reductase
Cytochrome c Nitrite reductase
a2
Containing 5 c-type hemes (per a)
Proposed mechanism
NO2- + 6e- + 7H+ → NH3 + 2H2O
NO – NO Synthase
NOS
endothelial NOS (eNOS)
inducible NOS (iNOS)
constitutive NOS (cNOS)
neural NOS
(nNOS)
iNOS
NO – NO Synthase
Schematic structure of the active site
of NHA-bound murine iNOS. NHA is
shown in bold.
H4B
(Tetrahydrobiopterin)
Current Opinion in Chemical Biology 2000, 4:687–695
NOS reactions
NO – NO Synthase
Proposed nucleophilic
hydroperoxoFe(III)heme mechanism
for the NOS-catalyzed oxidation of
N-hydroxyarginine. PPIX,
protoporphyrin IXCurrent Opinion in Chemical Biology 2000, 4:687–695
NO – NO Synthase
Proposed radical-type
autoxidation
mechansim of the NOS-
catalyzed oxidation of
NHA. Ellipses denote the
heme group.
P, peroxyFe(III)heme
intermediate.
Current Opinion in Chemical Biology 2000, 4:687–695
Metals in Medicine – History
2500 BC : Au, Ag in medical potion
15-16 C : Hg to treat syphilis
18 C : Bi for dyspepsia
1890 : Observation of the bactericidal action of gold cyanide, K[Au(CN)2]
1910 - 20 : Arsenic, bismuth compounds were used to treat syphilis
1930s : Gold drugs were used to treat rheumatoid arthritis
1964 : Barnett Rosenberg discovered the anticancer activity of cisplatin
1971 : Radiopharmaceutical technetium compound [99mTeO4]-
1979 : Auranofin for arthritis
1984 : Gd[DTPA]2- for MRI contrast agent
1993 : 153Sm-EDTMP for bond pain
Current medical practice
Therapeutic : gold drugs (rheumatoid arthritis), lithium (depression), platinum (cancer), bismuth
(stomach ulcers), vanadium (diabetes), iron (anaemia, blood pressure), cobalt (pernicious
anaemia)…
Diagnostic : imaging applications, In addition to technetium, radioactive forms of thallium, gallium and
indium are also used routinely for diagnostic imaging purposes.
Metals in Medicine – Cisplatin and related
Pt NH3Cl
NH3
Cl
Pt ClCl
NH3
NH3
cisplatin transplatin
Action
1. Hydrolysis of cisplatin
Cl- concentration
In blood, 100 mM
In cell, 3 mM
Metals in Medicine – Cisplatin and related
Action
2. Cisplatin binding to DNA 3. Kink of DNA 4. HMG binding to DNA
5. Cell death
excision repair
cell lives
Metals in Medicine – Cisplatin and related
Structure Activity Relationships (SAR)
1. A cis geometry is required with the general
formula cis-[PtX2(amine)2] for Pt(II), and
for Pt(IV) the formula cis-[PtX2Y2 (amine)2].
Monofunctional binding cationic complexes
are inactive.
2. The X ligands (leaving groups) should be of
intermediate strength (Cl-, SO42-,
carboxylate ligands). For Pt(IV) complexes
the Y ligands should have a trans
orientation and can be Cl-, OH-, or
[O(CO)CnH2n+1]-.
3. The non-leaving group amine ligands
should contain at least one NH moiety,
necessary for hydrogen-bonding
interactions with DNA (H-bonding to the
O6 of guanine and to the 5’ phosphate
group).
PtO
O
NH2
H2NPt NH3
NH3
O
C
C
O
O
O
PtO
C
CC
O
O
O NH
H2N
PtIV
ClH3N
O
ONH2
Cl
C
O
C
O
Oxaliplatin CBDCA; Carboplatin
DWA 2114R JM216
O
O
Pt anticancer compounds satisfying SAR
Pt
Cl
ClN
N
O
O
O
O
Pt
N
ClH2N
H2NPt
NH
ClNH
Cl
O
O
Pt anticancer compounds violating SAR
Metals in Medicine – Bleomycin
Anticancer activity by induction of DNA strand cleavage. DNA cleavage by bleomycin depends on
oxygen and metal ions.
Metals in Medicine – Antiarthritic drugs
Metal complexes as cysteine protease inhibitors (PCT/US1996/015527)Harry B Gray, Mark W Grinstaff, Thomas J Meade
Study of DNA using Inorganic Agents
Chemistry study - DNA is too big to be directly studied in molecular level.
Breaking DNA (or RNA) to be investigated
Binding to specific sites of DNA and using Fenton reaction
1-(p-bromoacetamidobenzyl)-EDTA Fe(II) [Cu(phen)2]+
Mn+ + H2O2 → M(n+1)+ + OH- + •OH