92 players in the nature (Earth) 26 main players in biological systems What are the roles of these guys? 16 Bioinorganic and Environmental Chemistry
Key roles of metal ions in biology Metal Ions Na +, K + Mg 2+, Ca 2+ Fe, Cu, Mo Zn : Roles charge carriers, osmotic and electrochemical balance across cell membranes enzyme activators, act as structure promoters and Lewis acids. redox (electron-transfer) proteins and enzymes involving Fe(III)/Fe(II), Cu(II)/Cu(I), Mo(VI)/Mo(V)/Mo(IV). xygen carrying proteins of iron and copper. Nitrogen fixation by Fe/Mo (V) containing nitrogenase enzymes structure promoter, Lewis acid
Bioinorganic Chemistry - Interdisciplinary subject Bioinorg. Chem Spectrocopy
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
Basics Proteins 일차구조 (primary structure): 단백질사슬의아미노산순서 이차구조 (secondary structure): 단백질안의부분적구조로서아미노산이규칙으로배열되어있는인 a-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) 1. Deoxyribose for DNA and ribose for RNA 2. N을포함하는유기염기 3. 인산 (H 3 P 4 ) Ribose (a pentose)
Basics Nucleic acids Polymerization 뉴클레오타이드 의형성 nucleoside nucleotide H 2 H P H CH 2 H H H H Dimerization Base H H H H P H CH 2 H H H H Base H P H CH 2 H H Base P H CH 2 H H Base H H H H H H H H
Basics Nucleic acids (DNA) A-DNA B-DNA Z-DNA DNA
Basics Nucleic acids (RNA) mrna rrna trna snrna sirna mirna rasirna piwirna
Metal ions in metalloenzymes
Porphyrin and related porphine metalloporphyrine chlorin corrin
Porphyrin and related Heme Hemeproteins metalloporphyrine heme xygen 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 Cytochrome c
Porphyrin and related Chlorin, Corrin chlorin Chlorophyll a corrin Coenzye B12 (Vitamin B12)
Porphyrin and related Hemoglobin, Myoglobn heme Hemoglobin (a 2 b 2 ) [oxygen transport] Myoglobin [oxygen storage]
Porphyrin and related Hemoglobin, Myoglobn 2 binding to heme (structure and spin) high spin Fe(II) low spin Fe(II)
Porphyrin and related Hemoglobin, Myoglobn 2 binding to hemoglobin (corperative) Hb + 2 Hb 2 + 2 Hb( 2 ) 2 + 2 Hb 2 Hb( 2 ) 2 Hb( 2 ) 3 K 1 = 5 to 60 Mb + 2 Mb 2 Hb( 2 ) 3 + 2 Hb( 2 ) 4 K 4 = 3000 to 6000 D. E. Benson, Wayne State University
Porphyrin and related Hemoglobin, Myoglobn 2 binding to hemoglobin (allosteric, Bohr effect) Relation of hemoglobin's oxygen binding affinity acidity and carbon dioxide concentration C 2 + 2H 2 HC 3- + H 3 + ph
Porphyrin and related Catalases Catalase (a 4 ) 2 H 2 2 2 H 2 + 2 Proposed mechanism J. AM. CHEM. SC. 2009, 131, 11751 11761 H 2 2 + Fe(III)-E H 2 + =Fe(IV)-E(.+ ) H 2 2 + =Fe(IV)-E(.+ ) H 2 + Fe(III)-E + 2
Porphyrin and related Peroxidases Glutathione peroxidase Haloperoxidase Myeloperoxidase (MP) Catalase Thyroid peroxidase Vanadium bromoperoxidase Lactoperoxidase H 2 2 + 2SH 2 H 2 + 2S Reaction cycle of peroxidase. (a) Classical peroxidase chemistry. (b) xygen-transfer rection. S represents the substrate
Porphyrin and related Peroxidases Glutathione peroxidase Haloperoxidase Myeloperoxidase (MP) Catalase Thyroid peroxidase Vanadium bromoperoxidase Lactoperoxidase H 2 2 + 2SH 2 H 2 + 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 P 450 strong absorption at 450 nm detoxification in liver : R-H + 2 + 2e - + 2H + R-H + H 2 Human Cytochrome P 450 2E1 Chem. Rev. 2004, 104, 3947-3980
Porphyrin and related Chlorophylls chlorin Chlorophyll a Chlorophyll b.. Where is chlorophylls?
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 Chloroplast Chlorophylls
Porphyrin and related Photosystems thylakoid membrane Photosystem II Photosystem I
Porphyrin and related Photosystems Z-Scheme 2 H 2 + 2 NADP + + 3 ADP + 3 P i + light 2 NADPH + 2 H + + 3 ATP + 2
Porphyrin and related Coenzyme B 12 corrin
ther 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 HiPiP Fds Low-potential Fds
ther Fe Proteins Ferritin Ferritin: intracellular iron-storage protein up to 4,500 Fe atoms Transferrin: transports iron through the blood to the liver, spleen and bone marrow. two specific high-affinity Fe(III) binding sites a 24 Storage: Fe 3+ forms Removal: reduction to Fe 2+ and chelation
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 Cu B Cu Z Type-3 Type-4 (T2/T3) Cu A reversible binding of 2 xy form: Cu(II)-Cu(II) Mixed-valence Cu(II)-Cu(I) in oxidized state
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 a 2 T4 copper center
Cu Proteins Cu, Zn SD Superoxide dismutase
Cu Proteins Cu, Zn SD Superoxide dismutase Ni-SD Mn-SD Fe-SD
Cu Proteins Cu, Zn SD
Nitrogen Cycle N 2 N NH 4+ / NH 3 N 2 - rganic N N 3 -
Nitrogen Cycle - Nitrogenase N 2 + 8H + + 8e - + 16ATP 2NH 3 + H 2 + 16ADP + 16 Pi Fe1 3 2 X 7 6 Mo R-homocitrate a-275 Cys 4 5 a-442 His
Nitrogen Cycle - Nitrogenase N N M D NH 2 N M NH N M 1 A NH NH M NH 3 N M 3 NH 2 NH M NH NH 2 NH 2 M NH 2 5 M M NH 3 NH 3 M NH 3
Nitrogen Cycle Nitrite Reductase Cu-containing Nitrite reductase Fe-containing Nitrite reductase N 2- N N 2 N 2 Cu-containing Nitrite reductase a 3
Nitrogen Cycle Nitrite Reductase Cu-containing Nitrite reductase T2/T1 T2
Nitrogen Cycle Nitrite Reductase Cu-containing Nitrite reductase Proposed mechanism N 2- N
Nitrogen Cycle Nitrite Reductase Cytochrome cd 1 Nitrite reductase Heme b a 2 Containing c-type cytochrome (for electron transfer) and d 1 -type cytochrome (for substrate reduction) Heme c Heme d 1
Nitrogen Cycle Nitrite Reductase Cytochrome cd 1 Nitrite reductase Proposed mechanism N 2- N Dalton Trans., 2005, 3410 3418
Nitrogen Cycle Nitrite Reductase Cytochrome c Nitrite reductase a 2 Containing 5 c-type hemes (per a) Proposed mechanism N 2- + 6e - + 7H + NH 3 + 2H 2
N N Synthase NS endothelial NS (ens) neural NS (nns) inducible NS (ins) constitutive NS (cns) ins
N N Synthase NS reactions Schematic structure of the active site of NHA-bound murine ins. NHA is shown in bold. H4B (Tetrahydrobiopterin) Current pinion in Chemical Biology 2000, 4:687 695
N N Synthase Proposed nucleophilic hydroperoxofe(iii)heme mechanism for the NS-catalyzed oxidation of N-hydroxyarginine. PPIX, protoporphyrin IX Current pinion in Chemical Biology 2000, 4:687 695
N N Synthase Proposed radical-type autoxidation mechansim of the NScatalyzed oxidation of NHA. Ellipses denote the heme group. P, peroxyfe(iii)heme intermediate. Current pinion 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 : bservation 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 [ 99m Te 4 ] - 1979 : Auranofin for arthritis 1984 : Gd[DTPA] 2- for MRI contrast agent 1993 : 153 Sm-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 NH 3 NH 3 Cl Pt NH 3 Cl Pt Cl Cl cisplatin NH 3 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 excision repair 5. Cell death cell lives
N N Pt Cl Cl H 2N H 2N Pt Cl N NH Cl Pt Cl NH C C H 2N Pt H 2N C Pt NH C H 3N C C C Cl Cl Metals in Medicine Cisplatin and related Structure Activity Relationships (SAR) 1. A cis geometry is required with the general formula cis-[ptx 2 (amine) 2 ] for Pt(II), and for Pt(IV) the formula cis-[ptx 2 Y 2 (amine) 2 ]. Monofunctional binding cationic complexes are inactive. 2. The X ligands (leaving groups) should be of intermediate strength (Cl -, S 4 2-, carboxylate ligands). For Pt(IV) complexes the Y ligands should have a trans orientation and can be Cl -, H -, or [(C)C n H 2n+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 6 of guanine and to the 5 phosphate group). NH Pt NH Pt anticancer compounds satisfying 3 3 N H 2 SAR xaliplatin DWA 2114R CBDCA; Carboplatin Pt anticancer compounds violating SAR NH 2 Pt IV JM216
Metals in Medicine Non-Pt anticancer complexes
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 ] + M n+ + H 2 2 M (n+1)+ + H - + H
Study of DNA using Inorganic Agents hn D-[Ru(en) 2 (phi)] 3+ Phi = phenanthrenequinone diimine