92 players in the nature (earth) 26 main players in ...bh.knu.ac.kr/~leehi/index.files/bioinorganic...

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

:

Bioinorganic Chemistry - Interdisciplinary subject

Spectro

copy

Bioinorg.

Chem

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

http://www.metabolic-nutrition.ch/bestellen_9_shop_Wheyprotein_Whey_Protein_Molkeprotein_Wheyprotein_Whey.html

http://www.metabolic-nutrition.ch/bestellen_9_shop_Wheyprotein_Whey_Protein_Molkeprotein_Wheyprotein_Whey.html

http://science.nasa.gov/headlines/images/spacesugar/sugarcompare.gif

http://science.nasa.gov/headlines/images/spacesugar/sugarcompare.gif

Basics – Proteins

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

Basics – Nucleic acids (DNA)

DNA

A-DNA B-DNA Z-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

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 – Chlorin, Corrin

chlorin

Chlorophyll acorrin

Coenzye B12 (Vitamin B12)

Porphyrin and related – Hemoglobin, Myoglobn

heme

Hemoglobin (a2b2)

[oxygen transport]

Myoglobin

[oxygen storage]


O2 binding to heme (structure and spin)

high spin Fe(II) low spin Fe(II)


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


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 – 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)


Chloroplast

Chlorophylls


thylakoid membrane

Photosystem I

Photosystem II


Z-Scheme

2 H2O + 2 NADP+ + 3 ADP + 3 Pi + light → 2 NADPH + 2 H+ + 3 ATP + O2

Porphyrin and related – Coenzyme B12

corrin

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

Cu Proteins – Cu, Zn SOD

• Superoxide dismutase


• Superoxide dismutase

Mn-SOD Fe-SOD

Ni-SOD

Nitrogen Cycle

N2

NO2-

NH4+/ NH3

NO3-

Organic N

NO

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


a3



T2

T2/T1



Proposed mechanism

NO2- → NO


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)


Cytochrome cd1 Nitrite reductase

Dalton Trans. , 2005, 3410–3418

Proposed mechanism

NO2- → NO


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


Action

2. Cisplatin binding to DNA 3. Kink of DNA 4. HMG binding to DNA

5. Cell death

excision repair

cell lives


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 – 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]+

Mn+ + H2O2 → M(n+1)+ + OH- + •OH

Study of DNA using Inorganic Agents

D-[Ru(en)2(phi)]3+

Phi = phenanthrenequinone diimine

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92 players in the nature (earth) 26 main players in ...bh.knu.ac.kr/~leehi/index.files/bioinorganic...

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