Microsoft PowerPoint - 일반화학 강의-2008

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1 Life Chemistry 화학 생물학 생명화학 (Life Chemistry) 생명현상의분자수준에서의연구 화학적기술을이용한생명현상연구 신약개발 고도의복합연구분야 21세기형연구 Chemical Biology

2 Chemical Biology ( 화학생물학 ) 유기분자를이용하여생명현상을분자수준에서이해하는연구분야 - 합성유기분자또는천연물을이용하여세포및생체내단백질, 복합당질 그리고핵산 (DA, RA) 등의기능을분자수준에서규명 - 이들생체고분자를인위적으로조작하여생명현상규명 - 궁극적으로질병치료제를개발하고자함 - 생화학은생명현상에의해발생되는물질들에대한분석과이해를기초로하여, 생명현상에서일어나는다양한메커니즘을화학적인조작없이이해하고자하는학문임. 화학 ( 유기화학 ) 생물학 ( 생화학, 유전학, 세포생물학등 )

3 Chemical Biology 화학유전학 (chemical genetics): 단백질의기능을제어할수있는소유기분자를이용한세포및생체내단백질기능연구 - 조합화학합성법을이용한소유기분자라이브러리합성 - 유기분자에의한세포표현형연구및세포내단백질의기능연구 - 화합물칩제작및작용단백질검색 - 단백질조작 - 의약제개발을위한단백질의저해제및길항제합성화학글라이코믹스연구 (chemical glycomics) - 탄수화물합성 - 세포내탄수화물의인위적인조작 - 탄수화물칩제작및탄수화물결합단백질검색 - 질병관련탄수화물변이효소 ( 글리코시다아제, 탄수화물전이효소등 ) 의저해제개발핵산화학 -Antigen 및 antisense 개발및응용 -DA, RA의기능해석 (Ribozyme, SiRA, Aptamer 등 ) 의약제및의약운반체개발 - 항암제, 항바이러스제및항생제개발 - 표적지향적의약제운반체개발 - 효과적인약물전달체개발생체모방연구 - 인공이온채널및인공수용체개발 - 인공조직및인공뼈개발바이오이미징연구 - 선택적인단백질 labeling 기술을이용한세포내특정단백질이미징 - 형광센서개발 - 방사성물질을이용한 metabolite 추적

4 화학과의이름을 Department of Chemistry and Chemical Biology 로개명한대학 대학명 arvard University (Department of Chemistry and Chemical Biology) Cornell University (Department of Chemistry and Chemical Biology) Rutgers University (Department of Chemistry and Chemical Biology) Purdue University (Department of Chemistry and Chemical Biology) Rensselaer Polytechnic Institute (Department of Chemistry and Chemical Biology) ortheastern University (Department of Chemistry and Chemical Biology) Stevens Institute of Technology (Department of Chemistry and Chemical Biology) University College Dublin, Ireland (Department of Chemistry and Chemical Biology) Peking University Collage of Chemistry (Department of Chemistry and Chemical Biology) Molecular and Cellular Biology Molecular Biology and Genetics Ecology and Evolutionary Biology Microbiology Biological and Environmental Engineering Biochemical Engineering Biochemistry Biological Sciences Cell & Developmental Biology Cell Biology & euroscience Biology Biochemistry and Molecular Biology Biology Biology 대학내관련학과 School of Biology & Environmental Science School of Biomolecular & Biomedical Science Collage of Life Science 내에관련학과 Biology Biochemistry Ecology Biotechnology

5 Flow of genetic information (DA RA Proteins Modified proteins)

6 Functional Studies of Biomolecules in Cells and rganisms Living organisms P - 3 C - P Cells Proteins DA 3 C C 3 C 2 Carbohydrates

7 Flow of genetic information (DA RA protein) 핵 세포질 tra 전사 리보솜 mra Eukaryotes ( 진핵생물 ) 단백질합성

8 게놈시대 Genomics uman genome project 염기서열해독 ~ 30 억개염기 ( 인간 ) 2003 년 5 월 >30,000 genes 동물세포

9 ucleic Acids DA DA DA DA RA 3 C Guanine Adenine Cytosine Thymine Purines Pyrimidines Uracil Bases ucleotides DA 2 -deoxyadenosine 5 -phosphate 2 -deoxyguanosine 5 -phosphate 2 -deoxycytidine 5 -phosphate 2 -deoxythymidine 5 -phosphate RA adenosine 5 -phosphate guanosine 5 -phosphate cytidine 5 -phosphate uridine 5 -phosphate - 5' 1' 4' 3' 2' () 2'-deoxyribose ribose Base 5' Base 4' 1' 3' 2' () 2'-deoxyribose ribose ucleosides ucleic acid (RA or DA) P - 5' Base 4' 1' 3' 2' () 2'-deoxyribose ribose ucleotides Phosphodiester Bonds P - 3 C A = T G C - P

10 Biosynthesis of Proteins Cell

11 Genetic Code 4 x 4 x 4 = 64 3 개의 stop codon 1 개의 start codon

12 atural amino Acids in Proteins 2 C 2 2 C 2 C 3 2 C 2 2 C 2 2 C 2 Gly, G Ala, A Val, V Leu, L Ile, I 2 C 2 2 C 2 2 C 2 2 C 2 S SC 3 Ser, S Thr, T Met, M Cys, C Pro, P C 2 2 C 2 2 C 2 2 C 2 2 C 2 2 C 2 2 C 2 Phe, F Tyr, Y Trp, W is, Lys, K 2 2 C 2 2 C 2 2 C 2 2 C 2 C 2 C 2 C 2 C 2 2 Arg, R Asp, D Glu, E Asn, Gln, Q

13 3 C C 3 C 2 R R R R R Peptide Bonds - + planar Peptide Bonds Peptide Bonds

14 Protein Structures Primary structure Secondary structure Tertiary structure β-sheet α-helix reverse turn

15 Protein Structures The primary structure of a protein is simply the amino acid sequence. The secondary structure of a protein describes how segments of the peptide backbone orient into a regular pattern. - local conformation of the polypeptide backbone The tertiary structure describes how the entire protein molecule coils into an overall three-dimensional shape. - the overall three-dimensional shape which results from further folding of the polypeptide chains The quaternary structure describes how different protein molecules come together to yield large aggregate structures. - two or more folded polypeptide chains aggregate into one protein complex. 15

16 β-sheet reverse turn elical structure

17 후게놈시대 Genomics Proteomics Glycomics Post-genomic era >60,000 genes 4,000 drug targets Functional genomics and glycomics ? Functional studies of proteins and carbohydrates Classic genetic approach Chemical genetic approach

18 Classic Genetic Approach Forward Reverse gene DA Random mutagenesis of cells Select mutant cells with phenotypic change x gene Mutate single gene Generate cells Look for phenotype change Identify mutated gene Identify the function of proteins

특정유전자의돌연변이는다른단백질에영향을끼쳐정확한기능규명이어려움 진핵세포및배아스크리닝

19 Chemical Genetic Approach 세포분화연구의기존유전학적방법의문제점 유기분자라이브러리 다양한유기분자라이브러리합성 특정유전자조작에따른세포성장불능 특정유전자의돌연변이는다른단백질에영향을끼쳐정확한기능규명이어려움 진핵세포및배아스크리닝 세포분화기전규명 세포및배아분화조절유기분자발굴 표적단백질검출및검증 생물학 유기화학 신약후보물질도출 질병표지단백질발굴

Chemical Genetic Approach 단백질기능을저해시키거나활성화시킬수있는소유기분자를이용한단백질기능연구 Plate with cells Forward Reverse protein Add one compound per well C 3 Find a ligand for protein of interest

20 Chemical Genetic Approach 단백질기능을저해시키거나활성화시킬수있는소유기분자를이용한단백질기능연구 Plate with cells Forward Reverse protein Add one compound per well C 3 Find a ligand for protein of interest by TS protein C 3 Add a ligand to cells Select a compound that produces phenotype of interest C 3 Assay for phenotype Identify protein target Identify the function of proteins

21 Functional Glycomics Genomics Proteomics Glycomics Functional glycomics ? Functional studies of carbohydrates

22 Functional Glycomics 복합당질관련연구 탄수화물 - 단백질상호작용 복합당질구조및기능연구 탄수화물 --단백질상호작용연구 Bacteria Toxin Antibody ormone 생명현상규명병인규명 Virus 탄수화물관련의약제개발 --탄수화물생합성과정을방해하는저해제개발 --탄수화물결합단백질저해제개발 --탄수화물에기반을둔백신개발 --질병관련표지단백질발굴 Protein (Tumor) Cell 기초생명현상 수정,, 발생,, 분화,, 성장및노화및질병관련 암전이 염증유발 박테리아및바이러스에의한감염

23 Glycoconjugates Carbohydrates exist in in the forms of of glycolipids and glycoproteins 세포표면의탄수화물 탄수화물의생물학적기능을총체적으로연구 ( 글리코믹스 )

24 Monosaccharides ccurring in in Glycoconjugates Ac Ac D-Glucose (Glc) D--acetyl glucosamine (GlcAc) D-Galactose (Gal) 2 C D--acetyl galactosamine (GalAc) D-Mannose (Man) D-Glucuronic acid (GlcA) Ac C 2 3 C -Acetylneuraminic acid (euac) D-Xylose (Xyl) L-Fucose (Fuc) Glycosidic Bonds

25 Biochips : 유리, 실리콘또는나일론등의재질로된기판위에 DA, 단백질, 탄수화물또는세포, 조직등을고정화시킨생물학적마이크로칩 (biological microchips) 을의미 (1) 마이크로어레이형바이오칩 (2) lab-on-a-chip DA 칩 고체기판 단백질칩 탄수화물칩

26 Biochips 종류 DA 칩또는 gene 칩 (DA microarray) 단백질칩 (protein microarray) 세포칩 (cell microarray) 조직칩 (tissue microarray) 탄수화물칩 (carbohydrate microarray) 응용 유전자결함 유전자발현양상 단백질분포 단백질-단백질상호작용 단백질-탄수화물상호작용 고성능생체기능조절분자검색 발현형 (phenotype) 조사 장점 한번의실험으로 1,000개이상의 assay가가능 적은양의샘플만필요 빠른 assay 쉽게원하는타겟을확인할수있다. 단점 제작이용이하지않다. 기판위에찍을수있는샘플의수가많지않다. 많은투자가필요

Biochips Protein chip Protein chip Protein-nucleic acid interaction Protein-protein interaction Catalytic activity Protein chip Glycoprotein-protein interaction Glycoprotein chip Carbohydrate-protein

27 Biochips Protein chip Protein chip Protein-nucleic acid interaction Protein-protein interaction Catalytic activity Protein chip Glycoprotein-protein interaction Glycoprotein chip Carbohydrate-protein interaction Carbohydrate chip 1. Protein-protein interactions Studies on protein network Find bioactive molecules Drug discovery 2. Protein-nucleic acid (DA or RA) interactions Find small molecules to regulate gene expression Drug discovery 3. Protein-carbohydrate (or glycoprotein) interactions Carbomics Drug discovery

28 Carbohydrate Microarrays Carbohydrate microarray S S S Carbohydrate S Glass slides α-fuc α-man β-glcac TV-Cy3 AAL-Cy5 ConA-FlTC (5.0 mm conc) α-man β-glcac α-fuc 1 mm 1 mm

29 Two Approaches for Treating Diseases Development of highly specific chemotherapic agents Development of targeted drug-delivery systems 세포밖 바이러스 박테리아 덴드리머 세포질 암세포 정상세포 리포솜

30 Drugs 항암제 항암제 암세포의 DA 공격 암세포사멸 암세포 암세포의 DA 함암제가암세포의 DA 에결합 항생제 항생제 박테리아공격 박테리아박멸 박테리아 항바이러스제 항바이러스제 바이러스공격 바이러스박멸 에이즈바이러스

31 Cancers Cancers Gastric cancer ( 위암 ) Lung cancer ( 폐암 ) Breast cancer ( 유방암 ) Uterine cancer ( 자궁암 )

32 Anticancer drugs Ac Bz Ph Bz Ac 주목나무 (yew) Taxol ( 천연항암제 ) R Cl Cl Mustard 3 Pt 3 Cl Cl Cis-platin Me Glivec (Imatinib) Me

33 Drug Action Cl R Cl Mustard 3 Cl Pt 3 Cl Cisplatin R G C G G C 3 G C Pt 3 G C Prevent DA replication and transcription (DA 복제및전사방해 ) Me Me Tyrosine kinase inhibitor 세포분열방해 Glivec (Imatinib) Bz Ph Ac Taxol Bz Ac Tubulin heterodimers Microtubule dynamics X

34 Bacteria Cel Cel wall wall Plasma Plasma membrane membrane Cytoplasm Cytoplasm Gram-positive outer membrane periplasmic space Plasma membrane Cytoplasm Gram-negative Peptidoglycan Peptidoglycan

35 Antibiotics Et Me Me 2 2 C 2 C Kanamycin 2 C 2 Me2 Tetracyclin Erythromycin Protein synthesis inhibitors Macrolides Aminoglycosides tetracyclines DA inhibitors Transcription-rifamycins Replication-quinolines Cell membrane inhibitors polymyxins Cell wall inhibitors β-lactams: Penicillins and cephalosporins Glycopeptides-vancomycin C 2 Me Et alidixic acid penicillin S C 2 R S C 2 Cephalosporin Ac rifamycin

36 Drug Resistance vancomycin resistance penicillin resistance β-lactam penicillin S C 2 β-lactamase β-lactam penicillin S C 2

37 AIDS uman Immunodeficient Virus IV life-cycle AIDS 환자 Drug targets IV reverse transcriptase IV TAT protein IV protease IV integrase 행복한삶

38 AIDS Drugs IV reverse transcriptase IV protease inhibitor 3 C t-bu S Lamivudine 3 Zidovudine (AZT) Indinavir (crixivan) in combination with AZT and lamivudine

$crystal X-ray diffractometer X-ray$

39 Drug Development Rational Design X-ray structure Computer-based Design Combinatorial Synthesis Random screening Rational Design Ph Ph Ph Ph crystal X-ray diffractometer X-ray structure Computer-based design Identify Drug candidates

40 Combinatorial Synthesis Speed vac LC-MS FT-IR igh throughput synthesis igh throughput purification igh throughput analysis t-bu Identify Drug candidates FRET SPA ELISA igh throughput screening

41 인간수명

42 (nitric oxide) Biological messengers to cause smooth muscle to relax. synthase inhibitor 심장협심증치료제 Et 2 S C3 C 3 Viagra (sildenafil) C 2 C 2 C 3 Drug for penile erection prblems 1998 년 top selling drug Viagra

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