化学生物学基础

1、化学生物学基础(I)时间：Tue（7-8节）； Fri（3-4节）地点：三教205主讲：陈兴Ofce Hour：Tue 2-3PM Ofce：化学学院A612 Tel：62752747：xingchenAbout the course课程介绍：This course introduces fundamental knowledge and modern topics in chemical biology with emphasis on applica8ons of chemical principles to biological research and biotechnology. T

2、here will be a discussion session every two to three weeks.About the courseSyllabus Chapter 00: History of chemical biology; Philosophy of Chemical Biologists 2学时 Chapter 01: Nucleic Acids Chemical Biology 6+2学时 Chapter 02: Protein Chemical Biology 6+2学时 Chapter 03: Chemical Glycobiology 6+2学时 Chapt

3、er 04: Lipids and Metabolites 4+2学时 Chapter 05: Small Molecules and Drug Discovery 4+2学时 Chapter 06: Other topics in ChemBio: Synthe8c Biology; Molecular Imaging; Cell Biology, etc 6+2学时About the course：Lectures will be based on largely on concepts from published literature. You may nd the following

4、 references to be helpful for background reading: Lehninger Principles of Biochemistry 3rd, 4thor 5th Edi8on David Nelson and Michael Cox Molecular Biology of the Cell Bruce Alberts. 4th or5th Edi8on Essen8als of glycobiology Ajit Varki Edi8onhp:/. 1st or 2ndAbout the course课程网盘：iazkAbout the course

5、成绩评定：Aendance 10%； Discussion 10%； Homework 40%;Exams 40%.About the course课堂要求：禁止使用个人电脑、IPAD、手机等电子！科学研究表明，使用传统纸笔的学习效果要远好于使用电子。化学生物学基础(I)Lecture 1September 16, 2014ChemBio Chapter 00Brief History of Chemical BiologyWhat is Chemical Biology?ChemicalBiology:Ascien8cdisciplinespanning the elds of chemis

6、try and biologythat involves the applica8on of chemical techniques and tools to the study and manipula8on of biological systems.from h/p:/揭示生命运动的化学本质发展生命调控的化学方法提供生命研究的化学技术运用化学的原理、语言和工具认识生命问题The Origin of Chemical Biologynitrous oxide carbon monoxide“using chemistry to advance biology

7、.”Nat. Chem. Biol. 2006, 2, 3.Emperor Shen Nung 2600 B.C.Molecular mechanisms?Why Chemical Biology?笛卡尔培根ReducLonism “还原论”牛顿伽利略宇宙生物细胞原子笛卡尔培根牛顿ReducLonism “还原论”伽利略EvoluLon “进化论”UniverseOrganismCellMoleculeAtomChemBio Chemical synthesis and biosynthesis Chemical mechanisms in biology Expanding biology

8、through chemistry Expanding chemistry through biology History of ChemBioChemistryPhysical Organic, Synthe8c Pharmacology & Pharmaceu8calBiologyDescrip8ve Biology Protein Biochemisty1960s1970sMechanis8c EnzymologyMolecular Biology1980sBioorganic ChemistryGene8cs1990sChemical BiologyStructural Bio

9、logy, Mechanis8c2000sGenomics, Proteomics, metabolomics Epigene8csics system based Complex, en8re organismsStreptomyces coelicolor genome5Modified Staudinger ligation8 Analog-sensitive kinases14 Ribosome structure3,4Activity-based probes7Personalized medicine27 Histone demethylation28Yeast chemical

10、genetic profiling29shRNA screens30Click chemis ry in situ9A TRP receptor senses temperature22 The druggable genome23200020012002200320042005MudPIT6Genetic code reprogramming11RNAi in mammals2 Imatinib becomes a drug15 Automated carbohydrate synthesis21Design of a novel protein fold24Kinase inhibitor

11、 specificity assays3Auxin receptor identified32A mechanism-based femtomolar inhibitor33Optical manipulation of neural activity34Semisynthetic Rab revealsits function25Origins of amyloidogenesis26UAGLifeFrom common origin evolutionarily 3.5 billion years agoBiochemically similar: cellsmacromolecules

12、DNA, RNA, proteins.细菌真核生物古细菌Cell Types Prokaryotes: without nuclear envelops; having no internal membrane or organelles. Eukaryotes: cells with nuclear envelops. Archaebacterial （古生细菌）: no nuclear membrane, but similar to eukaryotes in transcrip6on and transla6on; discovered in 1982, in deep sea the

13、rmal ventsBacterial CellsEukaryotic CellsFig. 6-­9bRough endoplasmic reticulumNuclear envelopePlant and animal cells have most of the same organellesSmooth endoplasmic reticulumCentral vacuoleGolgi apparatusMicrofilamentsIntermediate filamentsMicrotubulesCYTO- SKELETONMitochondrionChloroplastPl

14、asma membraneCell wallPlasmodesmataWall of adjacent cellNuclear envelopeTypical animal cellRough ERSmooth ERPlasma membraneCYTOSKELETON:MicrofilamentsIntermediate filamentsMicrotubulesGolgi apparatusMitochondrionLysosomeCytoskeleton system in eukaryoLc cellsCrowded!Central DogmaPost-­translaLon

15、al modicaLonsDNA modicaLonsRNA modicaLons生物大蛋白质核酸多糖脂ChemBio Chapter 00Philosophy of Chemical Biologist: a case studyThe Bioorthogonal Chemical Reporter StrategyH2OH2OBuilding blockRSHORSHOmetabolic or geneLc incorporaLonR(H)R(H)O2O2chemical labelingH2ORSHOR(H)bioorthogonal chemical reporter=O2Modied

16、 from: Prescher, J. A.; Bertozzi, C. R. Nat. Chem. Biol. 2005, 1, 13-­21Bioorthogonal Chemical ReactionscellcellcellcellcellcellN N+RN NNHRNZ. Hao, S. Hong, X. Chen, P.R. Chen Acc. Chem. Res. 2011, 44, 742Metabolic Labeling of Biomolecules With Bioorthogonal GroupsX, Y:bioorthogonal groupsYXpro

17、beYXXStep 2:Step 1: Metabolic incorporaLonBioorthogonal reacLonGlycansLipidsProteinsN3Nucleic acidsOONHN3OHNAcOAcOAcONOOOHOH2NOAcOHOnOHOHX. Ran,. Curr. Opin. Chem. Biol. 2013, 17, 747.Staudinger LigaLon:ChemBio Chapter 01ABCs of DNA and RNA:DNA ReplicationTranscription TranslationReading: Alberts, C

18、hapter 4-7Chemical Biology of Nucleic AcidsSmall molecule binderChemical reporter Chemical modificationFigure 4-3 Molecular Biology of the Cell (© Garland Science 2008)NucleoLdeFigure 4-5a Molecular Biology of the Cell (© Garland Science 2008)Watson-Crick base pairsDNA stability and sequen

19、ce maintenanceGerm cells and soma8c cells must be protected against high rates of muta8ons.Muta8on rates are extremely low:roughly 1 nucleo8de change per 109 nucleo8des in each replica8on cycle. The rate is similar across E. Coli, C. elegans, and human.Ques6on: how to measure the rates?REPLICATION F

20、ORK 1000 nt / sec ! Base by base One type 5 to 3 polymeraseFigure 5-2 Molecular Biology of the Cell (© Garland Science 2008)DNA synthesis: chemistryFigure 5-3 Molecular Biology of the Cell (© Garland Science 2008)DNA synthesis: catalyzed by DNA polymeraseFigure 5-4 Molecular Biology of the

21、 Cell (© Garland Science 2008)Bioorganic & Medicinal Chemistry 9 (2001) 2215 2235Molecular Recognition of DNA by Small MoleculesPeter B. Dervan*Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USASequence Specic RecogniLon of the DNA Minor Groove by Im/Hp/Py PolyamidesPeter Dervan at CaltechNature 391, 468471 (1998).Figure 13. Solid phase synthesis of polyamides.Derv