1、1Diversity and UnityFor the discovery that mature cells can be reprogrammed to become pluripotent“發現成熟細胞可以重新編程而獲得多能性發現成熟細胞可以重新編程而獲得多能性”Shinya Yamanaka John B. Gurdon 2012年，諾貝爾生理年，諾貝爾生理/醫學獎醫學獎中樞神經中樞神經軟骨軟骨肌肉肌肉脂肪脂肪上皮上皮畸胎瘤實驗畸胎瘤實驗iPS-derived mice引入關鍵基因引入關鍵基因體細胞重新編程體細胞重新編程iPS, induced pluripotent stem cel

2、l誘導多能干細胞誘導多能干細胞iMiceRobert J. Lefkowitz Brian K. Kobilka “for studies of G-protein-coupled receptors”表彰他們對表彰他們對G蛋白耦聯受體的研究蛋白耦聯受體的研究人高度緊張時人高度緊張時“腎上腺素開始大量分泌腎上腺素開始大量分泌”2012年，諾貝爾年，諾貝爾 化學獎化學獎How could the inside of the cell know what was happening on the outside?腦腦：神經信號警告神經信號警告身體各部位，釋放身體各部位，釋放激素激活腎上腺激素激活腎

3、上腺眼：眼：瞳孔瞳孔放大，視放大，視野變窄野變窄心臟心臟：心率加速心率加速肺：肺：氣管擴張，氣管擴張，呼吸頻率加快呼吸頻率加快肌肉：肌肉：血量增加，血量增加，肌肉收縮肌肉收縮肝臟：肝臟：糖原分解，糖原分解，糖被釋放到血液糖被釋放到血液脂肪細胞：脂肪細胞：脂肪脂肪酸被釋放到血液酸被釋放到血液腸胃：腸胃：流入消化流入消化系統的血量減少系統的血量減少Time to flee! 髓質髓質皮質醇皮質醇腎上腺素腎上腺素去甲腎上腺素去甲腎上腺素皮質皮質6G蛋白耦聯受體：蛋白耦聯受體：感受物化刺激，包括多種神經遞質、肽類激感受物化刺激，包括多種神經遞質、肽類激素和趨化因子受體素和趨化因子受體超過半數的現代藥物

4、靶向超過半數的現代藥物靶向7英國細菌學家弗萊明英國細菌學家弗萊明 - 1928- 1928年發現青霉素年發現青霉素弗萊明在簡陋的實驗室，研究葡萄球菌弗萊明在簡陋的實驗室，研究葡萄球菌蓋子沒蓋好蓋子沒蓋好，培養細菌的瓊脂上附了一層青霉菌，培養細菌的瓊脂上附了一層青霉菌( (來自樓上的一位研究青霉菌學者的窗口來自樓上的一位研究青霉菌學者的窗口) )在青霉菌的近旁，葡萄球菌不見了在青霉菌的近旁，葡萄球菌不見了 培養這種霉菌，發現青霉素可快速殺死將葡萄球菌培養這種霉菌，發現青霉素可快速殺死將葡萄球菌 發明了第一種能夠治療人類疾病的抗生素發明了第一種能夠治療人類疾病的抗生素- -青霉素青霉素也有的藥物：

5、有一定作用也有的藥物：有一定作用但其副作用是人類但其副作用是人類付出巨大代價付出巨大代價之后才了解之后才了解8沙利度胺沙利度胺: 1953: 195319531953年年合成，他們本來打算開發一合成，他們本來打算開發一種新型抗菌藥物，但是藥理試驗顯示，沙利度胺沒種新型抗菌藥物，但是藥理試驗顯示，沙利度胺沒有任何抑菌活性，有任何抑菌活性，cibaciba便放棄了對它的進一步研究。便放棄了對它的進一步研究。在在CibaCiba放棄沙利度胺的同時，放棄沙利度胺的同時，聯邦德國聯邦德國藥廠藥廠Chemie Chemie GrnenthalGrnenthal開始投入人力物力研究沙利度胺對中樞開始投入人力

6、物力研究沙利度胺對中樞神經系統的作用，并且發現該化合物具有一定的鎮神經系統的作用，并且發現該化合物具有一定的鎮靜催眠作用，還能夠顯著抑制孕婦的妊娠反應，靜催眠作用，還能夠顯著抑制孕婦的妊娠反應，19571957年年1010月反應停正式投放月反應停正式投放歐洲歐洲市場，不久進入日市場，不久進入日本市場，在此后的不到一年內，反應停風靡歐洲、本市場，在此后的不到一年內，反應停風靡歐洲、日本、非洲、澳大利亞和拉丁美洲，作為一種日本、非洲、澳大利亞和拉丁美洲，作為一種“沒沒有任何副作用的抗妊娠反應藥物有任何副作用的抗妊娠反應藥物”，成為，成為“孕婦的孕婦的理想選擇理想選擇”Thalidomide：195

7、3年合成，年合成，人類藥物史上的著名案例，人類藥物史上的著名案例，其出名不是因為藥物療效，其出名不是因為藥物療效，而是毒性而是毒性-“海豹胎事件海豹胎事件”沙利度胺沙利度胺 (Thalidomide)： 手性化合物手性化合物R(R(順時針順時針)- )-構型：抑制妊娠反應；構型：抑制妊娠反應；S- S-構型有致畸性構型有致畸性手性藥物銷售額：手性藥物銷售額：1990年年 180億，億，2010年年 2,000 億美元億美元沙利度胺的新認識：沙利度胺的新認識：在免疫、抗炎、抗血管生成的藥理和一些疑難病癥在免疫、抗炎、抗血管生成的藥理和一些疑難病癥上的研究和治療應用中取得了令人欣喜的結果上的研究和

8、治療應用中取得了令人欣喜的結果9 J U LY 2 0 1 5 | N AT U R E | 1 6 7Another action of a thalidomide derivativeThalidomide：an effective drug for myeloma and immuno-modulatory11二甲雙胍：糖尿病二甲雙胍：糖尿病Sosnicki et al. Pharmacological Reports 2016，68:91892512二甲雙胍二甲雙胍抗腫瘤，衰老抗腫瘤，衰老13生物化學是生物學和醫學研究的必備基礎生物化學是生物學和醫學研究的必備基礎血糖血糖食物糖食物糖消

9、消 化化葡萄糖葡萄糖吸收吸收肝臟肝臟葡萄糖葡萄糖肝糖原肝糖原合成合成分解分解乳酸乳酸糖異生糖異生血液血液肌糖原肌糖原葡萄糖葡萄糖合合 成成有氧氧化有氧氧化CO2+H2O+ATP糖酵解糖酵解乳酸乳酸+ATP血乳酸血乳酸肌肉肌肉轉變為轉變為其它物質其它物質(大量大量)(少量少量)糖代謝糖代謝 Carbohydrate Metabolism糖酵解概況糖酵解概況payoff phasereleases energy 1. 丙酮酸在丙酮酸在無氧條件下無氧條件下，經，經LDH催化還原催化還原為乳酸為乳酸。可通過乳酸可通過乳酸循環在循環在肝臟經糖異生途徑轉化為糖肝臟經糖異生途徑轉化為糖。糖酵解：在缺氧糖酵解

10、：在缺氧條件下迅速為生命活動提供條件下迅速為生命活動提供能量。能量。是某些組織獲能的主要途徑，如肌肉收縮，視網是某些組織獲能的主要途徑，如肌肉收縮，視網膜、神經、腫瘤等。膜、神經、腫瘤等。2. 在多數情況下，丙酮酸經過在多數情況下，丙酮酸經過 有氧代謝有氧代謝 Citric Acid Cycle (TCA)產生大量產生大量ATP 1930s by Albert Szent-Gyrgyi (1937) finally identified in 1937 by Hans Adolf Krebs (Nobel Laureate in 1953)cytosolmt21代謝方式轉變調控了腫瘤的發生代謝

11、方式轉變調控了腫瘤的發生(Warburg Effect)正常細胞正常細胞癌細胞癌細胞glucosepyruvateCoATCA cycleATPglucosepyruvatelactateATPWarburg癌細胞選擇糖酵解方式供能，以獲取低氧環境中的生存優勢癌細胞選擇糖酵解方式供能，以獲取低氧環境中的生存優勢22免疫微環境：雙向作用，腫瘤干預新靶標！免疫微環境：雙向作用，腫瘤干預新靶標！Anti-PD-1Anti-CTLA4免疫細胞：腫瘤微環境重要組分免疫細胞：腫瘤微環境重要組分抗腫瘤抗腫瘤免疫細胞免疫細胞促腫瘤促腫瘤23腫瘤如何腫瘤如何逃逸免疫監視？逃逸免疫監視？抑制分子抑制分子 - 如何

12、調控免疫如何調控免疫細胞的功能？細胞的功能？總體有效率：總體有效率： 6-28%; 6-28%; 為何臨床療效欠佳為何臨床療效欠佳 ? ? 24代謝方式轉變可能也是免疫細胞分化與功能的基礎代謝方式轉變可能也是免疫細胞分化與功能的基礎25（1）代謝方式轉變調控了）代謝方式轉變調控了T細胞的活化與分化細胞的活化與分化Bart Ghesquiere et al. Nat Rev 2014靜息狀態下，細胞通過脂肪氧化途徑獲取能量靜息狀態下，細胞通過脂肪氧化途徑獲取能量活化與分化時，細胞內糖酵解與氧化磷酸化水平上調活化與分化時，細胞內糖酵解與氧化磷酸化水平上調26（1）代謝方式轉變調控了）代謝方式轉變調

13、控了T細胞的活化與分化細胞的活化與分化T細胞活化后糖酵解與谷氨酰胺代謝通路相關基因表達上調細胞活化后糖酵解與谷氨酰胺代謝通路相關基因表達上調糖酵解糖酵解谷氨酰胺代謝谷氨酰胺代謝Ruoning Wang et al. Immunity 2011Glucose, glutamine and FA：main nutrients that support T cell bioenergetics and biosynthesis. Cells use nutrients to generateATP via glycolysis (cytosol) or via OXPHOS (mitochondri

14、a) Metabolic Competition in Tumor MicroenvironmentIs a Driver of Cancer ProgressionCell 2015，162, 12294129Ho et al., 2015, Cell 162, 12171228Competition between immune cells and other cells in microenvironment for nutrients and metabolites can mediate T cell differentiation and function Nature Immun

15、ology2016, April31 Definition of Biochemistry Biochemistry is the chemistry of life. The study of the molecular basis of life and the interact with each other or understanding life phenomena in chemical terms. The combination of biology and chemistry or the application of chemical principles to unde

16、rstand biology.32Living organisms vs. inanimate objects chemical complexity and organization use energy in a systemic way self-replication and self-assembly Biochemistry Explains:Diverse lives in unifying chemical termsAll macromolecules are made of a few simple compounds33Main Questions for Biochem

17、istry I (This semester） What are the composition and structure of bio-molecules? How do these bio-molecules act and interact in living organisms？341. Protein Structure and Function （蛋白質的結構和功能）（蛋白質的結構和功能）2. Enzymes: Basic Concepts and Kinetics (酶的基本概念及酶促動力學酶的基本概念及酶促動力學)3. Enzymes: Catalytic & Regulat

18、ory Strategies （酶催化和調控的策略）酶催化和調控的策略）4. Carbohydrates（碳水化合物）碳水化合物）5. RNA, DNA, and flow of genetic information (DNA,RNA及遺傳信息的傳遞及遺傳信息的傳遞)Contents for First semester:356. Lipids and Cell Membranes（脂質和細胞膜）脂質和細胞膜）7. Bio-Signaling (生物信號通路）生物信號通路）（Lehninger 和和Biochemistry 第第1 - 13章）章）8. Responding to Envir

19、onmental ChangesThe sensory systems & The Immune systemBiochemistry:Chpt. 32 &3336Part II Transducing and Storing Energy （能量的轉換和貯存）（能量的轉換和貯存）Part III Synthesizing the Molecules of Life （生物分子的合成）（生物分子的合成）Second semester : BiochemistryTo present dialogues, actions, stories, and drama with Biochemicals

20、 37 The Aims of this Courses1. Introduce the language of biochemistry：- meaning, origin, & significance of terms2. Understand the physical, chemical & biological context of bio-molecule, reaction & pathways3. The most important techniques or Exp. for our understanding of biochemistry38Biochemistry A

21、gricultureMolecular BiologyMolecular GeneticsMicrobiologyImmunologyMedicine & Pharmacy(藥藥)Clinical Medicine臨床醫學臨床醫學 Preventive MedicinePathology病理病理 Pharmacology藥理藥理 Application of Biochemistry39Stage I 1870s1930s - Chemical Constitution of Living OrganismsStage II 1930s1950s - Law of Chemical Chang

22、e and Control of Different Bio-moleculesStage III 1950s present - Principles that are Central for Understanding Living Organisms. The Development of Biochemistry401810 30: C, H, O, and N are the major substances from animals and plants. The term “Protein” was first used in 1838.1850 90: Carbohydrate

23、s, lipids, and nucleic acids were recognized. The term “biochemistry” was formed in 1877 by Hoppe-Seyler.1890s: Yeast extract ferment sugar to alcohol! Enzymes can function in cell-free system. The era of enzymology developed (1894).411920s James Sumner: Enzymes are proteins.1940s - 1950s Avery and

24、Hershey: DNA carries the genetic information.1950s Franklin, and Watson and Crick: DNA is a double helix.1960s Nirenberg: Genetic codes deciphered.1980s Cech: RNA has catalytic activity(Ribosome).42近近2020年年諾貝爾生理和醫學獎中諾貝爾生理和醫學獎中8080的發現與生化相關的發現與生化相關43Krebs: Citric Acid Cycle (TCA): an important way by

25、which the complex chemical processes provide living organisms with high energy phosphate.Sanger: Sequencing Method Amino acid sequencing method and the complete sequence of insulin. Sanger Sequencing Method for DNA44(有莢膜有莢膜, S; 致病性）致病性）4546S (heat-killed) Mouse lives47R + S (heat-killed/ extracts) M

26、ouse dies 48結果小結和分析結果小結和分析（背景：以往認為（背景：以往認為蛋白質蛋白質攜帶遺傳信息）攜帶遺傳信息）4950Part I Foundations of Biochemistry1. The molecular logic of life2. Bio-molecules3. Cells4. WaterSome Important Chemical Concepts and Principles for Studying Biochemistry51General Features of Living Organism complicated & highly organi

27、zed structures metabolize - use nutrients and energy from their environment respond (adapt/survive) to its surrounding to find energy and raw materials self replicate and self assembly evolve and diversifyThe molecular logic of life52 Chemical Unity of Diverse Living Organisms (生命體化學組成上的一致性和多樣性生命體化學

28、組成上的一致性和多樣性) Composed of lifeless molecules These molecules conform to physical and chemical laws when examined individually Living organisms maintain highly ordered states by consuming inanimate materials from environment53All living organisms build molecules from the same kinds of monomeric subuni

29、ts.54The structure of a macromolecule determines its specific biological function55Molecules contained in organisms Water (50 -95%) Ions (1%) Organic molecules (Rest)Living matter is composed mostly of the six lighter elements: C, H, O, N, P, SH, O, N, and C: the lightest elements lightest elements

30、form the strongest bonds Bio-molecules56The trace elements ( Fe, Cu, Mn, Zn, I, Mg )are absolutely essential to life.57 Bio-molecules: Compounds of Carbonl Carbon: 至少占細胞干重的一半至少占細胞干重的一半l Why Carbon? versatile bonding capacityl Each C atom can form very stable single bond with 1 - 4 other C atoms; and

31、 double or triple bonds between two C atoms.l Covalently linked C atoms can form different structures （linear, branched, or cyclic） ladding functional groups conferring specific activities to the molecules.58Versatility of carbon in formingcovalent bonds59l Organic compounds: Molecules containing co

32、valently bonding carbon backbones; e.g. alcohols, amines, aldehydes (醛醛), ketones, 羧基羧基, 巰基巰基, etc Most bio-molecules are organic compounds.l “C” : tetrahedral arrangement of its four single bonds. C - C single bonds have freedom of rotation, but not double nor triple bonds.l No other chemical eleme

33、nt has the capacity to form molecules of such widely different sizes, shapes, with variety of functional groups6061 Most biomolecules can be considered to be derived from hydrocarbons hydrophilic interactions between biomoleculesHydrocarbons甲烷甲烷己烷己烷62fisherBall-and-stickSpace filling Bio-molecules h

34、ave 3-D structures63 Bio-molecules have 3-D structuresThe special feature of organic compounds is NOT their compositions but the way their atoms are combined (structures, 1820s) Corollary（推論）（推論）: two substances may show the same chemical formula but physically and chemically different materials (di

35、fferent structures and functions).64Convention used for configuration65Light absorbing pigment in rhodopsinan integral membrane proteinChiral：手性：手性67 Interactions between bio-molecules are stereo-specificBetween pairs of enantiomers 對映對映(結構結構)體：體：usually only one form is biologically active. L-amino

36、 acids (S) are found in proteins D-glucose 右旋糖右旋糖 (R) is biologically active最高編號的手性最高編號的手性C原子上的原子上的-OH在右邊在右邊Only one chiral form is generated in living cells due to enzyme specificity (1975 Nobel Prize) In vitro chemical synthesis：the two enantiomers are usually synthesized in equal amounts 68Chewin

37、g gums綠薄荷綠薄荷香菜香菜Two stereoisomers may have totally opposite biological effects (e.g., Chewing gums)69Neutral sweet天冬酰苯丙氨酸甲酯天冬酰苯丙氨酸甲酯 Aspartame, a sugar substitute;its stereoisomer, bitter70Four families: Amino acids；Sugar；Fatty acids；NucleotidesFunctions:Used to synthesize larger molecules；Have spec

38、ial biological functions；Involved in complex reaction pathways；Major Classes of Small Bio-molecules71Five general types of reactions in cells:Oxidation-reduction (氧化還原反應氧化還原反應) Internal re-arrangements (isomerization, 異構異構)Cleavage & formation of “C-C” bondsGroup transfer (親核取代親核取代)Condensation Bioc

39、hemical ReactionSimilar to other chemical reactions - broken and formation of covalent bonds72Oxidation：gains oxygen or loses hydrogenReduction：loses oxygen or gains hydrogenOxidation-Reduction Reactions73the intramolecular shift of atoms/groups Internal re-arrangements (isomerization, 異構異構) 醛醣醛醣酮醣酮

40、醣74Energy：the central theme in Biochemistry Living cells need a constant flow of energy to prevent them from becoming disorderedLiving cells have evolved subtle mechanisms for generating and using energy75 All life processes consist of chemical reactions catalyzed by enzymes The reactions in a livin

41、g organism are known collectively as metabolism (代謝）代謝） Acquisition and utilization of energy Synthesis of molecules：for cell structure and functioningRemoval of waste products Biochemical Reaction in life76Definition of MetabolismThe highly integrated network of chemical transformations.Degradation

42、 (decreasing order, thus energy releasing) to provide energy, catabolism 分解代謝分解代謝; Synthesis (increasing order, thus energy consuming) to provide building materials, anabolism 合成代謝合成代謝.77Extract energy and reducing power from the environment (生命體通過光合作用和氧化生命體通過光合作用和氧化作用從外界吸收能并釋放廢棄物）作用從外界吸收能并釋放廢棄物）Gen

43、eration (interconversion) of all the biomolecules for a living organism (biosynthesis).（伴隨著物質和能量代謝，生物伴隨著物質和能量代謝，生物分子間通過分解和合成作用發生互換分子間通過分解和合成作用發生互換）78Anabolism 合成代謝合成代謝Catabolism 分解代謝分解代謝能源物質能源物質中間代中間代謝產物謝產物廢棄物廢棄物79 linear, branched or circular pathways; Highly interconnected 各個途徑相互交接，形成物與能的網絡化交流各個途徑

44、相互交接，形成物與能的網絡化交流 Tightly regulated to achieve best economy精密調控，保證機體最經濟的利用物質和能量精密調控，保證機體最經濟的利用物質和能量80All living organisms are made up of cells, the smallest unit both the structural and functional of living matters. Cells are capable of self-reproduction.Most cells are microscopic in size Eukaryotic

45、cells: 5 - 100 m mm in size； bacteria: 1-2 m mm; mycoplasma: 0.3 m mm Cell: Fundamental Unit of Life81Prokaryotic (原核）原核）cells: Lack a nucleus e.g., Eubacteria and archaea Simple structure; Abundant &diverseEukaryotic（真核）（真核）cells Possess a nucleus bounded by membrane, containing genetic information

46、 in the form of chromosomesComparison: see Table 2-1, p29 Lehninger Two category of cells 82A dividing E. coli 大腸桿菌大腸桿菌83EukaryotesLarger Cell volume；More complicated cell structure, with membrane-bounded nucleus and organelles (細胞器）細胞器）Energy metabolism: more unified and packed in mitochondriaWith

47、cytoskeleton and intracellular movementCell divided by mitosis Form multi-cellular organisms8485Permit the concentration of reactant and product moleculesMake intricate regulatory mechanism possible Cells of multi-cellular eukaryotes are able to respond quickly and effectively to the intercellular c

48、ommunicationAdvantages from Organelles86Advantages of Multi-cellular organisms over unicellular ones Possess a relatively more stable , controlled environment for cells Cells have a division of labor allowing greater complexity in both form and function Able to exploit environmental resources more e

49、ffectivelyThey are highly ordered living systems87Nucleus Store the genetic information carrier (DNA) Surrounded by an N envelop (double membranes with specialized pores). The outer layer is continuous with ER membrane system.DNA is condensed 螺旋螺旋 (compressed about 10 million fold in the linear dime

50、nsion) in a human chromosome 染色體染色體.88Nuclear poresnucleolus89DNA 被螺旋壓縮被螺旋壓縮 (10 million fold in the linear dimension) 后組成染色體后組成染色體9091Endoplasmic Reticulum (ER)內質網內質網continuous membrane system consist of tubes & flattened sacs forming an enclosed lumen Ribosomes (synthesize proteins) are attached t

51、o the cytoplasmic surface of ER, forming rough ER (RER) structure. Smooth ER (often tubular)： site for lipid synthesis；generates transport vesicles that fuse with other membrane systems in cell929394Golgi Apparatus: process and sort proteins a stack of flattened membrane sacs surrounded by many small vesicles. structurally and functionally asymmetric, the cis side fac