生物化学教学课件：生化引论

1、1 现代化大学现代化大学: : 培养科学思维和创新人才培养科学思维和创新人才 创造知识，社会发展的原动力创造知识，社会发展的原动力 科学研究科学研究: 凝练和提出问题凝练和提出问题 (思维思维) 如何去解决问题如何去解决问题 (人、经费、实验条件人、经费、实验条件) 你的成果如何得到社会的承认你的成果如何得到社会的承认 (回报回报) 如何做好这些？首先是打好基础如何做好这些？首先是打好基础 2 Diversity and Unity For the discovery that mature cells can be reprogrammed to become pluripotent “发现

2、成熟细胞可以重新编程而获得多能性发现成熟细胞可以重新编程而获得多能性” Shinya Yamanaka John B. Gurdon 2012年，诺贝尔生理年，诺贝尔生理/医学奖医学奖 中枢神经中枢神经 软骨软骨 肌肉肌肉 脂肪脂肪 上皮上皮 畸胎瘤实验畸胎瘤实验 iPS-derived mice 引入关键基因引入关键基因 体细胞重新编程体细胞重新编程 iPS, induced pluripotent stem cell 诱导多能干细胞诱导多能干细胞 iMice Robert J. Lefkowitz Brian K. Kobilka “for studies of G-protein-cou

3、pled receptors” 表彰他们对表彰他们对G蛋白耦联受体的研究蛋白耦联受体的研究 人高度紧张时人高度紧张时“肾上腺素开始大量分泌肾上腺素开始大量分泌” 2012年，诺贝尔年，诺贝尔 化学奖化学奖 How could the inside of the cell know what was happening on the outside? 脑脑：神经信号警告神经信号警告 身体各部位，释放身体各部位，释放 激素激活肾上腺激素激活肾上腺 眼：眼：瞳孔瞳孔 放大，视放大，视 野变窄野变窄 心脏心脏：心率加速心率加速 肺：肺：气管扩张，气管扩张， 呼吸频率加快呼吸频率加快 肌肉：肌肉：血量增

4、加，血量增加， 肌肉收缩肌肉收缩 肝脏：肝脏：糖原分解，糖原分解， 糖被释放到血液糖被释放到血液 脂肪细胞：脂肪细胞：脂肪脂肪 酸被释放到血液酸被释放到血液 肠胃：肠胃：流入消化流入消化 系统的血量减少系统的血量减少 Time to flee! 髓质髓质 皮质醇皮质醇 肾上腺素肾上腺素 去甲肾上腺素去甲肾上腺素 皮质皮质 7 G蛋白耦联受体：蛋白耦联受体： 感受物化刺激，包括多种神经递质、肽类激感受物化刺激，包括多种神经递质、肽类激 素和趋化因子受体素和趋化因子受体 超过半数的现代药物靶向超过半数的现代药物靶向 8 英国细菌学家弗莱明英国细菌学家弗莱明 - 1928- 1928年发现青霉素年发

5、现青霉素 弗莱明在简陋的实验室，研究葡萄球菌弗莱明在简陋的实验室，研究葡萄球菌 盖子没盖好盖子没盖好，培养细菌的琼脂上附了一层青霉菌，培养细菌的琼脂上附了一层青霉菌 ( (来自楼上的一位研究青霉菌学者的窗口来自楼上的一位研究青霉菌学者的窗口) ) 在青霉菌的近旁，葡萄球菌不见了在青霉菌的近旁，葡萄球菌不见了 培养这种霉菌，发现青霉素可快速杀死将葡萄球菌培养这种霉菌，发现青霉素可快速杀死将葡萄球菌 发明了第一种能够治疗人类疾病的抗生素发明了第一种能够治疗人类疾病的抗生素- -青霉素青霉素 也有的药物：有一定作用也有的药物：有一定作用 但其副作用是人类但其副作用是人类付出巨大代价付出巨大代价之后才

6、了解之后才了解 9 Thalidomide：人类药物史：人类药物史 上的著名案例，其出名不上的著名案例，其出名不 是因为药物疗效，而是毒是因为药物疗效，而是毒 性性-“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-构型：抑制妊娠反应；构型：抑制妊娠反应；S- S-构型有致畸性构型有致畸性 手性药物：手性药物：1990年销售额年销售额 180亿，亿，2005年年-1720亿美元亿美元 2006年全球畅销药物的前四名均为单旋体手性药物年全球畅销药物的前四名均为单旋体手性药物 沙利度胺的新认识：沙利度胺的新认识： 在免疫、抗炎、抗血管生成的药理

7、和一些疑难病症上在免疫、抗炎、抗血管生成的药理和一些疑难病症上 的研究和治疗应用中取得了令人欣喜的结果的研究和治疗应用中取得了令人欣喜的结果 11 生物化学是生物学和医学研究的必备基础生物化学是生物学和医学研究的必备基础 12 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 te

8、rms. The combination of biology and chemistry or the application of chemical principles to understand biology. 13 Living organisms vs. inanimate objects chemical complexity and organization use energy in a systemic way self-replication and self-assembly Biochemistry Explains: Diverse lives in unifyi

9、ng chemical terms All macromolecules are made of a few simple compounds 14 Main Questions for Biochemistry I (This semester） What are the composition and structure of bio-molecules? How do these bio-molecules act and interact in living organisms？ 15 1. Protein Structure and Function （蛋白质的结构和功能）（蛋白质的

10、结构和功能） 2. Enzymes: Basic Concepts and Kinetics (酶的基本概念及酶促动力学酶的基本概念及酶促动力学) 3. Enzymes: Catalytic 6-28%; 为何临床疗效欠佳为何临床疗效欠佳 ? ? 23 Stage I 1870s1930s - Chemical Constitution of Living Organisms Stage II 1930s1950s - Law of Chemical Change and Control of Different Bio-molecules Stage III 1950s present -

11、Principles that are Central for Understanding Living Organisms. The Development of Biochemistry 24 1810 30: C, H, O, and N are the major substances from animals and plants. The term “Protein” was first used in 1838. 1850 90: Carbohydrates, lipids, and nucleic acids were recognized. The term “biochem

12、istry” 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). 25 1920s James Sumner: Enzymes are proteins. 1940s - 1950s Avery and Hershey: DNA carries the genetic information. 1950s Frankli

13、n, and Watson and Crick: DNA is a double helix. 1960s Nirenberg: Genetic codes deciphered. 1980s Cech: RNA has catalytic activity (Ribosome). 26 近近2020年年 诺贝尔生理和医学奖中诺贝尔生理和医学奖中 8080的发现与生化相关的发现与生化相关 27 Krebs: Citric Acid Cycle (TCA): an important way by which the complex chemical processes provide livi

14、ng organisms with high energy phosphate. Sanger: Sequencing Method Amino acid sequencing method and the complete sequence of insulin. Sanger Sequencing Method for DNA 28 (有荚膜有荚膜, S; 致病性）致病性） 29 30 S (heat-killed) Mouse lives 31 R + S (heat-killed/ extracts) Mouse dies 32 结果小结和分析结果小结和分析 （背景：以往认为（背景：以

15、往认为蛋白质蛋白质携带遗传信息）携带遗传信息） 33 34 Part I Foundations of Biochemistry 1. The molecular logic of life 2. Bio-molecules 3. Cells 4. Water Some Important Chemical Concepts and Principles for Studying Biochemistry 35 General Features of Living Organism complicated and double or triple bonds between two C ato

16、ms. l Covalently linked C atoms can form different structures （linear, branched, or cyclic） ladding functional groups conferring specific activities to the molecules. 42 Versatility of carbon in forming covalent bonds 43 l Organic compounds: Molecules containing covalently bonding carbon backbones;

17、e.g. alcohols, amines, aldehydes (醛醛), ketones, 羧基羧基, 巯基巯基, 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 element has the capacity to form molec

18、ules of such widely different sizes, shapes, with variety of functional groups 44 45 Most biomolecules can be considered to be derived from hydrocarbons hydrophilic interactions between biomolecules Hydrocarbons 甲烷甲烷己烷己烷 46 fisherBall-and-stickSpace filling Bio-molecules have 3-D structures 47 Bio-m

19、olecules have 3-D structures The special feature of organic compounds is NOT their compositions but the way their atoms are combined (structures, 1820s) Corollary（推论）（推论）: two substances may show the same chemical formula but physically and chemically different materials (different structures and fu

20、nctions). 48 Convention used for configuration 49 Light absorbing pigment in rhodopsin an integral membrane protein 50 Chiral：手性：手性 51 Interactions between bio-molecules are stereo-specific Between pairs of enantiomers 对映对映(结构结构)体：体： usually only one form is biologically active. L-amino acids (S) ar

21、e found in proteins D-glucose (R) is biologically active 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 52 Chewing gums 绿薄荷绿薄荷 香菜香菜 Two stereoisomers may have tota

22、lly opposite biological effects (e.g., Chewing gums) 53 Neutral 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, bitter 54 Four families: Amino acids；Sugar； Fatty acids；Nucleotides Functions: Used to synthesize larger molecules； Have special biological functions； Involved in

23、 complex reaction pathways； Major Classes of Small Bio-molecules 55 Five general types of reactions in cells: Oxidation-reduction (氧化还原反应氧化还原反应) Internal re-arrangements (isomerization, 异构异构) Cleavage Synthesis (increasing order, thus energy consuming) to provide building materials, anabolism 合成代谢合成

24、代谢. 61 Extract energy and reducing power from the environment (生命体通过光合作用和氧化生命体通过光合作用和氧化 作用从外界吸收能并释放废弃物）作用从外界吸收能并释放废弃物） Generation (interconversion) of all the biomolecules for a living organism (biosynthesis).（伴随着物质和能量代谢，生物伴随着物质和能量代谢，生物 分子间通过分解和合成作用发生互换分子间通过分解和合成作用发生互换） 62 Anabolism 合成代谢合成代谢 Catabol

25、ism 分解代谢分解代谢 能源物质能源物质 中间代中间代 谢产物谢产物 废弃物废弃物 63 linear, branched or circular pathways; Highly interconnected 各个途径相互交接，形成物与能的网络化交流各个途径相互交接，形成物与能的网络化交流 Tightly regulated to achieve best economy 精密调控，保证机体最经济的利用物质和能量精密调控，保证机体最经济的利用物质和能量 64 All 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 cells: 5 - 100 m mm in size； bacteria: 1-2 m mm; mycoplasma: 0.3 m mm Cell: Fundamental Unit of Life 65 Prokaryotic (原核）原核）cells: Lack a nucleus e.g., Eubacteri