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1、Biochemistry Part II,Xianghui Yu National Engineering laboratory for AIDS Vaccine ,What will we learn? How to learn?,Basic biochemistry: The unit of all life is the cell. Single-celled organisms: Bacteria and protozoa Multi-celled organisms: All plants and animals Hierarchy of cellular life: Cells T
2、issues Organs Organisms Populations,Small molecules of life,What are the elements of living molecules? CHONPS biogenic elements: carbon, hydrogen, oxygen, nitrogen, phosphorus, sulfur Compose 99 percent of the organic matter in living cells.,Hydrocarbons HC Octane = C8H18(辛烷) (Lipids) Carbohydrates
3、CHO Glucose = C6H12O6 (Sugars) Amino acids CHON(S) Glycine = C2H5O2N (Proteins) Nucleotides CHONP AMP = C10H14N5O7P (DNA, RNA),The Four Molecules of Life,Lipids: 储能物质 Sugars:能源物质 Proteins:功能和结构物质 Nucleotides:遗传物质,contents,代谢总论和生物能学 ( metabolism and Bioenergetics) 糖酵解(Glycolysis) 柠檬酸循环 (The Citric Ac
4、id Cycle) 糖代谢的其他途径(Additional pathways in Carbohydrate Metabolism) 电子传递与氧化磷酸化(Electron transport and Oxidative Phosphorylation) 核酸结构和性质 (Structure and properties of nucleic acids) 核酸代谢 (Nucleotide Metabolism) 蛋白质代谢 (Amino Acid Metabolism) 脂类代谢 (Lipid Metabolism),团队介绍,于湘晖,苏维恒,吴慧,课程共分为五部分,代谢总论和生物能学(于湘
5、晖) 糖代谢(糖酵解、柠檬酸循环 、糖代谢的其他途径和电子传递与氧化磷酸化)(于湘晖和马俊峰) 核酸的结构和核酸的代谢(吴慧) 脂类代谢(苏维恒) 蛋白质代谢(苏维恒),10.1 metabolism is the Sum of Cellular Reactions,Metabolism is the entire network of chemical reactions carried out by living cells. 新陈代谢(metabolism)是生命最基本的特征之一,泛指生物与周围环境进行物质交换、能量交换和信息交换的过程。生物一方面不断地从周围环境中摄取能量和物质,通过一
6、系列生物反应转变成自身组织成分,即所谓同化作用(assimilation);另一方面,将原有的组成成份经过一系列的生化反应,分解为简单成分重新利用或排出体外,即所谓异化作用(dissimilation),通过上述过程不断地进行自我更新。,合成代谢与分解代谢,合成代谢 (anabolic reactions):synthesize the molecules needed for cell maintaince, growth and reproduction. 生物体内由小分子物质转化成大分子物质的过程,属同化作用的范畴。 分解代谢 (catabolic reactions):degrade
7、molecules to liberate smaller molecules and energy. 生物体内由大分子物质转变成小分子物质的过程,属异化作用的范畴。,新陈代谢的概念及内涵,小分子 大分子 合成代谢(同化作用) 需要能量 释放能量 分解代谢(异化作用) 大分子 小分子,物质代谢,能量代谢,新陈代谢,信息交换,Birds, beasts, plants, and soil microorganisms share with humans the same basic structural units (cells) and the same kinds of macromolec
8、ules (DNA, RNA, proteins and lipids) made up of the same kinds of monomeric subunits (nucleotides, amino acids). They utilize the same pathways for synthesis of cellular components, share the same genetic code, and derive from the same evolutionary ancestors.,Organisms change their inherited life st
9、rategies to survive in new circumstances. The result of eons of evolution is an enormous diversity of life forms, superficially very different but fundamentally related through their shared ancestry.,What is the Human Genome Project?,U.S. govt. project coordinated by the Department of Energy and the
10、 National Institutes of Health, launched in 1986 by Charles DeLisi. Definition: GENOME the whole hereditary information of an organism that is encoded in the DNA. Aims of the project: - to identify the approximate 100,000 genes in the human DNA. - determine the sequences of the 3 billion bases that
11、make up human DNA. - store this information in databases. - develop tools for data analysis. - address the ethical, legal, and social issues that arise from genome research.,Whose genome is being sequenced?,the first reference genome is a composite genome from several different people. generated fro
12、m 10-20 primary samples taken from numerous anonymous donors across racial and ethnic groups.,the Department of Energy and the National Institutes of Health Watson and 3 billions Dollars 1992年,Watson因为反对给人类基因申请专利退出HGP计划, Watson却认为所有与人类基因有关的知识都应该免费与全人类共享 1993年,时年43岁的Francis Collins接替了Watson的工作,开始领导国际
13、基因组计划 Craig Venter建议使用速度更快的“鸟枪法”测序代替链终止法。 1998年,PE 公司以其刚研制成功的300台最新毛细管自动测序仪(ABI 3700)和3亿美元资金,成立了Celera Genomics公司 1999年, Celera为人类的6500个基因申请专利保护。这意味着人体内将有6500条基因归Celera所有,任何人想要检测或者医药公司研发和这些基因有关疾病的新药,抑或科学家想研究这些基因都要给塞雷拉公司交钱。 2000年3月14日,时任美国总统,比尔克林顿和英国首相布莱尔联合发表声明称人类基因组数据不允许专利保护,必须对所有研究者公开。,从左至右依次为Vente
14、r、Clinton、Collins,2000年6月26日,伟大的时刻终于来临,美国总统克林顿等六国领导人共同宣布人类基因组计划的草图完成。,How is each area benefited specifically by the Human Genome Project?,Improvements in medicine: improved diagnosis of disease. Microbial research: new energy sources, bio fuels. DNA forensics: identifying potential suspects at a cr
15、ime scene. Agriculture: more nutritious produce. Evolution and human migration: study migration of different population groups based on female genetic inheritance. - Risk assessment: reduce the likelihood of heritable mutations.,What are the implications of the Human Genome Project specifically to e
16、ach of these areas?,Some questions to consider: Fairness and privacy: who should have access to your genetic information? Psychological stigmatization: how does knowing your predisposition to disease affect an individual? Genetic testing: should screening be done when there is no treatment available
17、? Some other issues: Reproductive issues: use of genetic information in decision making. Clinical issues: implementation of standards and quality control measures in testing procedures.,Organisms demonstrate the following common themes,Organisms or cells maintain specific internal concentrations of
18、inorganic ions, metabolites, and enzymes. Organisms extract energy from external sources to drive energy-consuming reactions. The metabolic pathways in each organism are specified by the genes it contains in its genome. Organisms and cells interact with their environments. The cells of organisms are
19、 not static assemblies of molecules. Many cell components are continually synthesized and degraded.,E.coli has about 900 genes that encode metabolic enzymes used in intermediary metabolism and has about 130 different pathways. These genes accounts for 21% of the genes in the genome. Mycobacterium tu
20、berculosis has about 250 enzymes involved in fatty acid metabolism-five times as many as E.coli.,Metabolic pathways are sequences of reactions,Within each of the four areas of metabolism, we recognize distinct sequences of metabolic reactions, called pathway. A pathway is the biological equivalent o
21、f a synthetic or degradative scheme in organic chemistry. 虽然新陈代谢包括数以千计的不同酶催化的反应,但仍可以从错综复杂的代谢网络中总结归纳成一些具有共同规律的途径,并将这些途径称为主要代谢途径。这些主要代谢途径在千差万别的生物界具有相当的普遍性。,1. Metabolism proceeds by discrete steps,A metabolic pathway has many steps That begin with a specific molecule and end with a product That are ea
22、ch catalyzed by a specific enzyme,One reason for multiple steps is the limitied reaction specificity of enzymes. (酶的特异性) Another reason for multiple steps in metabolic pathways is to control energy input and output. (有利于能量的摄入和释放的调控) Finally, multiple steps provide opportunities to establish control
23、points.(有利于调控),Burning vs. Metabolism,生物体内的氧化过程是缓慢地,逐步将能量释放出来,其中大部分能量转移到一些特殊的化合物中。 氧化作用所放出的能量与氧化途径无关,只要最后产物相同,释放出的总能量就相同。,2. Individual metabolic pathways can take different forms.,A linear metabolic pathway is a series of enzyme-catalyzed reactions in which the product of one reaction is the substr
24、ate for the next reaction. A cyclic metabolic pathway is also a sequence of enzyme-catalyzed steps, but the sequence forms a closed loop, so the intermediates are regenerated. In a spiral metabolic pathway, the same set of enzymes is used repeatedly .,10.2 metabolic pathways are regulated,The flow o
25、f material through a metabolic pathway, or flux, depends not only on the supply of substrates and the removal of products but also on the activities of the enzymes that catalyze individual reactions.,Substrate Specificity of Enzymes,The substrate Is the reactant an enzyme acts on The enzyme Binds to
26、 its substrate, forming an enzyme-substrate complex,The active site Is the region on the enzyme where the substrate binds,The catalytic cycle of an enzyme,In feedback inhibition(反馈抑制) The end product of a metabolic pathway shuts down the pathway through inhibition of an early step, usually the first
27、 committed step. Feed-forward activation(前馈激活) occurs when a metabolic produced early activates an enzyme that catalyzes a reaction further down the pathway.,新陈代谢的调节,生物机体的新陈代谢是一个完整的整体,机体代谢的协调配合,关键在于它存在有精密的调节机制。代谢的调节使生物机体能适应其内、外复杂的变化环境,从而得以生存。 新陈代谢的调节主要是: 1)靠酶数量和活性的调节 2)细胞中有许多由膜分割的部位,特定的代谢途径在特定的细胞部位进
28、行。 3)物质需要在细胞不同的部位间运输,有时还需要在细胞间或整个机体内运输。物质运输的方向、量及速度也影响代谢。,10.3 major pathways in cells,Roles of ATP and NADPH(NADH) in Metabolism,ATP:中心物质 两对能量携载分子: NADH和NAD+ FADH2和FAD,ATP是能量代谢的中心物质,生物体直接利用的能量物质主要是ATP,在分解代谢中,释放出的能量主要用于合成ATP,在需要提供能量的反应或其它生命活动中,主要是由ATP水解来提供能量的,所以ATP是能量代谢的中心物质。ATP不是一种能量贮存物质,而是一种传递能量的分
29、子,因为在一般情况下,ATP分子合成后,在1分钟之内就被利用。,辅酶和辅酶的递能作用,由营养物质的分解代谢释放出的化学能,除了通过合成ATP的途径捕获外,还有另外一种途径,就是以氢原子和电子的形式转移自由能。这种具有高能的氢原子是由脱氢反应形成的。脱氢反应产生的氢原子和电子可由辅酶或辅酶接受,形成还原型辅酶。当这些辅酶被氧化时,能量又被释放出来。 辅酶的作用:参与电子的传递、基团的转移等,决定了酶所催化反应的性质。,NAD+/NADH,烟酰胺腺嘌呤二核苷酸(氧化/还原) NADP+/NADPH,烟酰胺腺嘌呤二核苷酸磷酸(氧化/还原)。,维生素B3(也称维生素pp、或烟酰胺 nicotinami
30、de),(1)结构,维生素B3是吡啶的衍生物,吡啶-3-羧酸 nicotinic acid (烟酸),吡啶-3-酰胺 Nicotinamide (烟酰胺),(2)功能,B3是NAD和NADP的组成成分,NAD和NADP是许多脱氢酶的辅酶,参与递氢。,维生素B2的衍生物,辅酶A在能量代谢中的作用,乙酰CoA中有一个高能的硫酯键,这也可以看成是酰基的一种活化形式。ATP的酸酐键水解时释放出30.54 kJ/mol的自由能,而乙酰CoA的硫酯键水解时释放出31.38 kJ/mol的自由能。,B5是CoA的组成成分,CoA是生物体内转酰基酶的辅酶(主要作为转乙酰基酶的辅酶),参与转酰基作用。,10.4
31、 Compartmentation and interorgan metabolism,新陈代谢小结,1.代谢的功能概括为5个方面: 从周围环境中获得营养物质。 将外界引入的营养物质转变为自身需要的结构元件,即大分子的组成前体。 将结构元件装配成自身的大分子 合成或降解执行生物体特殊功能所需的生物分子。 提供生命活动所需的一切能量。,2.Anabolism and Catabolism,3.Properties of Metabolic Pathways,Irreversible (overall): reversibility of individual steps Separate Anabolic and Catabolic Pathways First Committed (Exergonic) Step: others close to equilibrium Regulation (usually first committed step): often rate-limiting,4.Features of Metabolic Pathways,A B C D E,Sequences and Energetics Enzymes and Mechanisms Control Mechanisms (Regulation) Compartmentation,
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