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1、BiochemistryPart II,Xianghui Yu National Engineering laboratory for AIDS Vaccine,contents,代谢总论和生物能学(metabolism and Bioenergetics)糖酵解(Glycolysis)柠檬酸循环(The Citric Acid 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)蛋白质代谢(Amino
2、Acid Metabolism)脂类代谢(Lipid Metabolism)核酸结构和性质(Structure and properties of nucleic acids)核酸代谢(Nucleotide Metabolism),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
3、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(cata
4、bolic reactions):degrade 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 kind
5、s of macromolecules(DNA,RNA,proteins)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 strateg
6、ies 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.,Basic biochemistry:The unit of all life is the cell.Single-celled organisms:Bacteria and protozoa Multi-cel
7、led organisms:All plants and animalsHierarchy of cellular life:Cells-Tissues-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 ce
8、lls.,HydrocarbonsHCOctane=C8H18(Lipids)CarbohydratesCHOGlucose=C6H12O6(Sugars)Amino acids CHON(S)Glycine=C2H5O2N(Proteins)Nucleotides CHONP AMP=C10H14N5O7P(DNA,RNA),The Four Molecules of Life,What is the Human Genome Project?,U.S.govt.project coordinated by the Department of Energy and the National
9、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 make up human DNA.
10、-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 from 10-20 primary samples tak
11、en from numerous anonymous donors across racial and ethnic groups.,从左至右依次为Venter、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 ener
12、gy sources,bio fuels.DNA forensics:identifying potential suspects at a crime 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
13、are the implications of the Human Genome Project specifically to each 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:s
14、hould screening be done when there is no treatment available?Some other issues:Reproductive issues:use of genetic information in decision making.Clinical issues:implementation of standards and quality control measures in testing procedures.,E.coli has about 900 genes that encode metabolic enzymes us
15、ed in intermediary metabolism and has about 130 different pathways.These genes accounts for 21%of the genes in the genome.Mycobacterium tuberculosis has about 250 enzymes involved in fatty acid metabolism-five times as many as E.coli.,Organisms demonstrate the following common themes,Organisms or ce
16、lls maintain specific internal concentrations of 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 th
17、eir environments.The cells of organisms are not static assemblies of molecules.Many cell components are continually synthesized and degraded.,Metabolic pathways are sequences of reactions,Within each of the four areas of metabolism,we recognize distinct sequences of metabolic reactions,called pathwa
18、y.A pathway is the biological equivalent of 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。,Individual metabolic pathways can take different forms.,A linear metabolic pathway is a series of enzyme-
19、catalyzed reactions in which the product of one reaction is the substrate 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 u
20、sed repeatedly.,Metabolism proceeds by discrete steps,A metabolic pathway has many stepsThat begin with a specific molecule and end with a productThat are each catalyzed by a specific enzyme,One reason for multiple steps is the limitied reaction specificity of enzymes.Another reason for multiple ste
21、ps in metabolic pathways is to control energy input and output.Finally,multiple steps provide opportunities to establish control points.,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。,10.2 metabolic pathways are regulated,The flow of material
22、 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 substrateIs the reactant an enzyme acts onThe enzymeBinds to its substrate,
23、forming an enzyme-substrate complex,The active siteIs the region on the enzyme where the substrate binds,The catalytic cycle of an enzyme,In feedback inhibitionThe end product of a metabolic pathway shuts down the pathway through inhibition of an early step,usually the first committed step.Feed-forw
24、ard activation 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
25、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
26、外,还有另外一种途径,就是以氢原子和电子的形式将自由能转移给生物合成的需能反应。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。,维生素B3(也称维生素pp、或烟酰胺 nicotinamide),(1)结构,维生素B5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,B5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。,NAD
27、+/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)。,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 Compartmentation and interorgan metabolism,新陈代谢的功能,代谢的功能概括为5个方面:从周围环境中获得营养物质。
28、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。,Properties of Metabolic Pathways,Irreversible(overall):reversibility of individual stepsSeparate Anabolic and Catabolic PathwaysFirst Committed(Exergonic)Step:others close to equilibriumRegulation(usually first commi
29、tted step):often rate-limiting,Features of Metabolic Pathways,A B C D E,Sequences and Energetics Enzymes and Mechanisms Control Mechanisms(Regulation)Compartmentation,生物能学,Thermodynamics and Metabolism,一、有关热力学的一些基本概念二、化学反应中自由能的变化和意义三、高能磷酸化合物,能量代谢,任何物质的变化都伴随着能量的变化,生物体内能量的变化过程称为能量代谢。能量代谢与物质代谢同时存在,不存在无
30、物质代谢的能量代谢,也不存在无能量代谢的物质代谢。,Kinetic energyIs the energy associated with motionPotential energyIs stored in the location of matterIncludes chemical energy stored in molecular structure,一、有关热力学的一些基本概念,The Laws of Energy Transformation,ThermodynamicsIs the study of energy transformations,The First Law of
31、 Thermodynamics,According to the first law of thermodynamicsEnergy can be transferred and transformedEnergy cannot be created or destroyed,热力学第一定律 能量守恒定律:热力学第一定律是对能量守恒和转换定律的一种表述方式。热力学第一定律指出,热能可以从一个物体传递给另一个物体,也可以与机械能或其他能量相互转换,在传递和转换过程中,能量的总值不变。DU=Q-W DU:一个体系的内能变化,Q:体系变化吸收的热量 W:代表体系所做的功 内能(internal en
32、ergy):指体系内部质点能量的总合,用U表示。,Energy can be convertedFrom one form to another,The Second Law of Thermodynamics,According to the second law of thermodynamicsSpontaneous changes that do not require outside energy increase the entropy,or disorder,of the universe,热力学第二定律:热的传导只能由高温物体传至低温物体。热的自发地逆向传导是不可能的。这表明:
33、热力学体系的运动有一定的方向性,即自高温流向低温。熵(entropy):代表体系能量分散程度的状态函数,用S表示。焓是一个热力学系统中的能量参数。由字母H表示。指内能和体积的变化。,二、化学反应中自由能的变化和意义(Free-Energy Change),1、化学反应的自由能变化的基本公式=H-TS2、化学反应自由能变化与平衡常数的关系3、偶联化学反应G变化的可加性4、能量学用于生物化学反应中的一些规定,The free-energy change of a reaction tells us whether the reaction occurs spontaneously,Free-Ene
34、rgy Change,G,A living systems free energyIs energy that can do work under cellular conditions,The change in free energy,G during a biological processIs related directly to the enthalpy change(H)and the change in entropy,G=H TS,Free Energy,Stability,and Equilibrium,Organisms live at the expense of fr
35、ee energyDuring a spontaneous changeFree energy decreases and the stability of a system increases,Free Energy&Spontaneity,自由能(free energy),物理意义:*(体系中能对环境作功的能量)自由能的变化能预示某一过程能否自发进行,即:G0,反应不能自发进行 G=0,反应处于平衡状态。,自由能的概念对于研究生物化学过程的力能学具有很重要的意义,生物体用于作功的能量正是体内化学反应释放的自由能,生物氧化释放的能量也正是为有机体利用的自由能。它不仅可以用来判断机体内某一过程
36、能否自发进行,而且还可以利用自由能这个函数来计算反应的其它有用参数。,化学反应中的标准自由能变化,在化学反应中,反应物和产物各自都有特定的自由能。产物自由能的总和与反应物自由能的总和之差,就是该反应的自由能变化。,计算标准自由能变化时的标准条件,标准条件指的是,反应的温度为25,大气压为101,325 Pa(1atm),反应物和产物的浓度都是1mol/L。标准自由能变化的符号用G0表示。对于生物化学反应,标准状况还规定反应进行的环境为pH=7,这时的标准自由能变化用G0表示。,标准自由能变化的计算公式,假设有如下的一个化学反应式:aA+bB cC+dD在恒温和恒压下,这一反应的自由能变化公式是
37、:式中G0是该反应的标准自由能变化,R是气体常数,T是绝对温度,A、B、C、D代表4种物质的摩尔浓度,严格地应为活度。,从以上的公式可以看出,一个化学反应自由能的变化值G,由两部分决定,一部分是不变因素,即由反应本身的性质所决定;另一部分是可变因素,即各物质的浓度、反应的化学当量以及反应的温度。,一些计算问题:,R1.98 x10-3kcal/mol.K 8.31 x 10-3 kJ/mol.KT=298 K,计算磷酸葡萄糖异构酶反应的自由能变化,达平衡时=Keq=19,解:,G=-RTlnKeq=8.314 10-3 311 ln19=-7.6KJ.mol-1,反应G-1-PG-6-P在38
38、0C达到平衡时,G-1-P占5%,G-6-P占95%,求 G0。如果反应未达到平衡,设,求反应的 G是多少?,G=G+RTlnQc(Qc-浓度商)=-7.6+8.314 10-3 311 ln0.1,未达平衡时=Qc=0.1,A B G=+20.92 KJ/mol B C G=-33.47 KJ/mol 则 A C G=-12.55 KJ/mol,该规则表明一个在热力学上不利的反应,可以与热力学有利的反应偶联进行,即可以被热力学有利的反应所驱动而进行。这在生物化学反应中是很多的。,偶联化学反应标准自由能变化的可加性及其意义,The Structure and Hydrolysis of ATP
39、,ATP(adenosine triphosphate)Is the cells energy shuttleProvides energy for cellular functions,ATP的特点,在pH=7环境中,ATP分子中的三个磷酸基团完全解离成带4个负电荷的离子形式(ATP4-),具有较大势能,加之水解产物稳定,因而水解自由能很大(G=-30.5千焦/摩尔)。,ATP4-+H2O ADP3-+Pi2-+H+G-30.5kJMOL-1,磷脂键,酸酐键,ATP中酸酐键不稳定的因素:,磷酸基团之间相邻的负电荷相互排斥,促使磷酸基团易于水解。当水解后,分子内相同电荷的排斥力得到缓和,同时A
40、DP3-和HPO42-再结合的可能性很小。从ATP的水解产物看,所形成的产物ADP3-和HPO42-都是共振杂化物。其中电子所处的位置与ATP相比都是具有最低能量的构象形式,因此具有很低的共振稳定性。,Energy is released from ATPWhen the terminal phosphate bond is broken,ATP powers cellular work by coupling exergonic reactions to endergonic reactions,Energy couplingIs a key feature in the way cells
41、 manage their energy resources to do this work,Various Pi Transfers,ATP hydrolysisCan be coupled to other reactions,三、高能磷酸化合物,Metabolites with high phosphoryl-group-transfer potentials,机体内有许多含磷酸的化合物,当其磷酰基水解时,释放出大量的自由能,这类含磷酸的化合物称为高能磷酸化合物。当这些磷酰基水解时,能释放出20.92kj/mol(5 kcal/mol)以上的能量,因此将这些磷酸基团与其它基团之间的键称为
42、“高能键”(high-energy bond),并用符号 表示。注意:生物化学中的“高能键”的含义与化学中使用的“键能”含义是完全不同的。化学中的“键能”是指断裂一个化学键所需要提供的能量;而“高能键”是指该键水解时所释放的大量的自由能。,高能磷酸化合物及其它高能化合物的类型,这些高能磷酸化合物中的磷酸大多数是与另一个酸形成酸酐,与之形成酸酐的酸有羧酸、磷酸、硫酸等。还有磷酸与胍基、烯醇式羟基之间结合的化合物也是高能磷酸化合物。除了含磷酸的高能化合物外,还有不含磷酸的高能化合物,如酰基CoA中的硫酯键、S-腺苷蛋氨酸中甲基与S之间的硫醚键也是高能键。,高能化合物与ATP的作用,高能化合物,磷酸
43、化合物,非磷酸化合物,磷氧型,磷氮型,硫酯键化合物,甲硫键化合物,烯醇磷酸化合物,酰基磷酸化合物,焦磷酸化合物,磷氧键型高能磷酸化合物(OP),乙酰磷酸,氨甲酰磷酸,1,3-二磷酸甘油酸,(1)酰基磷酸化合物(和羧基),焦磷酸,磷氧键型高能磷酸化合物,(2)焦磷酸化合物(磷酸),磷酸烯醇式丙酮酸,(3)烯醇式磷酸化合物(烯醇式羟基),磷氮键型高能磷酸化合物 胍基磷酸化合物,磷酸精氨酸,磷酸肌酸,硫酯键型高能化合物 活性硫酸基,3-腺苷磷酸5-磷酰硫酸,酰基CoA,甲硫键型高能化合物 活性甲硫氨酸,S-腺苷甲硫氨酸,一些磷酸化合物水解的标准自由能变化,ATP在能量转运中的地位和作用,它可以在磷酸
44、转移中起到“共同中间传递体”的作用。,磷酸肌酸的作用,神经和肌肉等细胞活动的直接供能物质是ATP,但ATP在细胞中的含量很低。在哺乳动物的脑和肌肉中约38mmol/kg。这些ATP只能提供肌肉剧烈活动1s左右的消耗。而肌肉和脑中磷酸肌酸的含量远远超过ATP,在脑中大约为ATP的1.5倍,在肌肉中则为ATP的4倍。受过良好训练的运动员其肌肉中磷酸肌酸的含量可高达30mmol/kg。磷酸肌酸可以看成是ATP的后备军,磷酸肌酸中贮存的能量可以很快转移到ATP中。,磷酸肌酸的作用,磷酸肌酸+ADP-肌酸+ATP,肌酸激酶,磷酸肌酸及其它贮能物质的作用,当细胞处于静息状态时,ATP的浓度较高,反应向合成
45、磷酸肌酸的方向进行。当细胞处于活动状态时,ATP的浓度下降,反应即转向合成ATP的方向进行,因此磷酸肌酸有“ATP缓冲剂”之称。磷酸精氨酸是某些无脊椎动物如蟹和龙虾等肌肉中的贮能物质,其作用与磷酸肌酸相似。有些微生物以聚偏磷酸作为贮能物质。,ATP以外的其它核苷三磷酸的递能作用,除了ATP外,其它核苷三磷酸也在某些情况下为反应提供能量。,Metabolism(Overview),Metabolism=Catabolism+AnabolismCatabolic reactions are energy yieldingThey are involved in the breakdown of m
46、ore-complex molecules into simpler onesAnabolic reactions are energy requiringThey are involved in the building up of simpler molecules into more-complex onesWe can consider these bioenergetics in terms of the physical laws of thermodynamics,Laws of Thermodynamics,First Law of Thermodynamics:Energy
47、can be neither created nor destroyedTherefore,energy“generated”in any system is energy that has been transformed from one state to another(e.g.,chemically stored energy transformed to heat)Second Law of Thermodynamics:Efficiencies of energy transformation never equal 100%Therefore,all processes lose
48、 energy,typically as heat,and are not reversible unless the system is open&the lost energy is resupplied from the environmentConversion to heat is the ultimate fate of chemical energy,Organisms are Energy Transducers,Organisms take in energy&transduce it to new forms(1st law)As energy transducers,or
49、ganisms are less than 100%efficient(2nd law)Organisms employ this energy to:GrowProtect ThemselvesRepair ThemselvesCompete with other OrganismsMake new Organisms(I.e.,babies)In the process,organisms generate waste chemicals&heatOrganisms create local regions of order at the expense of the total ener
50、gy found in the Universe!We are Energy Parasites!,Coupling the Biosphere,Anabolic process,Catabolic process,Chemically stored energy,本章小结,1.新陈代谢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,包括合成代谢和分解代谢。2.新陈代谢的共同特点:由酶催化,反应条件温和;诸多反应有严格的顺序,彼此协调;具有中间代谢。3.辅酶和辅酶,FMN和FAD和辅酶A在能量代谢中的作用.4.热力学第一定律:能量守恒定律 DU=Q-W5.热力