生物化学本科课件英文版讲授chapter

1、Chapter 17Metabolism: Basic Concepts and Design Definition the classic definition: The totality of the chemical reactions and physical changes that occur in living organisms, comprising anabolism合成代谢 and catabolism分解代谢the modern one: (From the view of the basic strategy要略 or three key elements要素of m

2、etabolism: energy, reducing power还原力and building block构建元件)：nMetabolism is a general term of a highly integrated network of chemical reactions高度整合(协调,统一)的化学反应网络 by which living cells extract energy and reducing power from their environment and synthesize the building blocks of their macromolecules.

3、1.从环境汲取能量和还原力 2.合成生物大分子的构建元件Pathways 代谢途经代谢途经(由首尾相接的化学反应组成由首尾相接的化学反应组成) Many of these reactions are organized into pathways. Each biochemical pathway consists of several reactions that occur sequentially; that is, the product of one reaction is the substrate for the one that follows.化学反应化学反应(代谢途经代谢途

4、经)网网络络(“点点”, “线线”,“面面”关系关系) Two major types of the pathways: (1) Anabolic合成合成 or biosynthetic ones:nLarge complex molecules are synthesized from smaller precursors从较小的前体合成复杂的大分子 Building block molecules (e.g., amino acids, sugars, and fatty acids) produced or acquired from the diet (i.e. environment

5、) are incorporated into larger, more complex molecules (i.e. macromolecules) 即从“构建元件”合成“大分子”nBecause biosynthesis increases order有序度 and complexity复杂性(macromolecules are more orderly and more reductive还原), anabolic pathways require free energy 消耗自由能消耗自由能nExamples: synthesis of polysaccharides多糖and p

6、roteins from sugars and amino acids, respectively (2) Catabolic分解分解ones: nLarge complex molecules are degraded into smaller, simpler products. Some of them release free energy. 释释放自由能放自由能nExamples: -oxidation (fatty acids are degraded into acetyl-CoA乙酰辅酶乙酰辅酶A).The primary functions of metabolism are

7、 nacquisition and utilization of energynsynthesis of macromolecules for cell structure and functioning (i.e., proteins, nucleic acids, lipids, and carbohydrates)nremoval of waste products. Metabolism has a coherent design containing many common motifs代谢包含许多共同的模式(框架): nThe number of reaction in metab

8、olism is large but the number of kinds of reactions is relatively small. 反应类型都少反应类型都少nThe mechanisms机制 of these reactions are usually quite simple. (e.g., a double bond is often formed by dehydration of an alcohol双键由醇脱水形成) 反应机制都简单反应机制都简单nA group of about 100 molecules(“central molecules”) plays a ce

9、ntral role in all forms of life. (e.g., acetyl CoA, G-6-P葡萄糖-6-磷酸, pyruvate丙酮酸, NADH烟酰胺腺嘌呤二核苷酸) 相同的相同的中心分子中心分子nMetabolic pathways are regulated in common ways. (e.g., allosteric interaction变构作用of PFK磷酸果糖激酶; covalent modification共价修饰of glycogen phosphorylase糖原磷酸化酶) 共同的调控模式共同的调控模式A thermodynamically u

10、nfavorable reaction can be driven by a favorable one The criterion of judgment whether a reaction can occur spontaneosly: only if G (the change in free energy) is negative.反应是否能自发进行的判据是G G= G0 + RTln CD/AB Thus, the G of a reaction depends on: 1. the nature of the reactants (i.e. G0, the standard fr

11、ee-energy change) 2. their concentrationsThe standard free-energy change at pH7 is denoted by G0. An important thermodynamic fact is that overall free-energy change for a chemically coupled series of reactions is equal to the sum of the free-energy changes of the individual steps 偶联的化学反应序偶联的化学反应序列列总

12、的自由能改变总的自由能改变等于等于各单步反应自由能改变之和各单步反应自由能改变之和.nHere the uphill and the downhill reactions are coupled by the shared chemical intermediate B 共同中间化合物B. A B + C B D / A C + DThe other two principal ways of the coupling arenactivated protein conformation构象. Here proteins serve as energy conversion devices.

13、Molecular motors convert the phosphoryl potential磷酸基团转移势能of ATP into mechanical energy(e.g. myosin肌动蛋白). The active transport of Na+ and K+ across membranes is driven by the phosphorylation of the sodium-potassium pump钠钾泵 by ATP and its subsequent dephosphorylation去磷酸化nIonic gradient离子梯度 across memb

14、ranes: proton质子gradient produced by the oxidation of fuel molecules or by photosynthesis ultimately powers the synthesis of most of ATP in cells. “偶联”的概念被极度放大Conclusion: Tight coupling is a general characteristic of biological assemblies复合体 (e.g., the above-mentioned Na+- K+ pump and the electron tr

15、ansport chain电子传递链) that mediate energy conversion. ATP is the universal currency通用货币通用货币 of free energy in biological systems Nonbiologic system may utilize heat energy to perform work, but biologic system is essentially isothermic等温的 and use chemical energy (especially ATP) to power living process

16、es. The use of free energy: motion运动, active transport主动转运, biosynthesis生物合成, signal amplification信号放大 The source of free energy: oxidation of foodstuffs (animals), light energy (plants). Part of the absorbed free energy is transformed into a highly accessible可用的formATP (adenosine triphosphate腺苷三磷酸)

17、 containingnadenine腺嘌呤nribose核糖 nand three phosphate groups (designated by adenosine-PPP)nIts active form is usually a complex of ATP with Mg2+ or Mn2+. ATP is an energy-rich molecule because its triphosphate unit contains two phosphoanhydride bonds磷酸酸酐键nSince large amount of free energy is liberate

18、d when ATP is hydrolyzed to (ADP + Pi) or to (AMP + PPi) (pyrophosphate焦磷酸) AP PP APP + Pi (or AP + PPi)nATP allows the coupling of thermodynamically unfavorable reactions热力学上不可行的反应 to favorable onesnG0 for both of the above-mentioned hydrolyses水解作用 is 7.3 kcal/molnUnder typical cellular conditions,

19、 the actual G for these hydrolyses is about 12 kcal/mol(浓度因素)nIn turn, ATP is formed from ADP and Pi in oxidative phosphorylation氧化磷酸化This ATP-ADP cycle is the fundamental mode of energy exchange in biological system. ATP is continuously formed and consumed ATP is the principal immediate donor即刻供体 o

20、f free energy in biological systemsn100-meter sprint短跑 is a good example to illustrate the concept immediatenThe runner is powered by ATP during the first second and by creatine phosphate磷酸肌酸 during the first four seconds nand hereafter by anaerobic glycolysis厌氧酵解 of muscle glycogen肌糖原nwhich means t

21、hat the storage of ATP in human bodies is quite limited (enough to keep strenuous exertion only for one second)nThe long-term storage of free energy is fat in adipose tissue脂肪组织 ATP磷酸肌酸磷酸肌酸肌糖原厌氧酵解肌糖原厌氧酵解脂肪分解脂肪分解In a typical cell, the ATP molecule is consumed within a minute following its formation.

22、The turnover转换 of ATP is very high, i.e., ATP is continuously (or ceaselessly) formed and consumednWhen organism is in the state of strenuous exertion, the extant现存的 ATP is consumed up at once and it begins to use the ATP converted from (in the order of) creatine phosphate, glycogen, and fat (mainly

23、 triglyceride甘油三酯)nA resting human consumes about 40 kg of ATP in 24h. During strenuous exertion, the rate of utilization of ATP may be as high as 0.5 kg/minnAll activities of living organisms need continuous supply of ATPnThe energy from light or oxidation of fuel molecules first pumps protons acro

24、ss a membrane (typically the inner membrane of mitochondrion线粒体内膜) to generate a proton-motive force and the proton gradient质子梯度 then powers the synthesis of ATP. Structural basis of the high phosphoryl transfer potential磷酰基转移潜势磷酰基转移潜势 of ATP The hydrolysis of ATP can produce a rather high standard

25、free energy (G0= 7.3 kcal/mol), i.e., ATP has a stronger tendency to transfer its terminal phosphoryl group to waterIn other words, ATP has a higher phosphoryl potential (phosphoryl group-transfer potential) nthan (e.g.) glyceral 3-phosphate 3-磷酸甘油, G-6-P, etc. The structural basis of the high phosp

26、horyl potential of ATP is its structural speciality. Two factors are important: nelectrostatic repulsion静电斥力静电斥力 (比较ATP和ADP)nresonance stabilization共振稳定作用共振稳定作用 (酸酐键的共振稳定性小于磷酯键) (比较高能键侧的磷酸和正磷酸)Besides ATP there are various other compounds in biological systems which have a high phosphoryl potential.

27、 Among them the followings have a higher phosphoryl transfer potential than does ATP:nPEP烯醇丙酮酸磷酸ncarbamoyl phosphate 氨甲酰磷酸nacetyl phosphate乙酰磷酸ncreatine phosphate nSo PEP can transfer its phosphoryl group to ADP to produce ATP. PEP + ADP + H+ pyruvate + ATP. In fact, this is the final step of glycol

28、ysis. It is significant that ATP is in the middle among the biologically important phosphorylated moleculesThis intermediate position (i.e. fall short of the best but be rather than the worst比上不足比下有余) enables ATP to be an extremely important carrier of phosphoryl groupnATP can transfer it to the oth

29、er phosphate compounds which have a lower phosphoryl group transfer potential nand in turn ADP can receive the group from the high energy phosphate compounds with a higher potential than ATP. Creatine phosphate is a reservoir of P in muscle The amount of ATP in muscle is rather limited and is only e

30、nough to maintain contractile activity for about 1 secondnVertebrate脊椎动物 muscle contains a reservoir of high-potential phosphoryl groups in the form of creatine phosphate nfor invertebrates, the corresponding one is phosphoarginine磷酸精氨酸nwhich can readily transfer its phosphoryl group to produce ATP

31、nAt pH7, G0 of hydrolysis of creatine phosphate is 10.3 kcal/mol, so for creatine phosphate + ADP + H+ATP + creatine; the total reaction G0 = 10.3（7.3）=3 kcal/molnThe abundance of creatine phosphate and its high phosphoryl transfer potential relative to that of ATP make it a highly effective P(high-

32、energy phosphate bond) buffernIt maintains a high concentration of ATP during periods of muscular exertionnIndeed, it is the major source of P for a runner during the first four seconds of a 100-meter sprint. ATP hydrolysis shifts the equilibria of coupled reactions by a factor 108 To enhance an und

33、erstanding of the role of ATP in energy coupling well illustrate it with a chemical reaction that is thermodynamically unfavorable without an input of free energynSuppose: AB G0 = 4 kcal/mol. It means that this reaction can not occur spontaneously toward B (under standard conditions) without an inpu

34、t of free energynThe equilibrium constant Keq of this reaction at 250 C is related to G0 by Keq =B eq /A eq =10G0/1.36 = 104/1.36 =1.15 x103 (平衡时平衡时, G0 = 1.36 lg Keq )n B is about 900 times lower than A. Only if B/A 1.15x103, A can not be converted into BnWe say, this reaction is unfavorable Howeve

35、r, the coupling of the hydrolysis of ATP with the above-mentioned reaction can convert this impossible one into possiblenThe total G0 =7.3+4=3.3 kcal/mol. nK eq =B eq /A eq x ADP eq Pi eq /ATP eq =103.3/1.36 =2.67 x 102 nAt equilibrium, the ratio of B/A is K eq x ATP eq /ADP eq Pi eq. nThe ATP-gener

36、ating system of cells keeps the ATP eq /ADP eq Pi eq ratio at a high level, typically of the order of 500nSo B eq /A eq =2.67x102 x 500=1.34 x 105, which means that the hydrolysis of ATP enables A to be converted into B until B/A ratio reaches a value of 1.34 x 105nThis ratio is about 108 times high

37、er than that of 1.15x103 for the uncoupled reaction 1.15x103 1.34 x 105 In other words, the coupled hydrolysis of ATP has changed the equilibrium ratio of B to A by a factor of about 108 We see here the thermodynamic essence of ATPs action as a energy-coupling agent.Cells maintain a high level of AT

38、P by using oxidizable substrates (i.e., fuel molecules) or light as sources of free energy (through oxidative phosphorylation)The existence of high-level ATP tends to couple the hydrolysis of ATP with other chemical energy-needed reactions (i.e.unfavorable reaction) necessary for living organisms能源足

39、量的ATP产生偶联需能反应The hydrolysis of 1 ATP molecule in a coupled reaction changes the equilibrium ratio of products to reactants by a very large factor, of the order of 108More generally, the hydrolysis of n ATP molecules changes the equilibrium ratio of a coupled reaction (or sequence of reactions, i.e.

40、a series of reactions) by a factor of 108n Thus an almost impossible reaction can occur only if coupled with the hydrolysis of a sufficient number of ATP moleculesHere, the meaning of A and B is not confines限于 to different compounds (different chemical species)nA and B may represent different confor

41、mations 构象of a molecule nor the different concentrations of an ion or molecule on the outside and inside of a cellnthe former as in muscle contraction, the latter as in the active transport of a nutrient. NADH and FADH2 are the major electron carrier in the oxidation of fuel molecules The free energ

42、y for chemotrophs化养生物 is mainly from the oxidation of fuel molecules (e.g., Glc and FA)nIn aerobic需氧 organisms, the ultimate electron acceptor is O2 (more reduced fuel molecules always liberate electrons)nHowever, the transfer of the electrons from fuel molecules and their break-down products to O2

43、is not direct, it is indirectni.e. the transfer of electrons requires various carriers. nPyridine nucleotides吡啶核苷酸including NAD+ or NADH; NADP+ or NADPH (nicotinamide adenine dinucleotide烟酰胺腺嘌呤二核苷酸)nand flavin黄素 nucleotides including FMN or FMNH2; FAD or FADH2 are among these special carriers The re

44、duced forms of these carriers (NADH, FADH2) transfer their high-potential electrons to O2 by means of an electron transport chain located in the inner membrane of mitochondria线粒体内膜nDuring the process of flowing of electrons along the electron transport chain the proton gradient is formed which then

45、drives the synthesis of ATP from ADP and PinThis process, i.e. oxidative phosphorylation is the major source of ATP in aerobic organisms需氧生物ATP的主要源泉. nBesides, the high-potential electrons derived from the oxidation of fuel molecules can be used in biosynthesis (in the form of NADPH) that requires r

46、educing power in addition to ATP (e.g., the synthesis of fatty acids) NAD+ is a major electron acceptor in the oxidation of fuel moleculesnIts reactive part is nicotinamide ring,烟酰胺(尼克酰胺)环a pyridine derivative嘧啶衍生物. In the oxidation of a substrate, this ring accepts a hydrogen ion and two electrons,

47、 i.e. a hydride ion氢阴离子 NAD+ + H+2e （or H）NADHnNAD+ serves as an electron acceptor in many reactions of the different types, e.g. NAD+ alcoholNADH+ aldehyde醛 (or ketone酮)+H+nHere, a hydride ion is directly transferred to NAD+, whereas a proton appears in the solventnThe substrate loses two hydrogen

48、atoms (2HH+H+) The another major electron carrier is FADnIt is the electron receptor in reactions of the following type: FAD+ R-CH2-CH2-R R-CH = CH-R+ FADH2, e.g., in -oxidation of fatty acid. nThe reactive part of FAD is its isoalloxazine ring异咯嗪环 (corresponding to nicotinamide ring of NAD+)Both FA

49、D and NAD+ can accept two electrons, but FAD takes up a proton as well as a hydride ion NADPH is the major electron donor in reductive biosynthesis In most biosyntheses the precursors are more oxidized than the productsn(e.g.) in the synthesis of fatty acids the more oxidized form of carbon atom (ke

50、tone group酮基酮基 -C=O) is reduced to its more reduced form (methylene group亚甲基亚甲基: -CH2-)nIn other words, the macromolecule is more reduced than its breakdown productsnSo, in biosynthesis, reducing power is needed in addition to ATPnIn the biosynthesis of fatty acid, the ketone group of an added C2 un

51、it is reduced to a methylene group in several steps, this sequence of reactions requires an input of 4 electronsNADPH is the major electron donor in most reductive biosynthesis nwhich differs from NADH in that the 2-hydroxyl group of its adenosine moiety腺苷 is esterified酯化 with phosphatenThey carry e

52、lectrons in the same way (the reactive part of both is their nicotinamide ring)nHowever, NADPH is used almost exclusively for reductive biosynthesis, whereas NAD+ is used primarily for the generation of ATP NADPH独特地用于还原性生物合成独特地用于还原性生物合成,而而NAD+则主要则主要用于用于ATP的产生的产生nThe extra phosphate group on NADPH is

53、 a tag标签 that directs this reducing agent to recognizing biosynthetic enzymesIn the absence of catalysts, NADH, NADPH and FADH2 react slowly with O2, ATP is slowly hydrolyzednThey are kinetically quite stable in the face of a large thermodynamic driving force for reaction with O2 or H2OnThe stabilit

54、y of these molecules in the absence of specific catalysts is essential for their biological function because it enables enzymes to control the flow of free energy and reducing power. Coenzyme A is a universal carrier of acyl groupsCoA is another central molecule in metabolismnIt is a heat-stable cof

55、actor required in many enzyme-catalyzed acetylations乙酰化nThe terminal sulfhydryl group巯基 in CoA is the reactive sitennicotinamide ring尼克酰胺(烟酰胺)环for NAD(P)+, isoalloxazine ring异咯嗪环 for FADAcyl groups are linked to CoA by a thioester bond硫酯键nAmong the acyl CoA the most often seen is acetyl CoAnAcetyl C

56、oA has a high acetyl group-transfer potentialnAcetyl CoA carries an activated acetyl group just as ATP carries an activated phosphoryl group and NAD(P)H carries electrons.Activated carriers exemplify the modular design and economy of metabolism代谢的模式化设代谢的模式化设计和经济化原则计和经济化原则 CoA carries different-size

57、activated acyl groups (C2C24 or even longer) for degradation and energy generation or for biosynthetic purposes nLikewise, pyridine nucleotides mediate many electron transfersnS-adenosylmethionine S-腺苷甲硫氨酸 participates in methylations甲基化 in bacterial chemotaxis趋化性Indeed, most interchanges of activat

58、ed groups in metabolism are accomplished by a rather small set of carriersThe existence of a recurring set of activated carriers in all organisms is one of the unifying motifs of biochemistry. Ion Gradients Across Membranes provide an Important Form of Cellular Energy That Can Be Coupled to ATP Synt

59、hesisMost water-soluble vitamins are components of coenzyme Vitamins are organic molecules that are needed in small amounts in the diet of some higher animals微量存在于食物中、为高等生物营养所必须的有机物质nThey serve nearly the same role in all forms of lifenbut higher animals have lost the capacity to synthesize themnMan

60、y enzymes require cofactors for activity. Such cofactors can be metal ions or small, vitamin-derived organic molecules called coenzymes.According to the solubility in water or in nonpolar solvents they are groupedThe water-soluble vitamins are ascorbic acid (VC,抗坏血酸) and a series known as the vitami