上海交大生化课件

Chapter 17Metabolism:Basic Concepts and DesignDefinitionthe classic definition: The totality of the chemical reactions and physical changes that occur in livingorganisms, 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 metabolism:energy, reducing power还原力and building block构建元件)：⏹Metabolism 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 theirenvironment and synthesize the building blocks of their macromolecules. 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(由首尾相接的化学反应组成) Many of these reactions are organized intopathways. 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—(代谢途经)—网络(―点‖, ―线‖,―面‖关系)Two major types of the pathways:(1) Anabolic合成or biosynthetic ones:⏹Large 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‘) are incorporated into larger, more complex molecules (i.e. ‗macromolecules‘) 即从―构建元件‖合成―大分子‖⏹Because biosynthesis increases order有序度and complexity复杂性(macromolecules are moreorderly and more reductive还原), anabolic pathways require free energy 消耗自由能⏹Examples: synthesis of polysaccharides多糖and proteins from sugars and amino acids,respectively⏹(2) Catabolic分解ones:⏹Large complex molecules are degraded into smaller, simpler products. Some of them release freeenergy. 释放自由能⏹Examples: β-oxidation (fatty acids are degraded into acetyl-CoA乙酰辅酶A).⏹The primary functions of metabolism are⏹acquisition and utilization of energy⏹synthesis of macromolecules for cell structure and functioning (i.e., proteins, nucleic acids, lipids,and carbohydrates)⏹removal 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):⏹The number of reaction in metabolism is large but the number of kinds of reactions is relativelysmall. 反应类型都少⏹The mechanisms机制of these reactions are usually quite simple. (e.g., a double bond is oftenformed by dehydration of an alcohol双键由醇脱水形成) 反应机制都简单⏹ A group of about 100 molecules(―central molecules‖) plays a central 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) 相同的中心分子⏹Metabolic 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A thermodynamically unfavorable reaction can be driven by a favorable oneThe criterion of judgment whether a reaction can occur spontaneosly: only if △G (the change in freeenergy) is negative.反应是否能自发进行的判据是△G△G= △G0 + RTln [C][D]/[A][B] Thus, the △G of a reaction depends on: 1.the nature of thereactants (i.e. △G0, the standard free-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 ofreactions is equal to the sum of the free-energy changes of the individual steps 偶联的化学反应序列总的自由能改变等于各单步反应自由能改变之和.⏹Here 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 are⏹activated protein conformation构象. Here proteins serve as energy conversion devices.Molecular motors convert the phosphoryl potential磷酸基团转移势能of ATP into mechanicalenergy(e.g. myosin肌动蛋白). The active transport of Na+ and K+ across membranes is drivenby the phosphorylation of the sodium-potassium pump钠钾泵by ATP and its subsequentdephosphorylation去磷酸化⏹Ionic gradient离子梯度across membranes: proton质子gradient produced by the oxidation offuel 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., theabove-mentioned Na+- K+ pump and the electron transport chain电子传递链) that mediate energy conversion.ATP is the universal currency通用货币of free energy in biological systemsNonbiologic system may utilize heat energy to perform work, but biologic system is essentiallyisothermic等温的and use chemical energy (especially ATP) to power living processes.The use of free energy: motion运动, active transport主动转运, biosynthesis生物合成, signalamplification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form—ATP (adenosinetriphosphate腺苷三磷酸) containing⏹adenine腺嘌呤⏹ribose核糖⏹and three phosphate groups (designated by adenosine-P~P~P)⏹Its 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⏹Since large amount of free energy is liberated when ATP is hydrolyzed to (ADP + Pi) or to (AMP+ PPi) (pyrophosphate焦磷酸) A—P～P～P→A—P～P + Pi (or A—P + PPi)⏹ATP allows the coupling of thermodynamically unfavorable reactions热力学上不可行的反应to favorable ones⏹△G0‘ for both of the above-mentioned hydrolyses水解作用is－7.3 kcal/mol⏹Under typical cellular conditions, the actual △G for these hydrolyses is about －12 kcal/mol(浓度因素)⏹In 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 consumedATP is the principal immediate donor即刻供体of free energy in biological systems⏹100-meter sprint短跑is a good example to illustrate the concept ‗immediate‘⏹The runner is powered by ATP during the first second and by creatine phosphate磷酸肌酸during the first four seconds⏹and hereafter by anaerobic glycolysis厌氧酵解of muscle glycogen肌糖原⏹which means that the storage of ATP in human bodies is quite limited (enough to keep strenuousexertion only for one second)⏹The long-term storage of free energy is fat in adipose tissue脂肪组织ATP→磷酸肌酸→肌糖原厌氧酵解→脂肪分解In a typical cell, the ATP molecule is consumed within a minute following its formation. The turnover转换of ATP is very high, i.e., ATP is continuously (or ceaselessly) formed and consumed⏹When organism is in the state of strenuous exertion, the extant现存的A TP is consumed up atonce and it begins to use the ATP converted from (in the order of) creatine phosphate, glycogen,and fat (mainly triglyceride甘油三酯)⏹ A resting human consumes about 40 kg of ATP in 24h. During strenuous exertion, the rate ofutilization of ATP may be as high as 0.5 kg/min⏹All activities of living organisms need continuous supply of ATP⏹The energy from light or oxidation of fuel molecules first pumps protons across a membrane(typically the inner membrane of mitochondrion线粒体内膜) to generate a proton-motive forceand 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of ATPThe hydrolysis of ATP can produce a rather high standard free energy (△G0‘= －7.3 kcal/mol), i.e., ATPhas a stronger tendency to transfer its terminal phosphoryl group to waterIn other words, ATP has a higher phosphoryl potential (phosphoryl group-transfer potential)⏹than (e.g.) glyceral 3-phosphate 3-磷酸甘油, G-6-P, etc.The structural basis of the high phosphoryl potential of ATP is its structural speciality. Two factors areimportant:⏹electrostatic repulsion静电斥力(比较ATP和ADP)⏹resonance stabilization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 phosphorylpotential. Among them the followings have a higher phosphoryl transfer potential than does A TP:⏹PEP烯醇丙酮酸磷酸⏹carbamoyl phosphate 氨甲酰磷酸⏹acetyl phosphate乙酰磷酸⏹creatine phosphate⏹So PEP can transfer its phosphoryl group to ADP to produce ATP.PEP + ADP + H+ →pyruvate + ATP. In fact, this is the final step of glycolysis.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 group⏹ATP can transfer it to the other phosphate compounds which have a lower phosphoryl grouptransfer potential⏹and in turn ADP can receive the group from the high energy phosphate compounds with a higherpotential than ATP.Creatine phosphate is a reservoir of ~P in muscleThe amount of ATP in muscle is rather limited and is only enough to maintain contractile activity forabout 1 second⏹Vertebrate脊椎动物muscle contains a reservoir of high-potential phosphoryl groups in the formof creatine phosphate⏹for invertebrates, the corresponding one is phosphoarginine磷酸精氨酸⏹which can readily transfer its phosphoryl group to produce ATP⏹At pH7, △G0‘ of hydroly sis of creatine phosphate is－10.3 kcal/mol, so forcreatine phosphate + ADP + H+≒A TP + creatine; the total reaction △G0‘ = －10.3－（－7.3）=－3 kcal/mol⏹The abundance of creatine phosphate and its high phosphoryl transfer potential relative to that ofATP make it a highly effective ~P(high-energy phosphate bond) buffer⏹It maintains a high concentration of ATP during periods of muscular exertion⏹Indeed, it is the major source of ~P for a runner during the first four seconds of a 100-metersprint.ATP hydrolysis shifts the equilibria of coupled reactions by a factor 108To enhance an understanding of the role of ATP in energy coupling we‘ll illustrate it with a chemicalreaction that is thermodynamically unfavorable without an input of free energy⏹Suppose: A≒B △G0‘ = 4 kcal/mol. It means that this reaction can not occur spontaneouslytoward B (under standard conditions) without an input of free energy⏹The equilibrium constant K‘eq of this reaction at 250 C is related to △G0‘ by K‘eq =[B] eq /[A]eq =10－△G0‘/1.36 = 10－4/1.36 =1.15 x10－3 (平衡时, △G0‘ = －1.36 lg K‘eq )⏹[B] is about 900 times lower than [A]. Only if [B]/[A] ＞1.15x10－3, A can not be converted into B⏹We say, this reaction is ‗unfavorable‘⏹However, the coupling of the hydrolysis of ATP with the above-mentioned reaction can convert this‗impossible‘ one into ‗possible‘⏹The total △G0‘ =－7.3+4=－3.3 kcal/mol.⏹K‘ eq =[B] eq /[A] eq x [ADP] eq [Pi] eq /[A TP] eq =103.3/1.36 =2.67 x 102⏹At equilibrium, the ratio of [B]/[A] is K‘ eq x [A TP] eq /[ADP] eq [Pi] eq.⏹The ATP-generating system of cells keeps the [ATP] eq /[ADP] eq [Pi] eq ratio at a high level,typically of the order of 500⏹So [B] eq /[A] eq =2.67x102x 500=1.34 x 105, which means that the hydrolysis of ATP enablesA to be converted intoB until [B]/[A] ratio reaches a value of 1.34 x 105⏹This ratio is about 108 times higher than that of 1.15x10－3for the uncoupled reaction 1.15x10－3 → 1.34 x 105 In other words, the coupled hydrolysis of ATP has changed the equilibriumratio of B to A by a factor of about 108⏹We see here the thermodynamic essence of ATP’s action as a energy-coupling agent.⏹Cells maintain a high level of ATP by using oxidizable substrates (i.e., ‗fuel molecules‘) or light assources of free energy (through oxidative phosphorylation)⏹The existence of high-level ATP tends to couple the hydrolysis of ATP with other chemical energy-neededreactions (i.e.‗unfavorable reaction‘) necessary for living organisms能源→足量的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 toreactants by a very large factor, of the order of 108⏹More generally, the hydrolysis of n A TP molecules changes the equilibrium ratio of a coupled reaction (orsequence of reactions, i.e. 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 numberof ATP molecules⏹Here, the meaning of A and B is not confines限于to different compounds (different chemical species)⏹ A and B may represent different conformations 构象of a molecule⏹or the different concentrations of an ion or molecule on the outside and inside of a cell⏹the 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 moleculesThe free energy for chemotrophs化养生物is mainly from the oxidation of fuel molecules (e.g., Glc andFA)⏹In aerobic需氧organisms, the ultimate electron acceptor is O2 (more reduced fuel moleculesalways liberate electrons)⏹However, the transfer of the electrons from fuel molecules and their break-down products to O2is not direct, it is indirect⏹i.e. the transfer of electrons requires various carriers.⏹Pyridine nucleotides吡啶核苷酸including NAD+ or NADH; NADP+ or NADPH (nicotinamideadenine dinucleotide烟酰胺腺嘌呤二核苷酸)⏹and flavin黄素nucleotides including FMN or FMNH2; FAD or FADH2 are among thesespecial carriersThe reduced forms of these carriers (NADH, FADH2) transfer their high-potential electrons to O2 bymeans of an electron transport chain located in the inner membrane of mitochondria线粒体内膜⏹During the process of flowing of electrons along the electron transport chain the proton gradientis formed which then drives the synthesis of ATP from ADP and Pi⏹This process, i.e. oxidative phosphorylation is the major source of A TP in aerobic organisms需氧生物ATP的主要源泉.⏹Besides, the high-potential electrons derived from the oxidation of fuel molecules can be used inbiosynthesis (in the form of NADPH) that requires reducing power in addition to ATP (e.g., thesynthesis of fatty acids)NAD+ is a major electron acceptor in the oxidation of fuel molecules⏹Its reactive part is nicotinamide ring,烟酰胺(尼克酰胺)环a pyridine derivative嘧啶衍生物. Inthe oxidation of a substrate, this ring accepts a hydrogen ion and two electrons, i.e. a hydride ion氢阴离子[NAD+ + H++2e（or H－）→NADH]⏹NAD+ serves as an electron acceptor in many reactions of the different types, e.g. NAD++alcohol≒NADH+ aldehyde醛(or ketone酮)+H+⏹Here, a hydride ion is directly transferred to NAD+, whereas a proton appears in the solvent⏹The substrate loses two hydrogen atoms (2H→H－+H+)⏹The another major electron carrier is F AD⏹It is the electron receptor in reactions of the following type: FAD+ R-CH2-CH2-R‘ ≒R-CH =CH-R‘+ FADH2, e.g., in β-oxidation of fatty acid.⏹The reactive part of FAD is its isoalloxazine ring异咯嗪环(corresponding to nicotinamide ringof NAD+)⏹Both FAD and NAD+ can accept two electrons, but FAD takes up a proton as well as a hydride ionNADPH is the major electron donor in reductive biosynthesisIn most biosyntheses the precursors are more oxidized than the products⏹(e.g.) in the synthesis of fatty acids the more oxidized form of carbon atom (ketone group酮基-C=O) is reduced to its more reduced form (methylene group亚甲基: -CH2-)⏹In other words, the macromolecule is more reduced than its breakdown products⏹So, in biosynthesis, reducing power is needed in addition to ATP⏹In the biosynthesis of fatty acid, the ketone group of an added C2 unit is reduced to a methylenegroup in several steps, this sequence of reactions requires an input of 4 electrons NADPH is the major electron donor in most reductive biosynthesis⏹which differs from NADH in that the 2‘-hydroxyl group of its adenosine moiety腺苷isesterified酯化with phosphate⏹They carry electrons in the same way (the reactive part of both is their nicotinamide ring)⏹However, NADPH is used almost exclusively for reductive biosynthesis, whereas NAD+ is usedprimarily for the generation of ATPNADPH独特地用于还原性生物合成,而NAD+则主要用于ATP的产生⏹The extra phosphate group on NADPH is a tag标签that directs this reducing agent torecognizing biosynthetic enzymes⏹In the absence of catalysts, NADH, NADPH and FADH2 react slowly with O2, A TP is slowly hydrolyzed⏹They are kinetically quite stable in the face of a large thermodynamic driving force for reactionwith O2 or H2O⏹The stability of these molecules in the absence of specific catalysts is essential for theirbiological function because it enables enzymes to control the flow of free energy and reducingpower.⏹CoA is another central molecule in metabolism⏹It is a heat-stable cofactor required in many enzyme-catalyzed acetylations乙酰化⏹The terminal sulfhydryl group巯基in CoA is the reactive site⏹nicotinamide ring尼克酰胺(烟酰胺)环for NAD(P)+, isoalloxazine ring异咯嗪环for FAD Activated carriers exemplify the modular design and economy of metabolism代谢的模式化设计和经济化原则CoA carries different-size activated acyl groups (C2~C24 or even longer) for degradation and energygeneration or for biosynthetic purposes⏹Likewise, pyridine nucleotides mediate many electron transfers⏹S-adenosylmethionine S-腺苷甲硫氨酸participates in methylations甲基化in bacterialchemotaxis趋化性⏹Acyl groups are linked to CoA by a thioester bond硫酯键⏹Among the acyl CoA the most often seen is acetyl CoA⏹Acetyl CoA has a high acetyl group-transfer potential⏹Acetyl CoA carries an activated acetyl group just as ATP carries an activated phosphoryl groupand NAD(P)H carries electrons.⏹Indeed, most interchanges of activated groups in metabolism are accomplished by a rather small set ofcarriers⏹The existence of a recurring set of activated carriers in all organisms is one of the unifying motifs ofbiochemistry.Most water-soluble vitamins are components of coenzymeVitamins 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⏹They serve nearly the same role in all forms of life⏹but higher animals have lost the capacity to synthesize them⏹Many 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 vitamin Bcomplex⏹Ascorbate serves as a reducing agent (an antioxidant)⏹The VB series are components of coenzymes, e.g., riboflavin核黄素(VB2) is a precursor of FAD,and pantothenate泛酸(VB5) is a component of CoA. Niacin(VB3) for NAD+.Fat-soluble vitamins participate in diverse processes such as blood clotting and visionVK, necessary for normal blood clotting (K: koagulation), participates in the carboxylation羧化of Gluresidues to γ-carboxyglutamateγ-羧基谷氨酸, which makes it a much stronger chelator螯合剂of Ca2+剂VK→使(构成凝血因子的)谷氨酸羧化→Ca2+螯合能力增强→凝血V A is the precursor of retinal视黄醛, the light-sensitive group in rhodopsin视紫红质and other visualpigments视觉色素⏹Retinoic acid视黄酸, which contains a terminal carboxylate羧基in place of the alcoholterminus of retinol视黄醇, activates the transcription of specific genes that mediate growth anddevelopmenthormone derived from VD regulates the metabolism of Ca and P, whose deficiency impairs boneformation in growing animalsVE (i.e. α-tocopherol生育酚) deficiency leads to infertility in rats and protects unsaturated membranelipids不饱和膜脂from oxidation.VC is required for the hydroxylation of Pro residues in collagenCollagen胶原with the triple-helical structure, the major protein of connective tissue, is noted forcontaining 4-hydroxyproline羟脯氨酸, an amino acid rarely found elsewherethe Pro on the amino side of Gly residues in nascent collagen chains becomes hydroxylated羟基化⏹Hydroxylation of a Pro residue at C-4 is by the action of prolyl hydroxylase脯氨酸羟化酶⏹Here. VC serves as a specific antioxidant to regenerate the enzymeVC(作为抗氧化剂)→使脯氨酸羟化酶(在被氧化后)复原→初生胶原链中Gly氨基侧的Pro得以羟基化→使胶原具有正常功能(抗坏血病)Collagen synthesized in vitro in the absence of VC has a lower melting temperature than does the normalprotein⏹The Tm of the poly(Pro-Pro-Gly) triple helix is 240C, compared with 580C for thepoly(Pro-Hyp-Gly) triple helix (Hyp: hydroxyproline)⏹Hyp stabilizes the collagen triple helix by forming interstrand hydrogen bonds⏹The abnormal fibers formed by insufficiently hydroxylated collagen contribute to the skin lesionsand blood vessel fragility脆弱seen in scurvy坏血病.Stages in the extraction of energy from foodstuffsThere are 3 stages in the generation of energy from the oxidation of foodstuffsStage I: large molecules in food are broken down into smaller units.⏹Protein→20 kinds of constituent amino acids⏹polysaccharides→simple sugar such as Glc⏹fats→glycerol and fatty acids. No useful energy is generatedStage II: these numerous small molecules are degraded to a few simple units that play a central role inmetabolism⏹Most of these small molecules—sugars, fatty acids, glycerol and amino acids — are convertedinto the acetyl unit of acetyl CoA⏹The amount of A TP generated in this stage is smallerStage III: It consists of the citric acid cycle and oxidative phosphorylation⏹which are the final common pathways in the oxidation of fuel molecules⏹Acetyl units brought into this cycle (or called ‗tricarboxylic acid cycle‘) by acetyl CoA arecompletely oxidized to CO2⏹The oxidation of each acetyl group in the cycle produces 4 pairs of electrons which aretransferred to NAD+ (3 pairs) and FAD (1 pair)⏹Then ATP is generated as electrons flow from their reduced form (NADH and FADH2) to O2 ina process called oxidative phosphorylation⏹More than 90% of the ATP generated by the degradation of foodstuffs is formed in this stage. Metabolic processes are regulated in 3 principal waysA great amount of interdependent reactions are taking place in living cells whose external environment isnot constantMetabolism must be regulated effectively and flexibly. There are 3 principal ways to control:(1) the amount of enzymesthat is adjusted by changing the rate of transcription of gene encoding theme.g., lactose乳糖(substrate of the enzyme) induces a more than 50-fold increases in the rate ofsynthesis of β-galactosidase β-半乳糖苷酶, an enzyme required for the breakdown of thisdisaccharide(2) their catalytic activitiesA. Reversible allosteric control可逆别构调节, e.g. the first reaction in many biosyntheticpathways is allosterically inhibited by the ultimate product of the pathway (i.e. feedbackinhibition反馈抑制)B. Reversible covalent modification可逆共价修饰, e.g. glycogen phosphory-lase糖原磷酸化酶,the enzyme catalyzing the breakdown of glycogen (a storage form of sugar), is activated byphosphorylation of a particular Ser residue when Glc is scarceHormones e.g. epinephrine肾上腺素trigger signal transduction cascades信号传导级联系统that lead to highly amplified changes in metabolic patternscAMP and Ca2+ serve as intracellular messengers胞内信使that coordinate the activities ofmany target proteins靶蛋白cAMP→促活PKA(蛋白激酶A; 使其调控部位与催化部位分离)→使靶蛋白的Ser或Thr残基磷酸化→从而调节其活性(3) the accessibility 可及性of substrates.⏹ A. Flux of substrates 底物流向e.g., insulin胰岛素promotes the entry of Glc into many kindsof cells⏹ B. compartmentation 区域化segregates opposed reactions, e.g. FA oxidation occurs in themitochondria, whereas FA synthesis occurs in the cytosolAn important general principal of metabolism is that biosynthetic and degradative pathways are almostalways distinct几乎总是分离的Besides, the energy status of the cell also control many reactions in metabolism⏹One index of the energy status is the energy charge 能荷= [ATP]+ 0.5[ADP]/[ATP]+[ADP]+[AMP]⏹The value of energy charge ranges from 0 (all AMP) to 1 (all ATP)⏹ATP-generating (catabolic) pathways are inhibited by a high energy charge, whereasATP-utilizing (anabolic) pathways are stimulated by a high energy charge⏹In plots of the reaction rates of such pathways versus the energy charge the curves usuallyintersect near an energy charge of 0.9, i.e. where the curves drop or go up rapidly⏹The energy charge is controlled within rather narrow limits, i.e. the energy charge, like the pH ofa cell is buffered. The energy charge of most cells is in the range of 0.8~0.95.The central role of ribonucleotides in metabolism reflects their ancient originsWhich came first in evolution: protein, DNA, or RNA? A likely explanation is: RNA⏹for many of the central molecules of metabolism in all forms of life are ribonucleotides核糖核苷酸⏹important activated carriers such as A TP, NADH, FADH2, and CoA contain adenosine腺苷phosphate unitsThe earliest catalysts most probably were RNA molecules, termed ribozymes核酶⏹Non-RNA units such as isoalloxazine ring (in FAD), nicotinamide ring (in NAD+),mercaptoethylamine巯基乙胺unit (in CoA) were recruited to serve as efficient carriers ofactivated electrons and chemical units⏹ a function not readily performed by RNA itself⏹When protein replaced RNA as the major catalysts to achieve greater versatility and DNAformed by reverse transcription of RNA replaced RNA as the genetic material⏹because its double helix is a more stable and reliable store of genetic information than issingle-stranded RNA⏹the ribonucleotide enzymes stayed essentially unchanged because they were already well suitedto their metabolic role and RNA was left with roles it has retained to this day⏹as the information carrier (mRNA) and adapter (tRNA) in protein synthesis and as criticalcomponents (rRNA) of ribosomes and other assemblies that mediate gene expression That molecules and motifs of metabolism are common to all forms of life testifies to their common origin共同起源and to the retention of functioning modules功能模式持续至今over billion of years of evolution.SummaryAll cells extract energy from their environment and convert foodstuffs into cellular components by ahighly integrated network of chemical reactions called metabolismMost of the central molecules of metabolism are the same in all forms of life. Ribonucleotides such asATP and NADH are especially prominent, reflecting their ancient origin. Moreover, many metabolic patterns are essentially the same in bacteria, plants, and animalsA reaction can occur spontaneously only if the change in free energy (△G) is negative. Athermodynamically unfavorable reaction can be driven by a thermodynamically favorable one ATP, the universal currency of energy to biological systems, is an energy-rich molecule because itcontains two phosphoanhydride bondsThe repulsion between the negatively charged phosphate groups is reduced when ATP ishydrolyzedADP and Pi are stabilized by resonance more than is A TPthis is why ATP has a higher phosphoryl group-transfer potentialThe hydrolysis of ATP shifts the equilibrium of a coupled reaction by a factor of about 108The basic strategy of metabolism is to form ATP, NADPH, and building blocks for biosynthesisATP is consumed in muscle contraction and other motions of cells, active transport, signal transductionprocesses, and biosynthesesNADPH, which carries two electrons at a high potential, provides reducing power in the biosynthesis ofcell components from more-oxidized precursorsATP and NADPH are continuously generated and consumedVitamins are small biomolecules that are needed in small amounts in the diet of higher animalsThe water-soluble ones are VC (ascorbate, an antioxidant) and VB complex (components ofcoenzymes)Ascorbate is required for the hydroxylation of Pro residues in collagen, which stabilizes the triplehelixThe fat-soluble ones are V A (a precursor of retinal), VD (a regulator of calcium and phosphorusmetabolism), VE (an antioxidant in membranes), and VK (a participant in the carboxylation ofGlu).There are 3 stages in the extraction of energy from foodstuffs by aerobic organismsIn the first one, large molecules are broken down into smaller molecules, such as amino acids,sugars, and fatty acidsIn the second one, these small molecules are degraded to a few simple units that have a pervasiverole in metabolism. One of them is the acetyl unit of acetyl CoA, a carrier of activated acylgroupsThe third one of metabolism is the citric acid cycle and oxidative phosphorylation, in which ATPis generated as electrons flow to O2, the ultimate electron acceptor, and fuels are completelyoxidized to CO2Most transfers of activated groups in metabolism are mediated by a recurring set of carriersMetabolism is regulated in a variety of waysThe amounts of some critical enzymes are controlled by regulation of the rate of proteinsynthesis and degradationIn addition, the catalytic activities of many enzymes are regulated by allosteric interactions (as infeedback inhibition) and by covalent modificationThe movement of many substrates into cells and subcellular compartments is also controlledDistinct pathways for biosynthesis and degradation also contribute to metabolic regulationThe energy charge, which depends on the relative amounts of ATP, ADP, and AMP, plays a role inmetabolic regulationA high energy charge inhibits ATP-generating (catabolic) pathways, whereas it stimulatesATP-utilizing (anabolic) pathwaysThe level of ATP and other key metabolites in living organisms can be monitored noninvasively by NMR(nuclear magnetic resonance核磁共振).Chapter 19 GlycolysisGlycolysis is the sequence of reactions that metabolizes one molecule of glucose to two molecules of pyruvate丙酮酸with the concomitant net production of two molecules of ATP.An overview of key structures and reactions♌the structure of the reactants•Hexose己糖or triose丙糖and their derivatives•phosphorylatedEster酯or anhydride酸酐♌the kinds of reactions•Phosphoryl transfer 转移by kinase激酶•Phosphoryl shift移位by mutase变位酶。