1、Berg Tymoczko Stryer Biochemistry Sixth EditionChapter 15:Basic Concepts and DesignMetabolism Is Composed of Many Coupled, Interconnecting Reactions ATP Is the Universal Currency of Free Energy in Biological Systems The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy Metabolic Pa

2、thways Contain Many Recurring Motifs OUTLINESINTRODUCTION Hummingbirds are capable of prodigious feats of endurance. For instance, the tiny ruby-throated hummingbird can store enough fuel to fly across the Gulf of Mexico, a distance of some 500 miles, without resting. This achievement is possible be

3、cause of the ability to convert fuels into the cellular energy currency, ATP, represented by the model at the right.INTRODUCTIONThe concepts of conformation and dynamics discussed in Part I, especially those dealing with the specificity and catalytic power of enzymes, the regulation of their catalyt

4、ic activity, and the transport of molecules and ions across membranes, enable us to explore questions fundamental to biochemistry: 1. How does a cell extract energy and reducing power from its environment? 2. How does a cell synthesize the building blocks of its macromolecules and then the macromole

5、cules themselves? INTRODUCTIONThese processes are carried out by a highly integrated network of chemical reactions that are collectively known as metabolism or intermediary metabolism. INTRODUCTIONMore than a thousand chemical reactions take place in even as simple an organism as E coli. The array o

6、f reactions may seem overwhelming at first glance. However, metabolism has a coherent design containing many common motifs. These motifs include (1) an energy currency; (2) a limited number of activated intermediates (In fact, a group of about 100 molecules play central roles in all forms of life.);

7、 (3) only 6 kinds of reactions involved in metabolism; (4) metabolic regulation in common ways. INTRODUCTION The purpose of this chapter is to introduce some general principles and motifs of metabolism to provide a foundation for the more detailed studies to follow.1.Metabolism Is Composed of Many C

8、oupled, Interconnecting Reactions Living organisms require a continual input of free energy for three major purposes: (1) the performance of mechanical work in muscle contraction and cellular movements, (2) the active transport of molecules and ions, and (3) the synthesis of macromolecules and other

9、 biomolecules from simple precursors. 1.Metabolism Is Composed of Many Coupled, Interconnecting Reactions The free energy used in these processes, which maintain an organism in a state that is far from equilibrium, is derived from the environment. Phototrophs (photosynthetic organisms) obtain this e

10、nergy by trapping sunlight, whereas chemotrophs, which include animals, obtain energy through the oxidation of foodstuffs generated by phototrophs. 1.Metabolism Is Composed of Many Coupled, Interconnecting Reactions Metabolism Consists of Energy-Yielding and Energy-Requiring Reactions Metabolism is

11、essentially a linked series of chemical reactions that begins with a particular molecule and converts it into some other molecule or molecules in a carefully defined fashion (Figure 15.1). Figure 15.1 Glucose metabolism. Glucose is metabolized to pyruvate in 10 linked reactions. Under anaerobic cond

12、itions, pyruvate is metabolized to lactate and, under aerobic conditions, to acetyl CoA. The glucose-derived carbons of acetyl CoA are subsequently oxidized to CO2. 1.Metabolism Is Composed of Many Coupled, Interconnecting Reactions There are many such defined pathways in the cell, and we will exami

13、ne a few of them in some detail later. These path-ways are interdependent, and the activity is coordinated by exquisitely sensitive means of communica-tion in which allos-teric enzymes are predominant. In Chapter 14, We considered the principles of this communication. Figure 15.2 Metabolic pathways.

14、 1.Metabolism Is Composed of Many Coupled, Interconnecting Reactions Two classes of Metablolic pathways Metabolic pathways can be divided into two broad classes: (1) those that convert energy from fuels into biologically useful forms (catabolic reactions， or catabolism, 分解代謝) and (2) those that requ

15、ire inputs of energy to proceed (anabolism, 合成代謝). Although this division is often imprecise, it is nonetheless a useful distinction in an examination of metabolism. 1.Metabolism Is Composed of Many Coupled, Interconnecting Reactions Some pathways can be either anabolic or catabolic, depending on th

16、e energy conditions in the cell. They are referred to as amphibolic pathways. An important general principle of metabolism is that biosynthetic and degradative pathways are almost always distinct. This separation is necessary for energetic reasons, as will be evident in subsequent chapters. It also

17、facilitates the control of metabolism.1.Metabolism Is Composed of Many Coupled, Interconnecting Reactions How are specific pathways constructed from individual reactions? A pathway must satisfy minimally two criteria: (1) the individual reactions must be specific and (2) the entire set of reactions

18、that constitute the pathway must be thermodyna-mically favored. A reaction can occur spontaneously only if G, the change in free energy, is negative.2.ATP Is the Universal Currency of Free Energy in Biological Systems Just as commerce is facilitated by the use of a common currency, the commerce of t

19、he cell metabolism is facilitated by the use of a common energy currency, ATP (adenosine triphosphate, which consists of adenine, a ribose, and a triphosphate unit. 2.ATP Is the Universal Currency of Free Energy in Biological Systems The active form of ATP is usually a complex of ATP with Mg2+ or Mn

20、2+. ATP is an energy-rich molecule because its triphosphate unit contains two phosphor-anhydride bonds. A large amount of free energy is liberated when ATP is hydrolyzed to ADP and Pi or when ATP is hydrolyzed to AMP and PPi.2.ATP Is the Universal Currency of Free Energy in Biological SystemsFigure

21、15.3 Structures of ATP, ADP, and AMP. These adenylates consist of adenine (blue), a ribose (black), and a trio-, di-, or mono-phosphate unit (red). The innermost phosphorus atom of ATP is designated P, the middle one P, and the outermost one P.2.ATP Is the Universal Currency of Free Energy in Biolog

22、ical Systems The precise Go for these reactions depends on the ionic strength of the medium and on the concentrations of Mg2+ and other metal ions. Under typical cellular concentrations, the actual G for these hydrolyses is approximately -50 kJ mol-1 (-12 kcal mol-1).2.ATP Is the Universal Currency

23、of Free Energy in Biological SystemsWhenThe equalibrium constantWhere the free energy is in kJ.2.ATP Is the Universal Currency of Free Energy in Biological SystemsIf this reaction is coupled with ATP hydrolysis that releases 30.5 kJ per mole,The equalibrium constant Coupling the hydrolysis of ATP wi

24、th the conversion of A into B under standard conditions has changed the equilibrium ratio of B to A by a factor of about 105. 2.ATP Is the Universal Currency of Free Energy in Biological SystemsIf this reaction is coupled with ATP hydrolysis that releases 50.2 kJ per mole,The equalibrium constant Co

25、upling the hydrolysis of ATP with the conversion of A into B under typical cellular conditions has changed the equilibrium ratio of B to A by a factor of about 108. More generally, the hydrolysis of nATP molecules changes the equilibrium ratio of a coupled-reaction (or sequence of reactions) by a fa

26、ctor of 108n. For example, the hydrolysis of 3 ATP molecules in a coupled-reaction changes the equilibrium ratio by a factor of 1024. Thus, a thermodynamically unfavorable reaction sequence can be converted into a favorable one by coupling it to the hydrolysis of a sufficient number of ATP molecules

27、 in a new reaction. 2.ATP Is the Universal Currency of Free Energy in Biological Systems It should also be emphasized that A and B in the preceding coupled-reaction may be interpreted very generally, not only as different chemical species. For example, A and B may represent activated and unactivated

28、 conformations of a protein that is activated by phosphorylation with ATP. Through such changes in protein conformation, molecular motors such as myosin, kinesin, and dynein convert the chemical energy of ATP into mechanical energy (Chapter34). Indeed, this conversion is the basis of muscle contract

29、ion. Alternatively, A and B may refer to the concentrations of an ion or molecule on the outside and inside of a cell, as in the active transport of a nutrient. The active transport of Na+ and K+ across membranes is driven by the phosphorylation of the sodium-potassium pump by ATP and its subsequent

30、 dephosphorylation.2.ATP Is the Universal Currency of Free Energy in Biological Systems2.ATP Is the Universal Currency of Free Energy in Biological SystemsThe High Phosphoryl Potential of ATP Results from Structural Differences Between ATP and Its Hydrolysis Products. What makes ATP a particularly e

31、fficient phosphoryl-group donor? Let us compare the standard free energy of hydrolysis of ATP with that of a phosphate ester, such as glycerol 3-phosphate. The magnitude of Go, for the hydrolysis of glycerol 3-Pi is much smaller than that of ATP, which means that ATP has a stronger tendency to trans

32、fer its terminal Pi to water than does glycerol 3-Pi. In other words, ATP has a higher phosphoryl-transfer potential (phosphoryl-group-transfer potential) than does glycerol 3-phosphate. 2.ATP Is the Universal Currency of Free Energy in Biological Systems The high phosphoryl-transfer potential of AT

33、P can be explained by features of the ATP structure. Because Go depends on the difference in free energies of the products and reactants, we need to examine the structures of both ATP and its hydrolysis products, ADP and Pi, to answer this question. Three factors are important: resonance stabilizati

34、on, electrostatic repulsion, and stabilization due to hydration.2.ATP Is the Universal Currency of Free Energy in Biological Systems2.ATP Is the Universal Currency of Free Energy in Biological Systems1. Resonance Stabilization. ADP and, particularly, Pi, have greater resonance stabilization than doe

35、s ATP. Ortho-phosphate has a number of resonance forms of similar energy (left), whereas the -phosphoryl group of ATP has a smaller number. Forms like that shown in right are unfavorable because a positively charged oxygen atom is adjacent to a positively charged phosphorus atom, an electrostaticall

36、y unfavorable juxtaposition.2.ATP Is the Universal Currency of Free Energy in Biological Systems2. Electrostatic Repulsion. At pH7, the triphosphate unit of ATP carries about four negative charges. These charges repel one another because they are in close proximity. There pulsion between them is red

37、uced when ATP is hydrolyzed.2.ATP Is the Universal Currency of Free Energy in Biological Systems3.Stabilization Due to Hydration. More water can bind more effectively to ADP and Pi than can bind to the phosphor-anhydride part of ATP, stabilizing the ADP and Pi by hydration. 2.ATP Is the Universal Cu

38、rrency of Free Energy in Biological Systems ATP is often called a high-energy phosphate compound, and its phosphor-anhydride bonds are referred to as high-energy bonds. Indeed, a squiggle(P) is often used to indicate such a bond. Nonetheless, there is nothing special about the bonds themselves. They

39、 are high-energy bonds in the sense that much free energy is released when they are hydrolyzed 2.ATP Is the Universal Currency of Free Energy in Biological SystemsPhosphoryl-Transfer Potential Is an Important Form of Cellular Energy Transformation The standard free energies of hydrolysis provide a c

40、onvenient means of comparing the phosphoryl-transfer potential of phosphorylated compounds. Such comparisons reveal that ATP is not the only compound with a high phosphoryl-transfer potential. In fact, some compounds in biological systems have a higher phosphoryl-transfer potential than that of ATP.

41、 These compounds include PEP (phosphoenolpyruvate), 1,3-bisphosphoglycerate (1,3-BPG), and creatine phosphate (Figure15.6). Thus, PEP can transfer its phosphoryl group to ADP to form ATP. 2.ATP Is the Universal Currency of Free Energy in Biological SystemsFigure 15.6 Compounds with high phosphoryl-t

42、ransfer potential. These compounds have a higher phosphoryltransfer potential than that of ATP and can be used to phosphorylate ADP to form ATP.Indeed, this transfer is one of the ways in which ATP is generated in the breakdown of sugars. 2.ATP Is the Universal Currency of Free Energy in Biological

43、Systems It is significant that ATP has a phosphoryl-transfer potential that is intermediate among the biologically important phosphorylated molecules. This intermediate position enables ATP to function efficiently as a carrier of phosphoryl groups. 2.ATP Is the Universal Currency of Free Energy in B

44、iological Systems The amount of ATP in muscle suffices to sustain contractile activity for less than a second. Creatine phosphate in vertebrate muscle serves as a reservoir of high-potential phosphoryl groups that can be transferred to ATP. Indeed, we use creatine phosphate to regenerate ATP from AD

45、P when we exercise strenuously. This reaction is catalyzed by creatine kinase. ATP serves as the principal immediate donor of free energy in biological systems rather than as a long-term storage form of free energy. In a typical cell, an ATP molecule is consumed within a minute of its formation. Alt

46、hough the total quantity of ATP in the body is limited to approximately 100g, the turnover of this small quantity of ATP is very high. For example, a resting human being consumes about 40 kg of ATP in 24 hours. During strenuous exertion, the rate of utilization of ATP may be as high as 0.5 kg / minu

47、te. For a 2-hour run, 60 kg (132 pounds) of ATP is utilized. Clearly, having mechanisms for regenerating ATP is vital. Motion, active transport, signal amplification, and biosynthesis can take place only if ATP is continually regenerated from ADP (Figure15.8).3.The Oxidation of Carbon Fuels Is an Im

48、portant Source of Cellular Energy3.The Oxidation of Carbon Fuels Is an Important Source of Cellular EnergyFigure 15.8 ATP-ADP cycle. This cycle is the fundamental mode of energy exchange in biological systems. The generation of ATP is one of the primary roles of catabolism. The carbon in fuel molecu

49、les such as glucose and fats is oxidized to CO2, and the energy released is used to regenerate ATP from ADP and Pi. In aerobic organisms, the ultimate electron acceptor in the oxidation of carbon is O2 and the oxidation product is CO2. Consequently, the more reduced a carbon is to begin with, the mo

50、re free energy is released by its oxidation.Figure15.9 shows the Go of oxidation for one-carbon compounds.3.The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy3.The Oxidation of Carbon Fuels Is an Important Source of Cellular EnergyFigure 15.9 Free energy of oxidation of single-c

51、arbon compounds.3.The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy Although fuel molecules are more complex (Figure15.10) than the single-carbon compounds depicted in Figure 15.9, when a fuel is oxidized, the oxidation takes place one carbon at a time. The carbon-oxidation ene

52、rgy is used in some cases to create a compound with high phosphoryl-transfer potential and in other cases to create an ion gradient. In either case, the end point is the formation of ATP. 3.The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy How is the energy released in the oxid

53、ation of a carbon compound converted into ATP? As an example, consider glyceraldehyde 3-phosphate, which is a metabolite of glucose formed in the oxidation of that sugar. The C-1 carbon (shown in red) is at the aldehyde-oxidation level and is not in its most oxidized state. Oxidation of the aldehyde

54、 to an acid will release energy. However, the oxidation does not take place directly. Instead, the carbon oxidation generates an acyl-phosphate, 1,3-bisphospho-glycerate. The electrons released arecaptured by NAD+.3.The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy3.The Oxidati

55、on of Carbon Fuels Is an Important Source of Cellular Energy3.The Oxidation of Carbon Fuels Is an Important Source of Cellular EnergyFor reasons similar to those discussed for ATP, 1,3-bisphosphoglycerate has a high phosphoryl-transfer potential. Thus, the cleavage of 1,3-BPG can be coupled to the s

56、ynthesis of ATP. The energy of oxidation is initially trapped as a high-phosphoryl-transfer-potential compound and then used to form ATP. The oxidation energy of a carbon atom is transformed into phosphoryl-transferpotential, first as 1,3-bisphosphoglycerate and ultimately as ATP.3.The Oxidation of

57、Carbon Fuels Is an Important Source of Cellular EnergyIon Gradients Across Membranes Provide an Important Form of Cellular Energy That Can Be Coupled to ATP Synthesis As described in Chapter 13, electrochemical potential is an effective means of storing free energy. Indeed, the electro-chemical pote

58、ntial of ion gradients across membranes, produced by the oxidation of fuel molecules or by photo-synthesis, ultimately powers the synthesis of most of the ATP in cells. In general, ion gradients are versatile means of coupling thermodynamically unfavorable reactions to favorable ones. Indeed, in ani

59、mals, proton gradients generated by the oxidation of carbon fuels account for more than 90% of ATP generation (Figure15.11).3.The Oxidation of Carbon Fuels Is an Important Source of Cellular EnergyFigure 15.11 Proton gradients. The oxidation of fuels can power the formation of proton gradients by th

60、e action of specific proton pumps. These proton gradients can in turn drive the synthesis of ATP when the protons flow through an ATP synthesizing enzyme. This process is called oxidative phosphorylation (Chapter18).3.The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy ATP hydrol