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Keshara Senanayake Ms.Reep AP BIOLOGY Chapter 6: Introduction to Metabolism In living cell is a chemical factory w/ thousands of reactions >process called cellular respiration drives the cellular economy by extracting the energy stored in sugars and other fuels (cells apply this to perform work) the totality of an organisms’ chemical reactions is called metabolism is an emergent properties of life that arises from orderly interactions between molecules in a metabolic pathways, a specific molecule is altered in a series of defined steps, resulting in a product each step of the bath way is catalyzed by a specific enzyme Starting molecule A - -enzyme 1/Reaction 1 - - -> B- - enzyme 2/reaction 2 - - - > C - - enzyme 3/reaction 3 - -> D product mechanisms that regulate enzymes balance metabolic supply and demand metabolism manages the material and energy resources of the cell >some metabolic pathways release energy by breaking down of complex molecules called catabolic pathways (or breakdown pathways) cellular respiration is an example energy stored in the organic molecules broken down becomes available to do work of the cell Anabolic pathways consume energy to build complicated molecules from simpler ones (called biosynthetic pathways) >Catabolic and anabolic pathways are “downhill” and “uphill” avenues of the metabolic landscape energy released from downhill catabolic pathways can be stored to drive the uphill reactions of anabolic pathways bioenergetics is the study of how energy flows through living organism Energy is the capacity to cause change can be used to do work (energy is the ability to rearrange a collection of matter) >energy exists in a variety of forms and life depends on ability of cells to transform energy to one form to another >energy associated with the relative motion of objects is called kinetic energy (moving objects can form work by imparting motion to other matter) thermal energy is kinetic energy associated with the random movement of atoms or molecules thermal energy in transfer from one object to another is called heat objects not moving have energy energy that is not kinetic is potential energy; it is energy that matter possesses because of its location or structure molecules posses energy due to arrangement of electrons in bonds between atoms chemical energy is the potential energy available for release in a chemical reaction catabolic pathways release energy by breaking down complex molecules which are high in chemical energy and during catabolic reactions some bonds are broken and others formed RELEASING energy and resulting in lower-energy breakdown products organisms are energy transformers the study for energy transformations in matter is called thermodynamics >system is matter under study everything outside the system is terms the surroundings >an isolated system is unable to exchange either energy or matter w/ surroundings (while an open system can) (organism are open systems) According to the first law of thermodynamics the energy of the universe is constant energy can be transferred or transformed but it cannot be created (known as the principal of conservation of energy) >during every energy transfer transformation some energy is converted into thermal energy and released as heat (becoming unavailable to do work) in body fraction of chemical energy from food is transformed to motion (rest is lost as heat) system can use thermal energy for work when there is a temperature difference that results in the thermal energy flowing from a warmer location to a cooler one (if temp is = like in living system the heat will simply warm the organism’s body) loss of useable energy = universe is more disordered quantified as entropy (measure of disorder/randomness) more random = greater entropy second law of thermodynamics: every energy transfer or transformation increases the entropy of the universe >even if order increase locally total randomization increases >entropy helps us understand why certain process occur without energy (it must increase entropy of universe) process can occur without energy is called a spontaneous process it means the process is energetically favorable a process that can’t occur on its own is no spontaneous (happens w/ energy to system) >can state 2nd law also by: for a process to occur spontaneously it must increase the entropy of the universe living systems increase entropy of surroundings >while cells make ordered structures from less organized starting material and at the organism level complex order red structures result from simpler starting material the organism also takes in organized forms of material/energy from surroundings and makes them less ordered (obtain starch/other complex molecules catabolic pathways break them down and animal releases CO2 and H2O -- contain less chemical energy than food accounting by heat generated by metbalism0 large-scale energy flows into ecosystems in form of light and exits via heat >from early history complex organism evolved from simpler ancestors this increase in organization does NOT violated second law entropy of system may decrease as long as total entropy of universe increases Willard Gibbs helped bring out Gibbs Free energy (symbol = G) free energy is the portion of a system’s energy that can perform work when temperatures and pressures are uniform throughout the system when system changes (as in chemical reaction) the change in free energy can be calculated by: (delta G = delta H - T(delta S) Delta H = system’s enthalpy (total energy in a biological system) Delta S = change in system’s entropy T = absolute temperature in Kelvin (K) Delta F can be used to predict is a particular process is energetically favorable reactions with negative delta G occur without energy so delta G can tell us about spontaneity >important for metabolism (to see which occur spontaneously) biologist focus on the change in free energy in chemicals reactions of life (think of delta G are the difference between the free energy for final and initial state) delta G = Gfinal - Ginitial breakdown of glucose into CO2 + H2O is a delta G of -686 kcal reaction with a negative delta G the system must lose free energy during the change from initial to final state because of less free energy the system in its final state is less likely to change and is therefore more stable than before >free energy can be a measure of a system’s instability (tendency to move to a more stable state) unstable (higher G) tend to change so they can become more stable (lower G) maximum stability = equilibrium >at equilibrium forward and reverse reactions occur at the same rate (no net change in relative concentration of product/reactants) system at equilibrium G is at its lowest possible values in that system any change from the equilibrium position will have a positive delta G and will not be spontaneous (system never spontaneously move from equilibrium) since as system at equilibrium can’t change spontaneous it can do not work a process is spontaneous and can perform work only when it is moving towards equilibrium based on free energy chemical reactions can be considered exergonic or endogenous >exergonic reaction proceeds with a net release of free energy (G decreases) >delta G is for exergonic reactions (so these occur spontaneously in this case it means it is energetically favorable) >magnitude of delta G for an exergonic reaction represents the maximum amount of work the reaction can perform (some free energy is release and can’t do work) greater decrease in free energy = more work can be done breaking of bonds does not release energy (its requires it) >“energy stored in bonds” is shorthand for potential energy that can be released when new bonds are formed after the original bonds break as long as the products are lower free energy than the reactants An endergonic reaction is one that absorbs free energy from its surroundings >stores free energy (G increases and is positive) are nonspontaneous and the magnitude of delta G is the quantity of energy required to drive the reaction >if process of exergonic the reverse is endergonic of that reaction reactions in an isolated system eventually reach equilibrium and can then do no work (chemical reactions of metabolism are reversible and will also reach equilibrium if occurring in isolation) since equilibrium = no work a cell w/ metabolic equilibrium is dead metabolism as a whole is never at equilibrium is one of the defining features of life constant flow of molecules in/out of a cell keeps metabolic pathways from reaching equilibrium (cell continuous to do work through its life) >some of the reversible reactions of respiration are pulled in one direction (keep it from equilibrium key to maintaining equilibrium is that product of reaction does not accumulate but becomes reactant in next step (and at last waste products are expelled from cell) kept going by huge energy difference between glucose and oxygen at the top of “hill” and CO2/H2O “downhill” end >shows how it’s important for an organism to be an open system (sunlight provides free energy for an ecosystem’s plants/photosynthetic organism) Cell does (3) main kinds of work >(1) Chemical work pushing of endergonic reactions that would not occur spontaneously (synthesis of polymers from monomers) >(2) Transport work pumping of substances across membrane against the direction of spontaneous movement >(3) Mechanical work like beating of cilia, contraction of muscle cells, and movement of chromosomes during cellular reproduction >key feature of cell managing energy resources to do this work is via energy coupling use of exergonic process to drive a endergonic one >ATP is responsible for mediating most energy coupling in cells (acts are immediate source of energy in many cases) ATP (adenosine troposphere) contains sugar ribose w/ nitrogenous base adenine and a chain of (3) phosphate groups bonded to it >other then its role in energy coupling ATP is also one of the nucleoside triphosphates used to make RNA bond between phosphate group of ATP is broken via hydrolysis >when terminal phosphate Is broken inorganic phosphate [HOPO3^2- abbreviated (P)i] leaves ATP >adenosine troposphere becomes adenosine diphosphate (ADP) is exergonic (releases 7.3 kcal of energy per mole of ATP hydrolyzed) >this is under standard conditions (STC) in cells STC doesn’t happen (concentration differ from 1M) (in real life 78% greater energy is released by ATP hydrolysis under STC) >since hydrolysis release energy because note that the reactants (ATP and water) are high energy RELATIVE to the energy of the products (ADP and (P)i) release of energy during hydrolysis of ATP comes from the chemical change to a state of lower free energy not from phosphate bonds themselves >ATP is useful to cell because the losing phosphate group gives greater energy than most other cells >WHY SO MUCH ENERGY? three phosphates are negatively changed (mutual repulsion contributes to instability of this region of ATP) triphopshate tail of ATP is like a compressed spring if ATP is hydrolyzed in test tube is merely releases heat to surrounding cell’s proteins harness the energy released during ATP hydrolysis in many ways to perform (3) types of cellular work (chemical, transport, and mechanical) >w/ help of specific enzymes cell can use energy released by ATP hydrolysis to directly drive chemical reaction that by itself are endergonic (if delta G of endergonic reaction is less than amount released by ATP hydrolysis than the reactions can be coupled so overall will be exergonic) involved phosphorylation (transfer of a phosphate group from ATP to some other molecules) recent w/ phosphate group covalently bonded to it is called a phosphorylated intermediate >key to coupling exergonic/endergonic reactions is the formation of phosphorylated intermediate (which is more reactable (less stable) than original unphosphorylated molecule) transport/mechanical work in cell is nearly always powered by the hydrolysis of ATP >in this case ATP hydrolysis causes a change in protein’s shape and its ability to bind to another molecule (can occur via phosphorylated intermediate) >in most instances mechanical work involved motor proteins “walking” along cytosketal elements textbook shows how a cycle occurs in which ATP is first bound no covalently to the motor protein then ATP is hydrolyzed released ADP and (P)i another ATP can then bind and at each stage the motor protein changes its shape and ability to bind to the cytoskeleton resulting in movement of the protein along the cytoskeleton track >phosphorylation and dephosphorylation also promote crucial protein shape changes during cell signaling >an organism at work uses ATP continuously but ATP is a renewable resource that can be regenerated by the addition of phosphate to ADP >free energy to phosphor late ADP is via exergonic breakdown reaction (catabolic) in cell >shutting of inorganic phosphate + energy is ATP cycle couples exergonic processes to endergonic ones very quick >the regeneration of ATP from ADP + (P)i is endergonic >since ATP formation if not spontaneous free energy is spent to make it occur catabolic pathways (like cellular respiration) give energy for endergonic process of making ATP (ATP cycle is like a revolving door through which energy passes during its transfer from catabolic to anabolic pathways) spontaneous reactions might occur without any energy but can occur slowly >an enzyme is a macromolecule that acts as a catalyst chemical agent that speeds up a reaction without being consumed by the reaction without enzymes any reactions would take a long time every chemical reaction involved breaking/forming bonds >changing one molecules into another generally involves contorting the starting molecule into a highly unstable state before the reaction can proceed to reach the contorted state where bonds can change reactant molecules must absorb energy from their surroundings >when new bonds of the product form energy is released as heat and molecules return to stable shapes w/ lower energy than contorted state >initial energy to start reaction/energy required to contort the reactant molecules so bonds can break is known as free energy of activation (activation energy) Ea >imagine as energy needed to push the reactants to the top of an energy barrier (uphill) so a “downhill” part of reaction can begin >Ea is often supplied by heat (in form of thermal energy) that reactant molecules absorb from surroundings this accelerates reactant molecules so they collide more often (and forcefully) agitates the atoms within the molecules making the breakage of bonds more likely when molecules have absorbed enough to break bonds the reactants are in an unstable condition known as the transition state AB + CD AC + BD (reactants) (products) Reactants AB and CD must absorb enough energy from surroundings to reach unstable transition state where bonds break After bonds have broken new bonds form releasing energy to surroundings A ~ B / C ~D (transition state) / | \ / Ea \ ---(reactants/ | \ products) A - C / B-D (delta D < 0) A-B / C-D >activation of reactant = uphill of the graph free energy content of the reactant molecules are increasing >at summit (energy = Ea has been absorbed) reactants are in transition state are activated and bonds can be broken >as atoms settle to new (stable) bonding arrangements energy is released to surroundings (downhill part of curve) overall decrease in in free energy means that Ea is repaid with interest as formation of new bonds release more energy than was invested in the breaking of old bonds Above reaction is exergonic/occurs spontaneously (delta G < 0) Ea barrier determines rate of reaction >reactants must absorb enough energy to reach top of Ea barrier before reaction can occur (like spark plug fire in an engine to give enough heat to give enough energy to overcome Ea for the spontaneous reaction to occur [reaction of oxygen and gasoline IS spontaneous but has a high Ea) Proteins/DNA/other molecules decompose naturally but persist because at temperatures typical for cell few molecules can make it over the Ea >barrier for selected reactions must occasionally be surmounted for cells to carry out the processes needed for life Heat speeds a reaction by allowing reactants to attain transition state more often (this solution would be inappropriate for biological reactions because high temp denatures proteins/kills cells and heat speeds up ALL reactions not just the ones needed) organisms use catalyses to speed up reactions Enzymes catalyze a reaction by lowering Ea and enabling reactant molecules to absorb enough energy to reaction transition state w/ moderate temperatures (enzymes DO not change delta G and cannot make an endergonic reaction exergonic .enzymes can hasten reactions that would occur anyways but makes it possible for cells to make DYNAMIC equilibrium routing chemicals through cell’s metabolic pathways >enzymes are specific for reactions they can catalyze Substrate is the reactant enzymes act on Enzymes bind to its substrate(s) forming an enzyme-substrate complex when enzyme and substrate are joined the catalytic action of the enzyme converts substrate to the product(s) Seen here: Enzyme + Substrate(s) Enzyme < - -> substrate complex Enzyme + < - -> product(s) Note most enzyme names end in –ase Reaction catalyzed by each enzyme is very specific; an enzyme can recognize its specific substrate even among related compounds >molecular recognization is due to the unique 3D shape of proteins (like enzymes) specificity of enzymes come from shape (consequence of its amino acid sequence_ active site is a restricted region of the enzyme molecule actively binds to the substrate >usually a pocket/groove on surface of enzyme where catalysis occurs usually formed by a few amino acids w/ rest of the protein molecule giving framework that gives configuration of the active site specificity of an enzyme is contributed to complementary fit between the shape of its active site and the shape of the substrate enzyme is not a stiff structure seems to “dance” w/ different shapes in dynamic equilibrium (slight difference in free energy in each pose) shape that best fit does not always have lowest free energy but the short time that enzyme takes a shape a substrate can bind as substrate enters active site the enzymes shape changes slightly due to interactions w/ substrate chemical groups and chemical groups on side chains of amino acids that form the active side shape change makes active site more snugly induced fit brings chemical groups of the active site into positions that enhance their ability to catalyze chemical reactions Substrate is held in the active site by “weak” interactions (hydrogen/ionic bonds) >R groups of a few amino acids that make up the active site catalyze the conversion of substrate to product (and products depart from active site) enzyme is then free to take another substrate molecule into its active site cycle happens fast enzymes merge from their reactions in original form (so very small amount of enzymes can have a huge metabolic impact by functi0ning over and over again in catalytic cycles Most metabolic reactions are reversible and enzymes can catalyze forward or reverse reaction depending on which direction has a negative delta G depends mainly on relative concentrations of reactants and products net effect is always in direction of equilibrium >enzymes use a variety of mechanism that lower Ea and speed up reactions (1) in reactions involving 2+ reactants the active site provides a template on which substrate can come together in the proper orientation (for reaction to occur) (2) active site of an enzyme clutches bound substrates the enzyme may stretch the substrate molecules toward transition state form stressing and bending critical chemical bonds that must be broken during the reaction Since Ea is proportional to the difficulty of breaking the bonds distorting substrate helps it approach the transition state/reduce amount of free energy that must be absorbed to achieve that state (3) active site may provide a microenvironment more conducive to a particular type of reaction than the solution itself would be without the enzyme (i.e. active site has acidic R groups (pocket of low pH) the acidic amino acid may facilitate H+ transfer to substrate as key step in catalyzing the reaction (4) mechanism of catalysis is the direct participation of the active site in the chemical reaction process may involve brief covalent bonding between the substrate and the side chain of an amino acid o the enzyme Subsequent step of reaction restore the side chain to original state so that active site is the same after the reaction it was before rate at which a particular amount of enzyme converts substrates to products is partly a function of the initial concentration of substrate more substrate = more frequently they access the active sites of the enzyme molecules >there is a limit to how fast the reaction can be pushed by adding more substrate to a fix concentration (at some point the concentration of substrate will be high enough that all enzyme molecules have their active sites engaged) as soon as product exits active site another substrate enters at this substrate concentration the enzyme is saturated and rate of reaction is determined by the speed at which the active site converts substrate to products when enzyme population is saturated only way to increase rate of formation is by adding more enzymes (cells does this) more efficiently an enzyme functions is affected by general environmental factors (temp/ph) and by chemicals 3D shape of proteins are sensitive to their environment each enzyme works better under some optimal conditions (these conditions favor the most active shape for enzyme molecule) temp/pH are environmental factors important in the activity of an enzyme (up to a point rate of enzyme reaction increases with temperature because substrate collide w/ active sites more but above that temp the speed of enzymatic reaction stops thermal agitation disrupts the hydrogen/ionic bonds and weaken interactions that stabilize the active shape of the enzyme (and then denatures) each enzyme has an optimal temperature at which reaction rate is greatest (most human enzymes have optimal temperatures about 35-40 Celsius) also an optimal pH (usually 6-8) (pepsin ~ 2 and trypsin ~8) non protein helpers for catalytic activity are cofactors cofactors of enzymes that are inorganic = (metal atoms) in ionic form cofactors of enzymes that are organic = coenzymes (most vitamins) >function in various ways but they perform crucial chemical functions in catalysis certain chemicals selectively inhibit the action of specific enzymes >if the inhibitor attaches to the enzyme by covalent bonds inhibition is usually irreversible >most enzyme inhibitors bind w/ weak interactions and are reversible they resemble the normal substrate molecule and compete for admission into the active site >these mimics = competitive inhibitors reduce the productivity of enzymes by blocking substrates from entering active sites this inhibition can be overcome by increasing concentration of substrate so that active sites become available more substrate molecules than inhibitor molecules are around to gain entry to the sites noncompetitive inhibitors do not directly compete w/ substrate to bind to the enzyme at the active site instead they impede enzymatic reactions by binding to another part of the enzyme this interaction causes the enzyme molecule to change its shape in a way that the active site becomes less effective at catalyzing the conversion of substrate to product >many antibiotics are inhibitors of specific enzymes in bacteria >molecules naturally present in the cell often regulate enzyme activity by acting as inhibitors selective inhibition is essential to the control of cellular metabolism >permanent change in a gene is a mutation can result in a protein w/ one or more changed amino acids in case of enzyme if the changed amino acids are in the active site/crucial region the altered enzyme might have a novel activity or might bind to different substrate under environmental conditions where new function benefits organism natural selection would tend to favor the mutated form of the gene causing to persist cell needs to regulate its metabolic pathways by controlling various enzymes does this either by switching on/off the genes that encode specific enzymes or by regulating the activity of enzymes once they are made the molecules that regulate enzyme activity in a cell behave like reversible noncompetitive inhibitors these regulatory molecules change an enzyme’s shape and the functioning of the its active site by binding to a site elsewhere by no covalent interactions allosteric regulation is the term to describe any case in which a protein’s function at one site is affected by the binding of a regulatory molecule to a separate sit may result either inhibition or stimulation of an enzyme’s activity most enzymes that are allosterically regulated are constructed from 2+ subunits composed of a polypeptide chain w/ its own active site complex oscillates between two different shapes one catalytically active and the other inactive >in the simplest kind of allotter regulation an activating or inhibiting regulatory molecule binds to a regulatory site (allosteric site) where subunits join >binding of an activator to a regulatory site stabilizes the shape that has functional active sites binding of an inhibitor stabilizes the inactive form of the enzyme >subunits of an allotter enzyme fit together in such a way that a shape change in one subunit is transmitted to all others via this interaction of subunit’s a single activator or inhibitor molecule that binds to one regulatory site will affect the active sites of all subunits >fluctuating concentrations of regulators can cause a sophisticated patter of response in activity of cellular enzymes >products of ATP hydrolysis (ADP (P)i) play a complex role in balancing the flow of traffic between anabolic and catabolic pathways by their effects on key enzymes >ATP binds to several catabolic enzymes allosterically lowering their affinity for substrate and thus inhibiting their activity ADP functions as an activator of the same enzyme >logical because catabolism functions in regenerating ATP is ATP production lags ADP accumulates and activates the enzymes that speed up catabolism producing more ATP if ATP supply exceeds demand then catabolism slows down as ATP molecules accumulate and bind to the same enzyme inhibiting them >ATP, ADP, and other related molecules also affect key enzymes in anabolic pathways. via this allotter enzymes control the rates of important reactions in both sorts of metabolic pathways another kind of allotter activation, a substrate molecule binding to one active site in a multisubunit enzymes triggers a shape change in all subunits thus increasing catalytic activity at the other active sites called cooperativity mechanism amplifies the response of enzymes to substrate >one substrate molecule primes an enzyme to act on additional substrate molecules more readily >cooperativity is considered “allotter regulation” because binding of one substrate to one active site affects catalysis in another active site (binding of one substrate molecule to active site of one subunit locks all subunits in active conformation) vertebrate oxygen transport protein (not an enzyme) classic studies of cooperative binding in this protein have elucidated the principal of cooperativity. Hemoglobin is made up of four subunits, each of which has an oxygen-binding site binding of an oxygen molecule to one binding site increases the affinity for oxygen of the remaining binding sites thus where oxygen is at high levels hemoglobin affinity of oxygen increases as more binding sites are filled (in oxygen deprived tissues the release of oxygen molecules decrease the oxygen affinity of other binding sites) cooperativity works in similar ways in multisubunit enzymes when ATP allosterically inhibits an enzyme in ATP-generating pathways the result is feedback inhibition common mode of metabolic control >a metabolic pathway is switched off by the inhibitory binding of its end product to an enzyme that acts early in the pathway feedback inhibition prevents the cell from wasting chemical resources by making no more of a product than is necessary cell is compartmentalized and cellular structures help bring order to metabolic pathways >in some cases team of enzymes for several steps of metabolic pathway is assembled into multienzyme complex >arrangement facilitates the sequence of reactions w/ the product from the first enzyme becoming the substrate for an adjacent enzyme in the complex until the end product is released some enzyme and enzyme complexes have fixed locations within the cell and act as structural components of particular membranes others are in solution within particular membraneenclosed eukaryotic organelles each w/ its own internal chemical environment