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by: Jaden Stiedemann


Jaden Stiedemann
Rice University
GPA 3.78


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This 11 page Class Notes was uploaded by Jaden Stiedemann on Monday October 19, 2015. The Class Notes belongs to BIOS 302 at Rice University taught by Staff in Fall. Since its upload, it has received 8 views. For similar materials see /class/225031/bios-302-rice-university in Biological Sciences at Rice University.

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Date Created: 10/19/15
VI GLYCOLYSIS Introduction During glycolysis glucose is converted to pyruvate The series of ten reactions responsible for this conversion do not require oxygen hence the process is also known as the anaerobic fermentation of glucose There are Four Phases Three are constant and do not depend upon the identity of the organism or the availability of oxygen while the fourth is variable The constant portion consists of 10 steps with an equilibrium constant of 105 AGOY of 85 kcalmole of pyruvate formed The largest changes occur with hexokinase phosphofructokinase and pyruvate kinase l The preparative phase Overall the glycolytic pathway occurs with the net production of 2 moles of ATP The metabolic sequence requires the fragmentation of a hexose into two trioses and this is the key step in the rearrangement of the carbon skeleton A priori the most likely mechanism for breaking a CC bond of a hydroxylated substrate is an aldol cleavage a reaction which requires a B hydroxycarbonyl functionality and results in cleavage between the on and 3 carbon atoms Glucose in the openchain form has such a group but as an aldohexose the products of cleavage would be a 2C plus a 4C unit39 these are not the observed set of products CIHO CHZOH H C OH 2 C Co 3 C HO C H HO CI H H C OH HCOH H C OH 4 C HCOH 3 C CH20H CHZOH However if the carbonyl group were at C2 and not at C1 the aldol cleavage would yield 2 3C products Thus one purpose of the initial steps of glycolysis is to convert glucose to fructose which having the carbonyl at C2 will produce 2 3C fragments after aldol cleavage The early intermediates are phosphorylated sugarsthis sets up the hexose molecule for the ATP syntheses that occur in the terminal phases of glycolysis However as we shall see 2 ATPs are actually consumed in this preparatory phase Phosphorylation also ensures that the intermediates cannot diffuse out of the cell compartment The products of the aldol cleavage are not identical they are glyceraldehyde3P G3P also 3PGA for historical reasons and dihydroxyacetone phosphate CDHAP However these compounds are in very rapid enzymewatalyzed equilibrium and conceptually we can consider the products to be 2 moles of G3P 2 The second phase of glycolysis is the oxidation of G3P to 37phosphoglyceric acid This is the major energy conserving step for not only is a mole of ATP synthesized but one NADH is also produced Although we normally view NADH as a source of reducing equivalents we will later see that l N ADH is the equivalent of 3 ATP a relationship which will become obvious when we come to study oxidative phosphorylation 3 In the third phase of glycolysis each molecule of 3phosphoglyceric acid is converted to a molecule of pyruvate a sequence which produces the second ATP 4 Finally we have the fauth and variable phase of glycolysis for the further metabolism of pyruvate depends upon whether or not oxygen is available and in which tissue glycolysis occurs muscle vs yeast etc However it must be emphasized that the first three phases are independent of the system and also do not depend on the presence of oxygen The Individual Reactions HEXOKINASE The first step in glycolysis is the nucleophilic attack of the C6 hydroxyl of glucose on the y P of ATP leading to the production of G6P This reaction proceeds via the formation of a ternary complex of the enzyme V171 hexokinase glucose and ATP and the reaction is strongly in favor of the products A GOV 34 kcalm ole ATP reacts as the Mg salt CHZOH CHZOP O O ATP ADP The reaction catalyzed by hexokinase is typical of kinase reactions with the OH at C6 activated by a base that quotrem oves the proton thus creating a very strong nucleophile O this nucleophile attacks the y P with the formation of a fivecoordinate trigonal bipyram id at the P subsequent departure of the ADP leads to inversion of configuration at the phosphorus Why doesn39t the ATP undergo hydrolysis After all water is much smaller than glucose and should have no trouble in fitting into the active center The xray structure of the enzyme shows that the free enzyme contains two domains and in the absence of substrate the two domains comprise an open cleft Upon binding the glucose the two domains come together and quotwrapquot themselves around the substrates effectively excluding water from the active center See V amp V Fig 165 As the reaction occurs within this hydrophobic pocket the removal of solvent lowers the dielectric within the active center and enhances both the nucleophilicity of the R039 and the electrophilicity of the y P Hexokinase is subject to strong inhibition by G6P endproduct inhibition PHOSPHOGLUCOMUTASE equivalent to phosphoglycerate mutase to follow moves the P A second important entry point into the glycolytic pathway appears when glycogen is the source of the glucose unitsas a result of the action of the enzyme called phosphorylase a the product of the reaction is glucoseiliP This GlP is converted into G6P by the enzyme known as phosphoglucomutase This enzyme contains a bound Pi at the active center and the reaction proceeds by reaction of the ocanomer of GlP with the intermediate formation of bound Gl6bisP CHZOH CHZOP CHZOP O O O l OP OP The reaction sequence is EPGlP ltgt EPGlP ltgt EGl6bisP EGl6bisP ltgt EPG6P ltgt E P G6P ie phosphate is transferred from a phosphorylated serine hydroxyl present at the active center of phosphoglucomutase to the incoming sugar to form a bound sugar bisphosphate this subsequently returns the P to the enzyme Gl6bisP occasionally dissociates to produce an unphosphorylated form of the enzyme which is inactive and this suggest that the reaction actually occurs with dissociation of the Gl6bisP presumably with retention within the active center pocket reorientation and subsequent rebinding before the sugar has a chance to escape to the solvent see aconitase in Ch 8 Note that the P that ends up at C6 is not the P present at Cl but the P originally present in the enzyme V172 PHOSPHOGLUCOSE ISOMERASE hexose phosphate isomerase formally equivalent to triose phosphate isomerase The second enzyme in the standard sequence catalyses an aldoseketose isom erization a 12 shift this is the reaction that moves the carbonyl cf Lobry de Bruynvan Eckenstein rearrangement in Ch H G6P binds and F6P is released in their respective ring forms with the enzyme catalyzing using an active center lysine ring opening and closing of hem iacetals thus the reaction actually proceeds with the sugars in the straightchain form The essence of the reaction is If If H20H 00 0H CO H d OH COH HO d H Ho d H 110 H H C OH H C OH HOH H C OH H C OH H 0H dHZOP CHZOP CH20P DGlucose6P Enediol Fructose6P A basic group probably histidine abstracts a proton at C2 of the glucose with subsequent rearrangement as shown to form the enediol the proton that is removed is on to a carbonyl and is therefore acidic The enediol then loses a proton and the rearrangement is reversed By moving the carbonyl in this way we have effected an internal oxidationreduction with C1 becoming reduced and C2 oxidized Tritium exchange studies show that protons exchange with the medium which is good evidence for the formation of the carbanion The reaction is absolutely stereospecific39 the uncatalyzed reaction converts fructose6P into glucose6P mannose6 P PHOSPHOFRUCTOKINASE the committing reaction of glycolysis K is large k is small POHZ O CHZOH POH2C CHZOP O ATP ADP PFKase catalyses nucleophilic attack by the C1 hydroxyl of 6P on the y phosphorus of ATP to yield F71 6bisP39 the reaction resembles that catalyzed by hexokinase This is an extremely important enzyme because it is one of the major control sites for the glycolytic pathway Consequently it is subject to activation and inhibition by a variety of metabolites Activators a ADP a product of the reaction b AMP c F26bisP ithis is the most potent Inhibitors a A P a substrate b citrate conveys information from another metabolic pathway Cataytic Inhibitors Activity A tmt03 F6P At this point you should be saying quotWait a minute ADP is a product of the reactionit should be an inhibitor not an activator If this enzyme were a conventional one then you would be correct But the enzyme is a member of a class of enzymes that contains both a catalytic center and a regulatory center Occupation of the regulatory center by the appropriate molecule modifies the behavior of the catalytic center When ADP is in the regulatory center the catalytic center is made more efficient when ATP is present it is made less efficient In the presence of the inhibitors the plot of velocity versus F6P changes from hyperbolic with a small Km to sigmoidal with a large Km The activators undo this transition Whether these activity modifiers bind to a common or to separate regulatory sites on the enzyme is not established The specific role of these activatorsinhibitors will be discussed later this semester when control of carbohydrate metabolism will be presented However we can note now that when energy demands are high the cell contains high amounts of ADP and AMP Large amounts of the latter arise because the demands for energy lead to the reaction 2 ADP ltgt ATP AMP catalyzed by nucleoside bisphosphate kinase m yokinase A large ratio of ADP over ATP leads to an activation of FDPase Conversely when energy is plentiful the ratio of ADPATP is small and this enzyme is inhibited Note that the ADPATP ratio is an important control quantity for many enzymes which participate in ATP metabolism FRUCTOSE 16 BISPHOSPHATE ALDOLASE Fig 169 of VampV The reaction catalyzed by this enzyme might be considered as the characteristic reaction of glycolysis This reaction in which a CC bond is cleaved is called an ALDOL cleavage although you should note that it is frequently written in the reverse direction ie the condensation of two smaller fragments to yield a longer chain carbon compound KmlO 4 This condensation reaction is in fact the spontaneous reaction The aldol condensationcleavage reaction is common in biochemical pathways although the identity of the reactants and products will differ in detail in the individual cases V174 There are two classes of aldolases In both kinds a cationic center within the enzyme is used to stabilize a carbanion which develops transiently as a catalytic intermediate In the first class Type I aldolases found predominantly in mammals and plants the reaction proceeds via the formation of a Schiff base between a lysine function at the active center and the carbonyl group of the substrate There are three important amino acids at the active center lysine cysteine and histidine The first step is the condensation of the carbonyl function of FDP with the activecenter lysine This reaction proceeds in several steps la Addition of an amino group from lysine to the carbonyl of FDP to form a carbinolamine lb Elimination of water dehydration from the carbinolamine to yield the ketimine or Schiffs basel lc Protonation of the Schiff base to yield the ketimine salt This step is invoked to rationalize the facile reaction of the Schiff base with borohydride BH39 Normally the electronrich double bond would be expected to repel this reagent CHZOP CHZOP CHZOP CHZOP 00 NH E Ho CNHE CNE CNHE I 2 R R R R C b 1 Schiff Base ketimine ar mo amme ketimine salt 2 Then a base cysteine captures a proton 2 carbons away from the Schiffs base yielding an alcoholate The positive charge on the N and the negative charge on the O are conducive to the electron flow shown an electron rearrangement occurs as indicated by the arrows resulting in cleavage of the CC bond adjacent to the alcoholate function and elimination of the aldo product glyceraldehyde3P 3 The carbon fragment remaining attached to the lysine is present as a carbanion it captures a proton from a nearby acid a protonated histidine yielding the ketimine salt which loses the proton on the N to become the ketimine Schiff base adduct of DHAP with the enzyme 4 This then eliminates the DHAP by reversal of Schiff base formation detailed in step 1 above ie it rehydrates and dissociates into free DHAP and enzyme Type II Aldolases In the second class the Type II aldolases found principally in microorganisms the active center contains the metal ion Zn2 Thus the Type II aldolases are metalloproteins The function of the Zn is to stabilize the carbanion that develops during the reaction and possibly to assist in the activation of the electrophilic carbonyl The cleavage of Fl6bisP introduces a wrinkle in the use of equilibrium constants as covered in Ch 4 See BioEnergetics Problem Set No 11 showing how composition of mixture can change with concentration Triose Phosphate Isomerase 3carbon analog of phosphohexose isomerase running in reverse The aldolase reaction yields two different products but both products are further metabolized by the same sequence of the glycolytic pathway However whereas the 3PGA is metabolized directly the second product DHAP is first converted to G3P prior to further reaction The enzyme that performs this reaction is called triose 1 The existence of this sugarEnzyme Schiff base is well documented Enzyme is incubated with radioactive DHAP to form the labeled ES complex CDHAP is used because it will not be converted to Fl6diP in the absence of the second reactant 3PGA This complex is then treated with sodium borohydride 0 C pH 6 the borohydride reduces the Schiff base to the secondary amine with the original carbonyl now covalently attached to the original amino group Subsequent hydrolysis of the protein produces betaglyceryllysine the phosphate is lost on acid hydrolysis Limited hydrolysis followed by peptide mapping and sequencing of the radioactive peptide establishes the point of attachment of the carbonyl to the enzyme In this case the point of attachment was lys227 in a chain containing 361 residues This expt is the standard protocol testing for establishing the participation of a Schiff base in enzyme reactions V175 phosphate isom erase TIM The reaction is formally equivalent to phosphoglucoisom erase p VIZ the enzyme that converted G6P to F6P except that i the R group is simply CHZOP and ii the reaction proceeds in the reverse direction The active center base is a carboxylate provided by a glutamic acid END OF PHASE 1 Triose Phosphate Dehydrogenase At this point the original 6C sugar has been converted to 2 moles of the 3C aldehyde G3P This conversion has consumed 2 moles of ATP and has thus been an energy drain on the cell The glyceraldehyde3P is now oxidized to the corresponding acid This reaction is one of the best understood examples of socalled substrate level phaspharyla an ie the synthesis of ATP which does not occur by means of oxidative phosphorylation The reaction proceeds in two steps each with its respective enzyme 1 Glyceraldehyde3P is oxidized and then phosphorylated to produce 13 bisphosphoglyceric acid a reaction catalyzed by the enzyme gblceraldelyldeSP dehydragenase triose phosphate dehydrogenase The steps of the reaction are a 1n the active enzyme a sul iydryl group is present at the active center tied up in an internal complex with enzyme bound NAD This SH group adds to the carbonyl of glyceraldehyde3P to form an adduct called a thiohemiacetal Note that this is the site of action of IODOACETATE b This adduct is then oxidized to the corresponding thioester with concomitant reduction of NADJr to NADH B side The thioester soformed is a highenergy compound Textbooks are a little misleading at this point because it is stated that the bound NADH does not dissociate but transfers the hydride to NADJr free in solution The evidence for this is not convincing and it has not been established whetherornot this bound NADH exchanges for NADJr present in the medium kinetic evidence for this or can reduce NADJr present in the medium without dissociating from the enzyme c This freeenergy is preserved by cleavage of the S acyl enzyme by phosphorolysis ie by nucleophilic attack of the oxygen atom of inorganic phosphate The sulfhydryl group is liberated and the acyl phosphate 13 bisphosphoglycerate is released 2 The enzyme phasphaglycerale kinase now transfers the P attached to the carboxyl group to ADP Thus the large amount of chemical free energy available from the oxidation of the aldehyde to the carboxyl has been preserved by the formation of 1 mole of ATP and also 1 mole ofNADH 13bisphosphoglycerate is a mixedanhydride analogous to an acyl halide The phosphoryl is a good leaving group and readily transferred to ADP I COP CIOH H fOH ADP gt H C OH ATP CHzOP CHzOP More accurately the O39 on the B P of ADP attacks as a nucleophile on the P of the carboxyl phosphate The overall free energy for this sequence of events is quite favorable AGO 30 kcalmole This overall free energy arises from the tradeoff between two strongly energetic reactions The oxidation of the CH0 to the COOH is very exergonic AGO 103 kcalmole The synthesis of the anhydride bond between the carboxyl carbon and the phosphate group is strongly endergonic A GOV 118 kcalmole and would not occur to any measurable extent if it were not coupled to the prior oxidation reaction The overall AGOY is 15 kcalmole for this part of the process But the free energy expended in 39 39 t e A A idc bond is J recovered when 13bishosphoglycerate is utilized for ATP synthesis In summary V176 Reaction A G0 RCHO 2 RCOOP 15 RCOOP ADP 2 RCOOH ATP 45 Net 30 Phosphoglycerate Mutase 3C analog ofphosphoglucomutase he next two reactions lead to the formation of the second mole of ATP obtained from each phosphoglyceraldehyde 3phosphoglycerate is a typical phosphate ester the phosphate ester bond is not high energy and cannot be activated However as we shall soon see the adjacent carbon can be activated and so the next reaction is the conversion of 3phosphoglyceric acid to 2phosphoglyceric acid This reaction is believed to be exactly analogous to the phosphoglucomutase reaction except that in this case 23bisphosphoglycerate not G16bisP is the relevant intermediate and there is a histidine residue not serine present at the active center The histidine is initially phosphorylated transfers a P to 1 r r 39 A A and then recaptures the P to yield 2phosphoglycerate Enolase The unactivated phosphate ester 2phosphoglycerate is now dehydrated to an enol and trapped in that form as the phosphate ester This is accomplished by a pair of glutamate acid residues s 168 211 which function together as a base to abstract the relatively nonacidic proton at C2 plus an active center MgZ facilitating the process by capturing the hydroxyl at C3 normally the OH is a poor leaving group See Biochemistry Vol 30 2817 As long as this phosphate ester bond exists as the enol it cannot isomerize to the thermodynamically much more stable ocketoacid tautomer39 thus a highenergy enol phosphate is formed The reaction is an internal redox step produced by the facile J J quot 39 followed by after the P has left The reaction proceeds by a carbanion intermediate Enolase has an absolute requirement for Mg2 which is part of the active center and this is the explanation for its potent inhibition by fluoride history lecture It is now known that uoride reacts spontaneously with phosphate present in the medium to produce fluorophosphate39 fluorophosphate has a high affinity for Mg and either removes it from solution thus depleting the Mg in the enzyme or binds to the Mg at the active center thus blocking reaction Pyruvate Kinase As before the energy capture step is followed by an enzymatic step whereby the activated phosphoryl group in PEP is transferred downhill to form ATP with the oxygen anion of ADP acting as a nucleophile during the phosphoryl transfer attacking the P of PEP The enzyme pyruvate kinase exhibits an unusually complex response to cations Cs K NH4 and RbJr all activate the enzyme whereas LiJr and Na both inhibit AGOY for the reaction is 75 kcalmole39 thus the reaction is overwhelmingly in favor of ATP synthesis and for all practical purposes this step in glycolysis is considered to be irreversible This irreversibility is also apparent in the kinetic parameters The enzyme has a turnover number TN in the forward reaction of 6000 sec391 while that in the reverse reaction is 12 sec391 Fermentation vs Glycolysis The Fate of Pyruvate It is at this point that the metabolic processes of Fermentation and Muscle Glycolysis diverge The three products of glycolysis to this point are 2 pyruvate 2 NADH and 2 ATP As the cell continues to function it will utilize the ATP and regenerate ADP and Pi However a mechanism must exist for recycling the NADH otherwise the depletion of NADJr would block further reaction The strategy that is adopted for this purpose is different in yeast and in muscle and is the most striking difference between these two systems although in both cases the NADH is recycled by Ihefunher metabolism afpyruvate V177 1 Muscle The NADH is oxidized by reducing the pyruvate to lactate by lactate dehydrogenase LDH CH3COCOOH NADH H lt2 CH3CHOHCOOH NAD The reaction sequence is typical for NADlinked enzymes see NADJr lecture although the enzyme has some unusual features As detailed by Dr Olson lecture 1 1 Bios 301 LDH is a protein of 140000 kDa containing 4 subunits The enzyme occurs in animal tissues as 5 different ISOZYMES multiple molecular forms which are readily separable by electrophoresis The isozymes arise through different combinations of two different sub units These subunits are called A previously designated M for Muscle and B previously designated H for Heart and differ by virtue of variations in amino acid sequence between residues 298315 out of a total chain length of 330 The A subunits have a more negative charge than the B subunits and so move more rapidly towards the anode of the electrophoresis apparatus LDH from skeletal muscle is a mixture which is dominated by the tetramer A4 M4 liver LDH is also M In heart the dominant species is B4 A4 is dominant in tissues that have high glycolytic activity white fast twitch whereas B4 predominates in tissue with high aerobic activity pink slow twitch The B subunits are inhibited by excess pyruvate and only favor rapid formation of lactate at low concentrations of pyruvate39 in contrast the A isozym es are much less sensitive to inhibition by high levels of pyruvate and can catalyze the formation of lactate even when pyruvate is high and the cell has a need for energy under anaerobic conditions see Zubay p321 In other tissues there are more complex distributions and comparable amounts of all 5 alternative combinations A3B1 AZBZ A1B3 B4 are present Isozyme analysis is frequently used in medical diagnosis The LDH isozyrne B4 which predominates in heart tissue greatly increases in the blood plasma after a heart attack due to the destruction of some of the heart tissue and consequent release of this cytosolic enzyme into the blood In liver damage eg infectious hepatitis the blood will contain the isozymes characteristic of the liver with a dominance of the A isozymes A4 and A3B1 2 In YEAST the NADH is recycled as the result of a twostep mechanism Yeast appears not to have LDH though fungi and bacteria do First of all the pyruvate is decarboxylated to yield acetaldehyde and C02 This reaction is catalyzed by the enzyme pyruvate decarboxylase39 this enzyme utilizes a prosthetic group called thiamin pyrophosphate The discussion of this prosthetic group and the mechanism of this reaction will be postponed for the time being Finally the acetaldehyde produced above is reduced to ethanol with the concomitant oxidation of NADH by alcohol dehydrogenase ADH Acetaldehyde NADH H lt2 Ethanol NAD This dehydrogenase is also a tetram er but in this case the subunits are identical Each subunit contains two atoms of Zn one of which is removed from the active center but the other is present at the substrate binding site and serves to enhance the polarization of the CO function discussed in detail in section on NAD Energetic Balance 1 Muscle The overall reaction is glucose 2 2 lactate 2H4r AGO39 2 124 96 218 267 218 49 kcalmole Note that because the reaction is conducted at pH 7 we are not at a standardstate for protons pH 0 and hence must include the free energy change associated with dilution of the proton 7 x l 37 96 kcalm ole V178 2 ATP are consumed in converting glucose 2 FDP 1 ATP is synthesized in oxidizing glyceraldehyde3 P to phosphoglyceric acid This step is occurs twice 2 2 ATP Likewise the reaction of PEP to pyruvate occurs twice so that another 2 ATP are generated The net yield of ATP is 2 and the energy recovered from the overall sequence is 2 76 152 kcalmole The efficiency is thus calculated to be 15249 N 30 If we had started from glycogen then only 1 ATP would have been expended per mole39 the efficiency would then be 37349 45 2 Yeast For glucose 2 2 ethanol C02 the free energy of reaction is 56 kcalmole The ATP balance is the same as for muscle a net yield of 2 ATP so that the efficiency is 27356 27 Note however that the complete combustion of glucose to C02 and H20 yields 686 kcal of free energy Thus approximately 600 kcal are still present in the products of glycolysis Catabolism 0f Carbohydrates Even though we have presented glycolysis as if glucose were the defined starting point it is perhaps better to think of it as the conceptual starting point because it is very possible to have diets that have littleorno free glucose even though glucose is the most abundant monosaccharide For example one could imagine that the sole source of carbohydrate in the diet is starch either animal starch glycogen or plant starch Then a necessary preamble to glycolysis is the conversion of the starch to glucose Both of these storage carbohydrates are polysaccharides with ocl 4 linear segments in addition glycogen and amylopectin contains ocl 6 branch p01nts Amylose is degraded by the enzyme amylase an endoglycosidase which catalyzes random hydrolytic acts at points far from chain ends thus reducing the polysaccharide in size to maltose and maltotriose These are then reduced to free glucose by the enzyme maltase Amylopectinthe major component of plant starch resembles glycogen in structure with amylopectin amylase yields a limit dexm39n as a third product see glycogen below this is converted to glucose by the action of a dextrinase The degradation of glycogen is more complex and requires the action of 3 enzyme activities First the polymers are partially degraded to glucoselP by phosphorolysis of the ocl 2 4 bond The enzyme that catalyses the phosphorolysis of glycogen is called phosphorylase a It is an exoglycosidase The reaction is glucosen Pi 2 glucosen1 GlP Conceptually this reaction is the nucleophilic attack of the Pi upon the C1 bond of the lefthand monomer unit This reaction is carried out repeatedly from the outside of the polymer the enzyme quotnibblingquot in along the ocl 4 chain from left to right However this enzyme cannot cleave the ocl 2 6 bonds and once the enzyme gets within 34 residues of a branch point degradation stops Further metabolism of this limit dextrin requires the action of a second enzyme which has two catalytic activities V179 gt gt o o o o O O O O V V V o o o o o o o o o o o o o o o G1P o oo o o o o o o o o o o o o o o o 0 1 A glycosyl transferase activity moves the last three glucose residues as a unit and transfers them to the end of a second chain Model building shows that the sugar tails of the limit dextrin are helical and the first glucose of the limit dextrin is physically adjacent to the glucose acceptor AGO for transfer may be zero 2 The quotnakedquot 16 branch point is now exposed and an ocl 6 glucosidase activity the debranching enzyme splits out the single residue at the branch point as glucose Both activities ie l and 2 are part of the same polypeptide 160 kDa Phosphorylase can then continue with its exaglycosidic action Glycogen phosphorylase is under complex control However discussion of this control will be postponed until the glycogen lectures after midterm Two other important carbohydrates in the diet are lactose and sucrose Sucrose is our common kitchen sugarit is synthesized only in green plants The metabolism of sucrose begins with the action of the enzyme sucrase invertase which hydrolyzes sucrose to its component monosaccharides glucose and fructose Glucose enters glycolysis normally but fructose is metabolized in two different ways In the heart fructose is first converted to FASAP F ATP ltgt F6P This reaction like the analogous phosphorylation of glucose is catalyzed by hexokinase The F6P is already on the glycolytic path However in liver the reaction is F ATP ltgtFlP catalyzed by fructokinase liver does not contain hexokinase rather it has glucokinase and fructokinase The Fl P is then cleaved by aldolase to yield DHAP and The i then A wit ATP by glyceraldehyde kinase to yield G3P The disaccharide LACTOSE is a major constituent of milk On hydrolysis by the enzyme laclase glucose and galactose are produced Further metabolism of the galactose is quite complicated First it is phosphorylated to GallP by the enzyme galaclakinase Gal ATP 2 GallP ADP Then the galactoselP is converted to glucoselP by an inversion of the orientation of the hydroxyl at C4 an epimerisaz ian reaction This process occurs while the sugar is bound to a nucleotide uridine diphosphate UDP This nucleotide occurs as its glucose complex UDPG It is an example of a nucleotide in which the V1710 heterocyclic base is a pyrimidine and the glucose is attached to the pyrophosphate moiety via a phosphodiester link to C1 CHZOH O gt O 390 r I i 039 O P 0 CH2 O 0 O O H H H H OH OH UDPG is made by the action of UTP pyrophosphorylase GlP UTP 2 UDPG PP The uridyl group of UDPG is transferred to l t 1 ph ph t in a 39 reaction catalyzed by phosphogalactose uridyl transferase GallP UDPglucose 2 UDPgalactose GlP The GlP is then converted to G6P by phosphoglucomutase and enters the glycolytic sequence The next step is the epim erisation reaction UDPgalactose ltgt UDPglucose UDPglucose epimerase which regenerates the UDPglucose cofactor This epim erisation actually proceeds by an oxidationreduction reaction The enzyme contains tightly bound NADJr and the first step is the Withdrawal of a H39 from C4 to yield a COJr species This is planar and addition of the H39 from the other side results in the epimerisation V1711


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