sa Chapt 14 Glyeolee,Gluconeogeness, and the Pentcse Phosphate Pathuay vay ae = Preparatory phase @ A\ 4 spheraten ase BYo Ket EE DP i Glace prosare Omi, @ uk a @ Hewhinawe ft © Prorpterae Fructne phosphate Coat 0 ot — . wy ® Proshe- ey Nw fentiast E ae ss @ Attdese Free 1Siephosphate OID Pa Ko ora © =) " " Cyersdchyde heaps cance Paviramaae tentne Oe @ ® ‘Pavotf phase Pp Ciiaive coven yor @ennceed’ gheenliehode Spbphateta eae iS 222coa [rndon ATP and NAD stint @ Latiohomteebeerte(@) Groce Clyoraideyte foe TP. ape by -® osm aoe | @ p Phos ‘3 Phoepogacerate(2) oom, geet ® Phosphe- he ‘2 Phosphnglycrato (2) ane favtace @eno " © mine e Perate Ponphoecolpyrat 2) og cl s= wae aApe Ee $ Sa oh -@ Tyree) ong FHEURE4-2 the two phases of hea Fr cach molecloo! ge ‘core tht pases dough he peparion phe (a two melecul of hcenldehvde phosphate ae fanned: th pst teh the yet tase). Fynnate she ond preduct of the second phase gly Js6.Foreachghcose ole eo ATP ae consaned nthe prepare (by phe ilar Arie prchcclit the ppl pce pre's re eld ft ATP pr mdecae of gucne converted o pate. “The mumbood reaction sp ar etlzad bythe ensyra td on the High and also corespon t the rumberedeacirgs in the tx Aéscussion. Keep in mind that ech phosphor group, represented ewe as ®), has mo neve chayes (PO!)aes a fcletides, coenzymes, DNA/RNA FIGURE 14-20 Genera scheme ofthe peniote phosphate patiway. [NADI fomed in the once phase wed to edace gation, (CSSG (ee Hox 14-3) and to suppor reductne bosithess. Theo Productoltheoxiatve phase bows 5-plonphate, which eve Precursor for nucleotides, coenzymes, anc nucleic acids. In cls fat, fe not using lose phosphate for bose, the roaoddaive hase recycles ix molecules ofthe pentose int five molecules ofthe hhexos gucose e-phusptute, alewng comued producion cf NADH and comartng glues ephomphat fn ex cj CD, By maintsining 2 educing atmosphere (a high ratio of [NADPH to NADP* and « high ratio of reduced to ox sized glutathione), they can prevent oF undo oxidative damage to proteins, fips. and other sensitive molecaes. In enyituceytes, the NADPH produced by the pentose ‘phosphate pathway is so important in preventing oxida- tive dammagethata genetic defect in glucose 6phosphate dehydrogenase, the frst enzyme of the pathway, can Ihave sorieus medical consequences (Box 14.3). Ml ‘The Oxidative Phase Producos Penteso Phosphates ‘and NADPH ‘The firs: reaction of the pentose phosphate pathway (ig. 14-21) is the cxidation of glucose 6-phosphate bby glucose 6-phosphate dehydrogenase (G6PD) to form G-phosphogluconoélactone, an intramolecular ‘stor. NADP” is the electron acceptor, and the overall, ‘equilitrium ies far in the direction of NADPH forma- tion. The lactone is hydrolyzed to the frec acid G-phos- phogluconate by a specific laetonase, then bphiospho- gluconate undergoes oxidation and decarboxylation by 6 phosphogluconate dehydrogenase to form the ko- topentose ribulose 5-phospitate. This reaction generates, 6 Phaspho- ‘phcone Slectone cHoP0s- sete YOO a nods ePhaepho- cH0P03- praca [ME iver NADPH C0. cuon oo eon, COR, cx1,0P03 a Ho. ‘Ribulose ‘psphato 2 Ritoso ‘pepe Noon FIGURE 14-21 Oxidative reactions ofthe pence phosphate path way The end producs ar ribose 5 pesphate, CO, and NADPH,516 chsptar15 Primes ot Metabotc Raguston: Giueere and Giyeagen| Glucose icone phosphate fren Practoe 6 phosphate bernard Pructone 1.6bispheophate Diiwdroyacetne ‘oaphate ac (2) Gyoeraldehyde3-phospate eee ene oo pingdroxyastone phowphate (2) 1L3-Bisphosphaglyerste Aoehndrerstnate (2)2Phosphaslycerate sehedrcrsemine (@)2Phospbuelycerate (2) Phosphosnolpyruvate (2) Oraloncetate (2) Pyeavate FIGURE 15-15 Gyeaisic and gluconeogence. Oppeing path mays of gh (pn) and gluconeogenesis ue I at Iver Te steps ar catalyzed by diferent enzymes 9 guconaogeresls allowed to proceed simultaneously ata high rate fn che same cella large amount of chemical energy would be dissipated as heat. This uneconomical process has been called a futile eyele. However, as we shall see later. such eyelet may provide advantages lor controlling pathways, and tho term substrate eyele isa better de- Ssenption. ‘Similar substrate cycles also occur with the other two sels of bypass reactions of gluconeogenesis (Gg. 15-15). ‘We begin aur examination ofthe eoontinated reg lation of gheolysis and ghiconsagenests by considering he regulatory pattems seen at the three main como the sbypos escone) ant aycaya: coven stp a8 catalysed by the se enzyees inthe wo pahways. Colac have been ced fr spi poinis of glycolysis. We then look at the regulation of the enzymes of gluconeogenesis, leading to a consifer ation of how the regulation of both pathways is tightly, reciprocally coordinated. Hexokinase Isozymes of Muscle and Liver Are Affected Differently by Their Product, Glucose 6-Phosphate Hexokinase, which catahes the entry of free glucse into the glycolytic pathway, is a regulatory enayme. ‘There are four isozymes (designates! I to 1V), encoded© +P, FIGURE 16-7 Reactions ofthe citi acid cyte, Tho carbon atom: ‘taded in lok ae those derived fom the ace of aczy-CoA Ia the fist tum of ho yea; tse ate not he earns released as CO, efit ur. Note that in sucinte and ame, the trea up derived rm seeste can no longer be specially note Deca suecnate one urate ae prec molec, C1 and (C2 am dsinguishabe fren C4 and C-.The number beside each 16.2 Reactions ofthe Chile Acid Cyclo 607 (ADP) accny-Caa CO» action sep coroxponds to a numba heacing on pages 608-612. ‘he ted aows show wiere ens i corsened by eecion rans {FAD or NAD', forming FADH, ce ADH +H Sope Q, © rd @) ave esentllyirevrble fhe ell ll other step ae ‘eb The product of sep ©) maybe ether AT or GTP, dep Jngon which suciy-CoA syrhete sacyie isthe cata© (Cy RCH, —CH, CH, —C-S.CoA 6 PalmitoylCos acy-con 7 FAD ayer A pay Hn I RCH, C=C—CS.CoA, ud ‘rans. (610 RC =C=SCOA + CH E-S-CoA ° ° Joker, Acetyl CoA » Cu —> Acetyl -CoA Cu racy cod ip Kacey CoA Ce —+ Acetyl CoA Co —+ Acetyl -CoA ce + Acetyl CoA ‘Acetyl -CoA. FIGURE 17-8 The B-oxidation pathway. (a) In each pass through this, four-step sequence, one acetyl residue (shaded in pink) is removed in the form of acetyl-CoA from the carboxyl end of the fatty acyl chain— in this example palmitate (C14), which enters as palmitoyl-CoA. (b) Six more passes through the pathway yield seven more molecules of acetyl-CoA, the seventh arising from the last two carbon atoms of the 16-carbon chain. Eight molecules of acetyl-CoA are formed in allFatty acid synthesis FIGURE 17-12 Coordinated regulation of fatty acid synthesis and breakdown When the diet provides 2 ready source of carbohycate 235 fue, oxidation oat acids is unecessary an tstherefoe dow. regulated, Two enzymes are Key to the coordination of fatty acid metabolism: acelyCoA carboxylase (ACC), the fst enzyme in the synthesis of fatty acids (ce Fig. 21-1), and carnitine acy! vansorse | vic limits the transport of fatty acids into the mitochondrial mat {or oxidation (Fig, 17-6) Ingestion of a high-carbotykate meal raises the blood glucose level and thus (7) triggers the release of in- sulin. @ Insulin dependent protein phosphalase dephosphorylaes ‘ACC, sativatng it. @) ACC catalyzes the formation of malonyl-CoA Fatty acyl CoASH Fatty acid Boxidation —— ‘te st intermectat of tty aciasyrihess), and @ malonyl: CoA in hibits carnitine cytransferas I thereby reverting faty acid entry ini the milochondtal mat When blood glucose levels drop between meals, () glucagon re- {ease activates CAMP-dependent protein kinase (PKA), which @) phos: phorylats and Inacthates ACC. Tho concentration of malonyl-CoA fal, the inhibition of fatty acid entry into mitochon i elioved, ‘and @ fat acids enter the mitochon mati and @ became the major fue. Because glucagon alsa gers the mobilization of faty ‘cid in adipose tissue, a supply of fay aces aging atving in he blood° ° cm eee 'S.COA 'S.CoA 2 Acetyh.Con oP 1 e ny 'SCoA AcetoaetyCo, anescaa ACEOECOA +40 some can SH on % t 2 Sect CH 0 dn, ‘s-con Hon etna Cok a Ne cr —C-crn, o Acetoacetate scxmetste / NADH SN of ntontuyrnte eSatniae// SPE Cookeonnen Nap" ° ° on ci, —C—cH Seca CHcn, “0 Acetone pigdrosybuyrate FIGURE 17-18 Formation of ketone bodies from acetyl-CoA. Healthy, wolLnourished individuals produce ketone bovis at a rol tively low rate, When acety-CoA accumulates (asin starvation or un treated dlabees, or example), thiolase catalyzes the condensation of two acey-CaA molecules to acetoscey-CoA, the paren compound | ofthe thre ketone bodies. The reactions of Kelone body formation ‘occur inthe matrix of liver mitochondria, The six-catbon compound | ‘Bryony. B-matyiglutay-CoA (HMG-CoA) is aso an intermediate 1 serolblosynibesis, but the enzyme that forms HMG-CoA In tat pathway Is eyosolic. HMG-CoA lyase fs presen only In the rito- ‘hone mat this is simply the reversal of the last step of f oxidation. ‘The acetoacetyl-CoA then condenses with acetyl-CoA to, form p-hydroxy-f-methylglutaryl-CoA (HMG-CoA), which is cleaved to free acetoacetate and acetyl-CoA. ‘The acetoacetate is reversibly reduced by o-B-hydroxy- butyrate dehydrogenase, a mitochondrial enzyme, to p-B-hydroxybutyrate, This enzyme is specific for the 173 Ketone Bodies 651 p stereoisomer: itdoes not act on L-B-hydroxyacyl-CoAs and is not to be confused with L-B-hydroxyacyl-CoA dehydrogenase of the B-oxidation pathway. In healthy people, acetone is formed in very small amounts from acetoacetate, which is easily de. carboxylated, either spontaneously or by the action of acetoacetate decarboxylase (Fig. 17-18). Because individuals with untreated diabetes produce large quan: tities of acetoacetate, their blood contains significant amounts of acetone, which is toxic. Acetone is volatile and imparts a characteristic odor to the breath, which is sometimes useful in diagnosing diabetes. i In extrahepatic tissues, D-B hydroxybutyrate is ox ized to acetoacetate by o-B-hydroxybutyrate dehy- drogenase (Fig. 17-19). The acetoacetate is activated to its coenzyme A ester by transfer of CoA from suc- cinyl-Cod., an intermediate of the citric acid cycle (see Fig, 16-7), in a reaction catalyzed by B-ketoacyl-CoA transferase. The acetoacetyl-CoA is then cleaved by thiolase to yield two acetyl-CoAs, which enter the citric acid cycle. Thus the ketone bodies are used as fuels. ‘The production and export of ketone bodies by the liver allow continued oxidation of fatty acids with only minimal oxidation of acetyl-CoA. When intermediates of | the citric acid cycle are being siphoned off for glucose oH 9 cnc H a Nave a ° I - enter 2 -snyCok D8 Hydronybutyrate pe trantunate “oes preach Ca vwamiroe hy succinate t eo cuy—C—c1 ce Acetoacety-Coh Ss.coa i Pe gear ae “s.coa Ss.cos 2 AcetyhCoA FIGURE 17-19 op Hydroxybutyrate as fut. 06 Hydronybutyate, synthesized inthe Ther, passes int the blood and thus to other tis sus, here Its corweted In thee taps to acetyl fst ox Iaized to acetoacetate, whichis activaied with coenzyme & dona | from succiny-CoA, ton spit by thiolase. The acetyl-CoA thus formed '5 used for energy production,181 Metabo Fates of Amino Groups 6857 Iniraelslar 7 Dietary Amino protain —> “sede mnie A, sp skeletons Biosynthesis ofamino acid, biological amines carbamoyl Keto phosphate ‘eis Urea (nitrogen Oxaloscetate ‘excretion product) | FIGURE 18-1 Overview of amino acid catabolism in mammals. The Gloeose amino groups and the carbon skeleton take Separate but intercon (eynthesized in nected pathways. shucuncogenesis)‘copter 18 Amino Acid Osdation and tho Production of Urea FOURE 18-10 icing page Urea cyte and reactions that feed ‘mine groups nt the pte The eyes ae ne resco inthe oul. One ain ou ters he rea eyelet ‘hosghte famed in he mati the omer er at apa, formed {ite mae by taneaminaton of caatasotate and pane, et slyecd by epaateaminoartrse The pe ele consis of for pe feat of ane hom ering sa came! pe [hate ey ofthe fat amino group te line passes ino thee fou, ronson of ariooncciane Haugh x carly LAME i {eomedot ety ofthe sean amino roup 3 Formation nine ‘an thine. th pny by which NPE ats inthe mio 182 Nitrogen Excretion and the Ure Cycle ‘The liver also receives some arnmonia via the portal vein from the intestine, from the bacterial oxidation of amine acids, Whatever Its source, the NH generated in liver Iitechondria is immediately used, together sith COs {as HCO3) produced by mitochondrial respiration, 10 form canhamoyt phosphate in te mates (Pu 18-11 see also Fig 18410). This ATP-dependent reaction Is Satalyzea by earbamoy! phosphate synthetase Ty 0 eaulatory ensyine (ove below) The mitochondrial fore fof the enayime is distinct trom the cytosolic {I} form, ‘which has a separate function in pyrimidine biosynthe. Si (Chapter 23) “The carbamos! phosphate, which finetionsas.an ac- tivated carbamoy! group donot, no enters the urea eSFIGURE 18-12 Links between the urea cycle and citric acid cycle, The interconnected cycles have baen called the “Krebs bicycle.” The pathways linking the clric acid and urea cycles are called the _spartate-argininosuccinat shunt these effectively ink the fats ofthe [amino groups and the carbon skeletons of amino acids, The inter ‘connections are even mote elaborate than the arrows suggest. For Urea rine Aer eile omitine ee a cone a cannes ‘phosphate example, some citi acid cycle enzymes, such as furarase and malate dehydrogenase, have both cytosolic and mitochondFal isozymes. Fu- Imarate produced in the cytosol-—whether by the urea cycle, putine biosynthesis, or other processes—can be converted to cytosolic malate, ‘which s used inthe eylonol or transported into mitochondhia (via the malate-aspartate shutle; see Fig, 19-27) o enter the citric acid cycleFGURE 18-18 summary of amino acd [a-Ketoglutarate] ‘ctabolison, Amino acids are grouped Seong ther major death end Tasecing!| pret Sore ino ais we ised mee Netisoine fan once case dee’ parse tear SaecnyrGaa}— Personne [hon senate dea odie ‘end products. The figure shows the most important catabolic pathways in vertebrates, ‘ut thete are minor variations among, vericbrate species. Threonine, for instance, degraded via at least two diferent pathways ‘see Figs 18-19, 18.27), andthe impontance ‘of given pathway can vary with the ibaa ‘organism and its metabolic conditions. The slucogenic and ketogenic amino acids are alo delineated in the igre, by color shading, Notice that five ofthe amino acids are both glucogenic and ketogenic. The [ Chucogenic | amino acids degraded to pyruvate are also [a Ketogenie | potentially ketogenic. Only two amino acs, LF leucine and Iysine, are exclusively hetogenic.Amino acids an ‘Sugars 2 Fatty acids HO Nitrogenous bases NH FIGURE 3 Energy relationships between catabolic and anabolic pathways. Catabolic pathways deliver chemical energy in the form of ATP, NADH, NADPH, and FADH)p. These energy carriers are used in anabolic pathways to convert small precursor molecules into cell macromolecules.