25., Fatty ocid oxidation

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25.3 Fatty Acid Oxidatin Stimulus (lwbld glucse) + Epinephrine Fat cell Fatty acids Figute 25.2 Mbilizatin f fatty acids frm adipse tissue. streanl. Fat mbilizatin is shr,rrn in Figure 25.2.The mbilized fatty acids becme tighy attached t a plasma prtein, serum albumin.

1 25.3 Fatty Acid Oxidatin Stimulus (lwbld glucse) + Epinephrine Fat cell Fatty acids Figute 25.2 Mbilizatin f fatty acids frm adipse tissue. streanl. Fat mbilizatin is shr,rrn in Figure 25.2.The mbilized fatty acids becme tighy attached t a plasma prtein, serum albumin. The serum albumin transpfis the fatty acids t tissues where they are taken up by cells that need them. The glycerl prduced by the hydrlysis f the triglyceride als enters these cells. 25., Fatty cid xidatin AMS: T nme and describe the prcess f the ctblism f fatty cids, indicting the end prducts. T predict the hydrlysis prducts f typicl lipid mlecules. T determine the number f mlecules f cetyl CA, NADH, nd FADH, tht result frm the bet xidtin f given ftty cid. Fatty acids are degraded t acetyl cenzymea. Fatty acids enter tissue cells that need energy. Befre a fatty acid mlecule can be xidized t prduce energy, hwever, it must be cnverted t a fatty acyl CA-a thil ester frmed frm a fatty acid and CA. R-C + ',S-CA R-C-S-CA + H,O Fatty acid Fattyacyl CA

25 Liid Metablism CHAPTER Lipid StrageDiseases nbrn errrs assciatedwith lipid metablism include Tay-Sachsdisease,Gaucher's disease, and Niemann-Pick disease.

2 25 Liid Metablism CHAPTER Lipid StrageDiseases nbrn errrs assciatedwith lipid metablism include Tay-Sachsdisease,Gaucher's disease, and Niemann-Pick disease.all three cnditins are lipid strage diseases. Nrmally, bth triglycerides and cmplex lipids are cnstany being brken dwn and synthesizedin the bdy. The lipid strage diseases seem t ccur requiredt catbecausethe bdy lacksenzy.rnes lipids. cmplex alyze the breakdwn f certain t accumulatin This enzyme deficiency leads f abnrmally high levels f cmplex lipids in specific tissues, particularly the brain, spleen, and liver. n all lipid strage diseases,there is retardatin f mental and physical develpment fr reasns that are nt well understd. disease,in which lipids primarily Tay-Sachs accumulate in the brain, is characterized by paralysis, a deterirated mental state, and the stredlipids are priblindness.n Tay-Sachs, marily ganglisides,the mst cmplexmembers f the lipids cntaining sphingsine isee figure, part a). As shwn in the figure, the ganglisides cntain fur different sugar units. Gaucher'sdiseasehas many variants with certain clinical features,including elevated cncentratins f serum acid phsphatase. The structure f a typical cerebrside that accumulates in this disease is shwn in part (b) f the figure. The spleen becmes enlarged because spleen cells accumulate cerebrsides(see Sec. 16.3). Gaucher's disease may prgress rapidly and be fatal in infancy, but sme patients live fairly nrrnal life spans. This suggests that Gaucher's disease is a grup f inheritable diseases.the inherited mutatin may be different in each frm f the disease,but all these mutatins affect cerebrside metablism. The chemical abnrmality fund in Niemann-Pick disease is an increased cntent f sphinglipids (see Sec. 16.3) in the rgans, but especially the spleen (see figure, part c). As in Gaucher'sdisease,lhere are many variants f Niemann-Pick disease,indicating a variety f mutatins affecting sphinglipid metablism. At right: The three lipids whse excessivestrage disease,caucher'sdisease,and causestay-sachs disease,the disease.ln Tay-Sachs Niemann-Pick the mst cmplex stredlipidsare ganglisides, membersf the lipidscntainingsphingsine(a). The cntainglucse(cu), sugarunits f the ganglisides galactse(cal), and tw unusual sugarstn-acetyl(naga)and ff-acetylneurminic acid galactsamine (Nana).ln Gaucher'sand Niemann-Pick the diseases, lipids that cannt be brken dwn are the cerebrsides (b) and the sphingmyelins(c), respectively. The cnversin f fatty acids t fatty acyl CA ccurs in the cytplasm f cells, but the subsequent xidatin f fatty acyl CA ccurs in the mitchndria. This presentsa prblem, since fatty acyl CA mlecules cannt passthrugh the mitchndrial membrane.the passagef fatty acyl CA frm the cytplasm int the mitchndria is dne indirecy. The fatty acyl CA is flrst cnverted int an ester f the amin alchl carnitine..l --'-la- li:rr,-l H t-l R-C-SCA Fatty acyl CA R-C-O -l + (H3C)3N-CH2-CH-CO2H Carnitine (H3C)gN-CH2-CH-CO2H Fatty acyl carnitine + H-SCA

$25.5 Fatty Acid Oxidatin 767 ch2h ul CJ, CH K *""'),---\Cnn HOOC \t t/ l---1 NHCCH3 (a) A gangliside (accumulates in Tay-Sachs disease) CH2 l- -\Q-CHz-QH-CH-CH:CH(CHz)rzCHs.$

3 25.5 Fatty Acid Oxidatin 767 ch2h ul CJ, CH K *""'),---\Cnn HOOC \t t/ l---1 NHCCH3 (a) A gangliside (accumulates in Tay-Sachs disease) CH2 l- -\Q-CHz-QH-CH-CH:CH(CHz)rzCHs./t / \ \s/l 'l HO\ l/ rl l_{ NH-C-R (b) A cerebrside (accumulates in Gaucher's disease) 9H. *ll H CH3 - N - CH2CH2- O - P - O - CH2 - CH - CH - CH : CH(CHz) rzche chr-l 'l,l'"-8-,. (c) A sphingmyelin (accumulates in Niemann-Pick disease) The fatty acyl carnitine passes thrugh the mitchndrial membrane, where reactin with CA cnverts it back t fatty aryl CA..- _ n mitchndrin R-C-O,l (H3C)3N-CHr-CH-CO2H + H-SCA + Fattyaryl carnitine R-C-SCA Fatty acy CA *l + (H3C)3N-CH2-CH-CO2H iu*ititt" The fattyacyl camitine ls s imprtant in the metablism f fatty acids that a carnitine deficiency can be life-threatening. Clarence, the sick baby in the Case in Pint earlier in this chapter, is an example.

758 2s LipidMetablism CHAPTER r rhecnsrlx Pnrr:Carnitinedeficiency Flr.w-up Clarence was fund t be suffering frm a ptentially fatal carnitine deflciency.

4 758 2s LipidMetablism CHAPTER r rhecnsrlx Pnrr:Carnitinedeficiency Flr.w-up Clarence was fund t be suffering frm a ptentially fatal carnitine deflciency. This deficiency was the result f a defect in the genes respnsible fr fatty acid metablism. Clarence's symptms-vmlting, slw heart rate, and breathlng prblemswere generai, and the cnditin ls rare. He was frtunate that his carnitine deficiency was diagnsed befre it tk its fatal curse. Mst f the symptms f his disease disappeared when carnitine was added t his frmula three times a day. Since his carnitine deficiency was accmpanied by ther defects in his fatty acid metablism, Clarence als was placed n a lw-fat diet. Clarence, whse prgnsis was pr, seems t be thriving n his carnitine supplement and lw-fat diet. Carnitinesupplements help in the xidatinf lng-chainfatty acids. Fatty acid activatin Frmatin f fatty acyl CA mlecules shws hw the energy stred in the phsphatebnds f AP can be used t drive chemical prcessesthat nrmally culd nt ccur. Neither the fatty acid nr the CA is sufficieny energetic t frm the fatty acyl CA direcy, s the cell bsts the chemical ' reactivity f the fatty acid carbxyl grup by investing ATP The triphsphate grup f the AP mlecule is cleaved t give p1'rphsphate (PPi)' and the remaining adensinemnphsphate (AMP)frms a high-energy anhydride bnd with the fatty acid. Lih-cnclq- an1'rt-dricie linkage R-C- l r---tj-? a + P-C + PPr R-C-O-P-O -,rll Mixed anhydride Fatty acid The anhydride linkage frmed between the fatty acid and AMP in this reactin is energeticenugh t be brken by reactin with the thil grup f CA' :. fil*l R-C-O-:-- O Adensine + HS_CA -> R_C_S_CA + P Mixed anhydride CA Eethz acyl CA Adensine mnphsphate (AMP)

5 25.5 Fatty Acid Oxidatin 759 The thiester bnd f the fatty acyl CA is a high-energy bnd, just as it is in acetyl CA. Therefre, sme f the energyinvested in the breakdr,m f ATP t AMP has been cnserved in the thiester bnd f the fatty acyl CA. The cst t the cell f activating ne mlecule f fatty acid is the lss f tw high-energy phsphric acid anhydride bnds: ne in the frmatin f the anhydride between the fatty acid and AMP and ne when PP; is hydrlyzed t2p;. Beta ddatin The frmatin f fatty acyl CA mlecules prepares fatty acids fr entry int the mitchndria. n the mitchndria, fatty acyl CA mlecules are degraded t acetyl CA in the catablic prcess calledbetaxidatin. During beta xidatin, the third (beta) carbn f the saturated fatty acid chain f the fatty acyl CA mlecule is xidized t a ketne. Pq tt H/ /O / / C-C-C-C-C-C-S-CA 6 5 4ls 2 r H Fatty acyl CA xidarin ^ ll There are fur reactins invlved in beta xidatin. An example is the fatty acyl CA frmed frm a 16-carbn acid, palmitic acid. Any NADH r FADH2 prduced in these reactins must be'accunted fr, since the reducing pwer f these mlecules may be used t prduce ATP in respiratin. As in all the metablic reactins we have discussed, every step f beta xidatin is catalyzed by enzymes. Step 1: Dehydrgenatin. A carbn-carbn duble bnd is frmed between the secnd and third carbns f the palmitic acid chain. One mlecule f FADH2 is prduced. HHO il CH" " + CH, ---lt':" +-C^- C -C - S -CA HH -,-=-_= CH3+CH2+zCH:CH-C-S tsad FADrr, B a -CA As we have seen, FAD is ften the cen4/rne fr en4rmes that catalyze the remval f hydrgen frm saturated carbn cmpunds. This is the case here, and ne FADH, mlecule is prducec. Step 2: Hydratin. A mlecule f water is added t the duble bnd f the fatty acyl CA. This step is the hydratin reactin f beta xidatin. CH3+CH,+'CH:CH-C-S-CA + H-H -* HO t CHr_FCrrb?B?;C-S-CA HH Step 3: Oxidatin. The hydrxyl grup is nw xidized t a ketne. NAD+ is the cenzyme that acts as the xidizing agent in this secnd xidatin

$HO H llll CH3 + CH2 Jrz- C6- Ca C - S - CA --Z---- ilt CH3 + C H2 JrT C - C - C - S - CA l' NAD -\ADH-H HHH Step 4: Carbn-carbn bnd cleauage.$

6 770 CHAPTER 25 Lipid Metablism l6 carbns reactin f beta xidatin. Thus beta xidatin has nw prduced ne mlecule f FADH2 and ne mlecule f NADH. HO H llll CH3 + CH2 Jrz- C6- Ca C - S - CA --Z---- ilt CH3 + C H2 JrT C - C - C - S - CA l' NAD -\ADH-H HHH Step 4: Carbn-carbn bnd cleauage. The carbn-carbn bnd between the secnd and third carbns is cleaved t give acetyl CA and a new fatty acyl CA that is tw carbns shrter than the starting thiester: This reactin invlves anther mlecule f CA, but n AP is expended. H illll CH"+CH,JlrC-C-C-S-CA + HS-CA CHs-FCH2-lrrC-S-CA + CH3C-S-CA H 14 carbns 2carbns The fragmentatin f fatty acyl CA mlecules int mlecules f acetyl CA is similar t ther metablic cycles. The steps f beta xidatin repeat ver and ver again until the fatty acyl CA is cmpletely degraded t aceryl CA. Lk at Figure The fatty acyl CA that starts each rund f the R-CH2-CH2-C- Activatin AMP + 2P1 il R-CH2-CH2-C-S-CA FADH2 Cycle repeats with fatty acyl CA that is tw carbns shrter than in previus rund Dehydrgenatin (xidatin) Figure 25.5 The fatty acid spiral. R-C- S-CA CH.-C- n,/ S-CA Acetyl CA il R-C-CH2-C-S-CA R- CH: CH-C- S-CA T citric acidcvcre t -Hz Hydratin V$ R-CH-CHr-C-S-CA lelq.

7 25.4 ATP Yield 771 Studies have shlvn that exercising less frequeny but fr a lnger duratin is a gd apprach t burning bdy fat. After 40 minutes f exercising, the percentage f energy supplied by fat is greater than that supplied by carbhydrates. Still lnger exercise perids lead t an even higher percentage f energy being supplied by bdy fat. beta-xidatin cycle is tw carbns shrter than in the previus rund. Fr this reasn, the pathway fr the degradatin f fatty acids t acetyl CA is fien called thefatty acid spiral. Every rund f the spiral prduces ne mlecule each f acetyl CA, NADH, and FADH2 until the fatty acyl CA mlecule is nly fur carbns lng. At this pint, the first three steps f the final rund f beta xidatin prduce the cmpund acetacetyl CA. The furth step, the reactin f acetacetyl CA with CA, prduces an extra mlecule f aceryl CA frm the tail end f the fatry acid withut frmatin f NADH and FADHz. n Chapter 24 we saw that the carbns f the aceryl CA prduced by the catablism f glucse can be cmpletely xidized t carbn dixide in the citric acid cycle. Each mlecule f acetyl CA xidized in this fashin yields enugh energy t make ne mlecule f AB ne mlecule f FADH2, and three mlecules f NADH. The reducing pwer f each mlecule f NADH can make three mlecules f ATP by cellular respiratin; FADH2 prduces tw mlecules f AP in the same way. t was shr,rm that 38 AP mlecules is the ttal useful energyyield f aerbic glucse catablism. Mlecules f acetyl CA are the same, regardless f their surce. Like acetyl CA mlecules prduced frm glucse, the acetyl CA mlecules frmed in the fatty acid spiral can be xidized in the citric acid cycle. Since we can find the yield f NADH, FADH2, and AP frm the beta-xidatin reactins f the fatty acid spiral and frm the citric acid cycle, we can calculate hw many mlecules f AP are prduced by the ttal xidatin f ne mlecule f any fatty acid t carbn dixide and water. Table 25.1 shws a calculatin f this kind fr palmitic acid. n calculating the ttalap yield btained frm the cmplete xidatin f the fatty acid, we can cunt the investment f tw high-energy phs il CH3-C-CH2-C-S-CA + HS-Cfi + Acetaceryl CA CH3-C-S-CA + CH.-C-S-CA n ther wrds, the cmplete cnversin f a fatty acyl CA t tw-carbn fragments f acetyl CA always prduces ne mre mlecule f acetyl CA than f NADH r FADHT. T summarize, the breakd'vrrn f palmitic acid gives eight mlecules f acetyl CA, but nly seven mlecules f NADH and seven mlecules f FADH2 are prduced. PRACTCE EXERCSE 25. Lauric acid is cnverted t acetyl CA in beta xidatin. Determine the yields f (a) acetyl CA, (b) NADH, and (c) FADH ATP yield AM: T calculte the number f ATP mlecules frmed by the xidtin f ftty cid mlecule. Fcus The cmplete xidatin f 1 mlecule f palmitic acidyields 129 mlecules fatp.

Module 3. Chapter 5 Microbial Metabolism. Catabolic and Anabolic Reactions Metabolism Two general types of metabolic reactions: o :

Module 3. Chapter 5 Microbial Metabolism. Catabolic and Anabolic Reactions Metabolism Two general types of metabolic reactions: o : Mdule 3 Chapter 5 Micrbial Metablism Catablic and Anablic Reactins Metablism Tw general types f metablic reactins: : : Recall frm Chapter 2: Energy can be when bnds Energy can be when bnds Catablism Purpse