Harper's Biochemistry Chapter 22 - Oxidation of Fatty Acids (Ketogenesis) PDF

C H A P T E R Oxidation of Fatty Acids: Ketogenesis Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc 22 O B J E C TI V E S Describe the processes by which fat...

C H A P T E R Oxidation of Fatty Acids: Ketogenesis Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc 22 O B J E C TI V E S Describe the processes by which fatty acids are transported in the blood, activated and transported into the matrix of the mitochondria for breakdown After studying this chapter, you to obtain energy. should be able to: Outline the β-oxidation pathway by which fatty acids are metabolized to acetyl- CoA and explain how this leads to the production of large quantities of ATP. Identify the three compounds termed “ketone bodies” and describe the reactions by which they are formed in liver mitochondria. Recognize that ketone bodies are important fuels for extrahepatic tissues and indicate the conditions in which their synthesis and use are favored. Indicate the three stages in the metabolism of fatty acids where ketogenesis is regulated. Indicate that overproduction of ketone bodies leads to ketosis and, if prolonged, ketoacidosis, and identify pathologic conditions when this occurs. Give examples of diseases associated with impaired fatty acid oxidation. BIOMEDICAL IMPORTANCE OXIDATION OF FATTY ACIDS Fatty acis are broken own in mitochonria by oxiation OCCURS IN MITOCHONDRIA to acety-CoA in a process that generates arge amounts of Athough acety-CoA is both an en point of fatty aci catabo- energy. When this pathway is proceeing at a high rate, three ism an the starting substrate for fatty aci synthesis, break- compouns, acetoacetate, d-3-hyroxybutyrate, an ace- own is not simpy the reverse of the biosynthetic pathway, tone, known coectivey as the ketone boies, are prouce but an entirey separate process taking pace in a ifferent by the iver. Acetoacetate an d-3-hyroxybutyrate are use as compartment of the ce. The separation of fatty aci oxia- fues by extrahepatic tissues in norma metaboism, but over- tion in mitochonria from biosynthesis in the cytoso aows prouction of ketone boies causes ketosis. Increase fatty each process to be iniviuay controe an integrate with aci oxiation an consequenty ketosis is a characteristic of tissue requirements. Each step in fatty aci oxiation invoves starvation an of iabetes meitus. Since ketone boies are acy-CoA erivatives, is catayze by separate enzymes, uti- aciic, when they are prouce in excess over ong perios, izes NAD+ an FAD as coenzymes, an generates ATP. It is an as in iabetes, they cause ketoaciosis, which is potentiay aerobic process, requiring the presence of oxygen. ife-threatening. Because guconeogenesis is epenent on fatty aci oxiation, any impairment in fatty aci oxiation eas to hypoglycemia. This occurs in various states of car- Fatty Acids Are Transported in the nitine eficiency or eficiency of essentia enzymes in fatty Blood as Free Fatty Acids aci oxiation, for exampe, carnitine palmitoyltransferase, Free fatty acis (FFAs)—aso cae unesterifie (UFA) or non- or inhibition of fatty aci oxiation by poisons, for exampe, esterifie (NEFA) fatty acis (see Chapter 21)—are fatty acis hypoglycin. that are in the unesterifie state. In pasma, onger-chain FFA 217 218 SECTION V Metabolism of Lipids are combine with albumin, an in the ce they are attache Long-Chain Fatty Acids Cross the to a fatty aci–bining protein, so that in fact they are never reay “free.” Shorter-chain fatty acis are more water soube Inner Mitochondrial Membrane as an exist as the unionize aci or as a fatty aci anion. Carnitine Derivatives Acy-CoAs forme as escribe earier enter the intermem- Fatty Acids Are Activated Before brane space (see Figure 22–1), but are unabe to cross the inner Being Catabolized mitochonria membrane into the matrix where fatty aci breakown takes pace. In the presence of carnitine (β-hyroxy- Fatty acis must first be converte to an active intermeiate γ-trimethyammonium butyrate), a compoun wiey istrib- before they can be cataboize. This is the ony step in the ute in the boy an particuary abunant in musce; however, compete egraation of a fatty aci that requires energy from carnitine palmitoyltransferase-I, an enzyme ocate in the ATP. In the presence of ATP an coenzyme A, the enzyme outer mitochonria membrane, transfers the ong-chain acy acyl-CoA synthetase (thiokinase) catayzes the conversion group from CoA to carnitine, forming acylcarnitine an reeas- of a fatty aci (or FFA) to an “active fatty aci” or acyl-CoA, ing CoA. Acycarnitine is abe to penetrate the inner membrane using one high-energy phosphate an forming AMP an PPi an gain access to the β-oxiation system of enzymes via the (Figure 22–1). The PPi is hyroyze by inorganic pyrophos- inner membrane exchange transporter carnitine-acylcarnitine phatase with the oss of a further high-energy phosphate, translocase. The transporter bins acycarnitine an transports ensuring that the overa reaction goes to competion. Acy-CoA it across the membrane in exchange for carnitine. The acy synthetases are foun on the outer membrane of mitochonria group is then transferre to CoA so that acy-CoA is reforme an aso in the enopasmic reticuum an peroxisomes. an carnitine is iberate. This reaction is catayze by carnitine palmitoyltransferase-II, which is ocate on the insie of the inner membrane (see Figure 22–1). a-OXIDATION OF FATTY ACIDS INVOLVES SUCCESSIVE CLEAVAGE WITH RELEASE OF ACETYL-COA In the pathway for the oxiation of fatty acis (Figure 22–2), two carbons at a time are ceave from acy-CoA moecues, starting at the carboxy en. The chain is broken between the α(2)- an β(3)-carbon atoms—hence the process is terme β-oxiation. The two-carbon units forme are acety-CoA; thus, pamitoy(C16)-CoA forms eight acety-CoA moecues. FIGURE 22–1 Role of carnitine in the transport of long-chain fatty acids through the inner mitochondrial membrane. Long- chain acyl-CoA formed by acyl-CoA synthetase enters the intermem- brane space. For transport across the inner membrane, acyl groups must be transferred from CoA to carnitine by carnitine palmitoyl- transferase-I. The acylcarnitine formed is then carried into the matrix by a translocase enzyme in exchange for a free carnitine and acyl-CoA is reformed by carnitine palmitoyltransferase-II. FIGURE 22–2 Overview of β-oxidation of fatty acids.  CHAPTER 22 Oxidation of Fatty Acids: Ketogenesis 219 The β-Oxidation Cycle Generates FADH2 & NADH Severa enzymes foun in the mitochonria matrix or inner membrane ajacent to the respiratory chain catayze the oxia- tion of acy-CoA to acety-CoA via the β-oxiation pathway. The system procees in cycic fashion which resuts in the eg- raation of ong fatty acis to acety-CoA. In the process, arge quantities of the reucing equivaents FADH2 an NADH are generate an are use to form ATP by oxiative phosphorya- tion (see Chapter 13) (Figure 22–3). The first step is the remova of two hyrogen atoms from the 2(α)- an 3(β)-carbon atoms, catayze by acyl-CoA ehyro- genase an requiring favin aenine inuceotie (FAD). This resuts in the formation of Δ2-trans-enoy-CoA an FADH2. Next, water is ae to saturate the oube bon an form 3-hyroxyacy-CoA, catayze by Δ2-enoyl-CoA hyratase. The 3-hyroxy erivative unergoes further ehyrogenation on the 3-carbon catayze by l-3-hyroxyacyl-CoA ehyro- genase to form the corresponing 3-ketoacy-CoA compoun. In this case, NAD+ is the coenzyme invove. Finay, 3-ketoacy- CoA is spit at the 2,3-position by thiolase (3-ketoacy-CoA- thioase), forming acety-CoA an a new acy-CoA two carbons shorter than the origina acy-CoA moecue. The shorter acy-CoA forme in the ceavage reaction reenters the oxiative pathway at reaction 2 (see Figure 22–3). In this way, a ong-chain fatty aci with an even number of carbons may be egrae competey to acety-CoA (C2 units). For exampe, after seven cyces, the C16 fatty aci, pamitate, wou be con- verte to eight acety-CoA moecues. Since acety-CoA can be oxiize to CO2 an water via the citric aci cyce (which is aso foun within the mitochonria), the compete oxiation of fatty acis is achieve. Fatty acis with an o number of carbon atoms are oxi- ize by the pathway of β-oxiation escribe earier, prouc- ing acety-CoA unti a three-carbon (propiony-CoA) resiue remains. This compoun is converte to succiny-CoA, a con- stituent of the citric aci cyce (see Chapter 16). Hence, the propionyl resiue from an o-chain fatty aci is the only part of a fatty aci that is glucogenic. Oxidation of Fatty Acids Produces a Large Quantity of ATP Each cyce of β-oxiation generates one moecue of FADH2 an one of NADH. The breakown of 1 mo of the C16 fatty aci, pamitate, requires seven cyces an prouces 8 mo of acety- CoA. Oxiation of the reucing equivaents via the respiratory chain eas to the synthesis of 28 mo of ATP (Table 22–1 an see Chapter 13) an oxiation of acety-CoA via the citric aci FIGURE 22–3 β-Oxidation of fatty acids. Long-chain acyl- cyce prouces 80 mo of ATP (see Tabe 22–1 an Chapter 16). CoA is cycled through reactions 2 to 5 , acetyl-CoA being split off, The breakown of 1 mo of pamitate, therefore, yies a gross each cycle, by thiolase (reaction 5 ). When the acyl radical is only tota of 108 mo of ATP. However, two high-energy phosphates four carbon atoms in length, two acetyl-CoA molecules are formed in reaction 5. are use in the initia activation step (see Figure 22–3), thus there is a net gain of 106 mo of ATP per moe of pamitate use 220 SECTION V Metabolism of Lipids TABLE 22–1 Generation of ATP From the Complete Oxidation of a C16 Fatty Acid Amount Product Formed (mol)/mol ATP Formed (mol)/ Total ATP Formed ATP Used (mol)/ Step Product Palmitate mol Product (mol)/mol Palmitate mol Palmitate Activation – 2 β-Oxidation FADH2 7 1.5 10.5 – β-Oxidation NADH 7 2.5 17.5 – Citric acid cycle Acetyl-CoA 8 10 80 – Total ATP formed (mol)/mol palmitate 108 Total ATP used (mol)/mol palmitate 2 The table shows how the oxidation of 1 mol of the C16 fatty acid, palmitate, generates 106 mol of ATP (108 formed in total—2 used in the activation step). (see Tabe 22–1), or 106 × 30.5* = 3233 kJ. This represents 33% KETOGENESIS OCCURS WHEN of the free energy of combustion of pamitic aci. THERE IS A HIGH RATE OF FATTY ACID OXIDATION IN THE LIVER Peroxisomes Oxidize Very-Long-Chain Uner metaboic conitions associate with a high rate of Fatty Acids fatty aci oxiation, the iver prouces consierabe quantities A moifie form of β-oxiation is foun in peroxisomes of acetoacetate an d-3-hyroxybutyrate (3-hyroxybutyrate or an eas to the breakown of very-ong-chain fatty acis β-hyroxybutyrate). Acetoacetate continuay unergoes spon- (eg, C20, C22) with the formation of acety-CoA an H 2O2, taneous ecarboxyation to yie acetone. These three sub- which is broken own by cataase (see Chapter 12). This sys- stances are coectivey known as the ketone boies (aso cae tem, however, is not inke irecty to phosphoryation an acetone boies or [incorrecty*] “ketones”) (Figure 22–5). the generation of ATP. The peroxisoma enzymes are inuce Acetoacetate an 3-hyroxybutyrate are interconverte by the by high-fat iets an in some species by hypoipiemic rugs mitochonria enzyme d-3-hyroxybutyrate ehyrogenase; such as cofibrate. the equiibrium is controe by the mitochonria [NAD+]/ Another roe of peroxisoma β-oxiation is to shorten [NADH] ratio, that is, the reox state. The concentration of the sie chain of choestero in bie aci formation (see tota ketone boies in the boo of we-fe mammas oes Chapter 26). Peroxisomes aso take part in the synthesis of not normay excee 0.2 mmo/L. However, in ruminants, ether gyceroipis (see Chapter 24), choestero, an oi- 3-hyroxybutyrate is forme continuousy from butyric aci cho (see Figure 26–2). (a prouct of rumina fermentation) in the rumen wa. In nonruminants, the iver appears to be the ony organ that as significant quantities of ketone boies to the boo. Extra- Oxidation of Unsaturated Fatty Acids hepatic tissues utiize acetoacetate an 3-hyroxybutyrate as respiratory substrates. Acetone is a waste prouct which, as it Occurs by a Modified β-Oxidation is voatie, can be excrete via the ungs. Because there is active Pathway synthesis but itte utiization of ketone boies in the iver, The CoA esters of unsaturate fatty acis are egrae by the whie they are use but not prouce in extrahepatic tissues, enzymes normay responsibe for β-oxiation unti there is a there is a net fow of the compouns to the extrahepatic tissues cis oube bon in the Δ3 or Δ4 position (Figure 22–4). A Δ3- (Figure 22–6). cis compoun is isomerize (Δ 3cis → Δ2-trans-enoyl-CoA isomerase) to the corresponing Δ2-trans-CoA stage of β-oxiation for subsequent hyration an oxiation. Any Acetoacetyl-CoA Is the Substrate for Δ4-cis-acy-CoA either remaining, as in the case of inoeic Ketogenesis aci (shown in Figure 22–4), or entering the pathway at this The enzymes responsibe for ketone boy formation (ketogen- point after conversion by acy-CoA ehyrogenase to Δ 2- esis) are associate mainy with the mitochonria. Acetoace- trans-Δ 4-cis-ienoy-CoA, is then metaboize as inicate ty-CoA is forme when two acety-CoA moecues prouce in Figure 22–4. via fatty aci breakown conense to form acetoacety-CoA *The term ketones shou not be use as there are ketones in boo *ΔG for the ATP reaction, as expaine in Chapter 11. that are not ketone boies, for exampe, pyruvate an fructose.  CHAPTER 22 Oxidation of Fatty Acids: Ketogenesis 221 O CH3 C CH3 CO2 Acetone us eo tan on Sp O CH3 C CH2 COO– Acetoacetate D-3-Hydroxybutyrate dehydrogenase NADH + H+ OH NAD+ CH3 CH CH2 COO– D-3-Hydroxybutyrate FIGURE 22–5 Interrelationships of the ketone bodies. d-3-Hydroxybutyrate dehydrogenase is a mitochondrial enzyme. by a reversa of the thiolase reaction (see Figure 22–3), an may aso arise irecty from the termina four carbons of a fatty aci uring β-oxiation (Figure 22–7). Conensation of acetoacety-CoA with another moecue of acety-CoA by 3-hyroxy-3-methylglutaryl-CoA (HMG-CoA) synthase forms HMG-CoA. HMG-CoA lyase then causes acety-CoA to spit off from the HMG-CoA, eaving free acetoacetate. Both enzymes must be present in mitochonria for ketogenesis to take place. In mammas, ketone boies are forme soey in the iver an in the rumen epitheium. 3-Hyroxybutyrate is forme from acetoacetate (see Figure 22–7) an is quantita- tivey the preominant ketone boy present in the boo an urine in ketosis. Ketone Bodies Serve as a Fuel for Extrahepatic Tissues Whie an active enzymatic mechanism prouces acetoacetate from acetoacety-CoA in the iver, acetoacetate once forme can ony be reactivate by inkage to CoA irecty in the cyto- so, where it is use in a ifferent, much ess active pathway as a precursor in choestero synthesis (see Chapter 26). This accounts for the net prouction of ketone boies by the iver. In extrahepatic tissues, acetoacetate is activate to aceto- acety-CoA by succinyl-CoA-acetoacetate-CoA transferase. CoA is transferre from succiny-CoA to form acetoacety- FIGURE 22–4 Sequence of reactions in the oxidation of CoA (Figure 22–8). In a reaction requiring the aition of unsaturated fatty acids, for example, linoleic acid. β-Oxidation a CoA, two acety-CoA moecues are forme by the spitting proceeds as for saturated fatty acids until there is a cis double bond in the Δ3 position. This is then isomerized to the corresponding Δ2-trans of acetoacety-CoA by thioase an these are oxiize in the compound allowing one cycle of β-oxidation to proceed, producing citric aci cyce. 3-Hyroxybutyrate is utiize by conversion the Δ2- trans- Δ4-cis derivative. Δ4-cis-fatty acids or fatty acids forming to acetoacetate by the reversa of the reaction by which it is Δ4-cis-enoyl-CoA enter the pathway here. A reduction step forming forme in the iver, generating an NADH in the process (see Δ3-trans-enoyl-CoA followed by an isomerization to the Δ2-trans form Figure 22–8). Thus, 1 mo of acetoacetate or 3-hyroxbutyrate is required to enable β-oxidation to then go to completion. NADPH for the dienoyl-CoA reductase step is supplied by intramitochondrial yies 19 or 21.5 mo of ATP, respectivey, by these pathways. sources such as glutamate dehydrogenase, isocitrate dehydrogenase, If the boo eve of ketone boies rises to a concentration of and NAD(P)H transhydrogenase. ~12 mmo/L, the oxiative machinery becomes saturate an 222 SECTION V Metabolism of Lipids Extrahepatic Liver Blood tissues Acyl-CoA FFA Glucose Glucose Acyl-CoA Acetyl-CoA Urine Acetyl-CoA Ketone Ketone Ketone bodies bodies bodies Acetone Citric Citric acid acid cycle cycle Lungs 2CO2 2CO2 FIGURE 22–6 Formation, utilization, and excretion of ketone bodies. (The main pathway is indicated by the solid arrows.) FIGURE 22–7 Pathways of ketogenesis in the liver. (FFA, free fatty acids.)  CHAPTER 22 Oxidation of Fatty Acids: Ketogenesis 223 FIGURE 22–8 Transport of ketone bodies from the liver and pathways of utilization and oxidation in extrahepatic tissues. CoA transferase, succinyl-CoA-acetoacetate-CoA transferase. The breakdown of acetoacetyl-CoA by thiolase produces two acetyl-CoA molecules and requires the addition of one CoA (not shown). at this stage, a arge proportion of oxygen consumption may be to increase. Malonyl-CoA, the initia intermeiate in fatty accounte for by their oxiation. aci biosynthesis (see Figure 23–1) is a potent inhibitor In moerate ketonemia, the oss of ketone boies via the of CPT-I (Figure 22–10). In the fe state, therefore, FFAs urine is ony a few percent of the tota ketone boy prouc- tion an utiization. Since there are rena thresho-ike effects (there is not a true thresho) that vary between species an iniviuas, measurement of the ketonemia, not the ketonuria, is the preferre metho of assessing the severity of ketosis. KETOGENESIS IS REGULATED AT THREE CRUCIAL STEPS 1. Ketosis oes not occur in vivo uness there is an increase in the eve of circuating FFAs arising from ipoysis of tria- cygycero in aipose tissue. FFAs are the precursors of ketone boies in the liver. Both in fe an in fasting coni- tions, the iver extracts ~30% of the FFAs passing through it, so that at high concentrations the fux passing into the organ is substantia. Thus, the factors regulating mobili- zation of FFA from aipose tissue are important in con- trolling ketogenesis (Figures 22–9 an 25–8). 2. After uptake by the iver, FFAs are either oxiize to CO2 or ketone boies or esterifie to triacygycero an phos- phoipi (acygyceros). There is reguation of entry of fatty acis into the oxiative pathway by carnitine palmitoyl- transferase-I (CPT-I) (see Figure 22–1), an the remainer FIGURE 22–9 Regulation of ketogenesis. 1 to 3 show of the fatty aci taken up is esterifie. CPT-I activity is ow three crucial steps in the pathway of metabolism of free fatty acids in the fe state, eaing to epression of fatty aci oxia- (FFA) that determine the extent of ketogenesis. (CPT-I, carnitine tion, an high in starvation, aowing fatty aci oxiation palmitoyltransferase-I.) 224 SECTION V Metabolism of Lipids FIGURE 22–10 Regulation of long-chain fatty acid oxidation in the liver. (FFA, free fatty acids; VLDL, very-low-density lipoprotein.) Positive ( ) and negative () regulatory effects are represented by broken arrows and substrate flow by solid arrows. enter the iver ce in ow concentrations an are neary a that aows the iver to oxiize increasing quantities of fatty esterifie to acygyceros an transporte out of the iver acis within the constraints of a tighty coupe system of in very-low-ensity lipoprotein (VLDL). However, as the oxiative phosphoryation. concentration of FFA increases with the onset of starvation, A fa in the concentration of oxaoacetate, particuary within acety-CoA carboxyase is inhibite irecty by acy-CoA, the mitochonria, can impair the abiity of the citric aci an (maony-CoA) ecreases, reeasing the inhibition of cyce to metaboize acety-CoA an ivert fatty aci oxia- CPT-I an aowing more acy-CoA to be β-oxiize. These tion towar ketogenesis. Such a fa may occur because of an events are reinforce in starvation by a ecrease in the increase in the (NADH)/(NAD+) ratio cause when increase (insulin)/(glucagon) ratio. Thus, β-oxiation from FFA β-oxiation aters the equiibrium between oxaoacetate an is controe by the CPT-I gateway into the mitochonria, maate so that the concentration of oxaoacetate is ecrease, an the baance of the FFA uptake not oxiize is esterifie. an aso when guconeogenesis is eevate ue to ow boo 3. In turn, the acety-CoA forme in β-oxiation is oxiize gucose eves. The activation by acety-CoA of pyruvate car- in the citric aci cyce, or it enters the pathway of ketogen- boxyase, which catayzes the conversion of pyruvate to oxa- esis via acetoacety-CoA to form ketone boies. As the eve oacetate, partiay aeviates this probem, but in conitions of serum FFA is raise, proportionatey more of the acety- such as starvation an untreate iabetes meitus, ketone CoA prouce from their breakown is converte to ketone boies are overprouce an cause ketosis. boies an ess is oxiize via the citric aci cyce to CO2. The partition of acety-CoA between the ketogenic pathway CLINICAL ASPECTS an the pathway of oxiation to CO2 is reguate so that the tota free energy capture in ATP which resuts from the Impaired Oxidation of Fatty Acids oxiation of FFA remains constant as their concentration in the serum changes. This may be appreciate when it is rea- Gives Rise to Diseases Often ize that compete oxiation of 1 mo of pamitate invoves Associated With Hypoglycemia a net prouction of 106 mo of ATP via β-oxiation an Carnitine eficiency can occur particuary in the newborn— the citric aci cyce (see earier), whereas ony 26 mo of an especiay in preterm infants—owing to inaequate ATP are prouce when acetoacetate is the en prouct biosynthesis or rena eakage. Losses can aso occur in hemo- an ony 16 mo when 3-hyroxybutyrate is the en pro- iaysis. This suggests there may be a vitamin-ike ietary uct. Thus, ketogenesis may be regare as a mechanism requirement for carnitine in some iniviuas. Symptoms of  CHAPTER 22 Oxidation of Fatty Acids: Ketogenesis 225 eficiency incue hypogycemia, which is a consequence of epetion of avaiabe carbohyrate coupe with mobiization impaire fatty aci oxiation, an ipi accumuation with of FFA. An exaggeration of this genera pattern of metaboism muscuar weakness. Treatment is by ora suppementation prouces the pathoogic states foun in iabetes mellitus, the with carnitine. type 2 form of which is increasingly common in Western Inherite CPT-I eficiency affects ony the iver, resuting countries; twin lamb isease; an ketosis in lactating cattle. in reuce fatty aci oxiation an ketogenesis, with hypo- Nonpathoogic forms of ketosis are foun uner conitions of gycemia. CPT-II eficiency affects primariy skeeta musce high-fat feeing an after severe exercise in the postabsorptive an, when severe, the iver. The sufonyurea rugs (glyburie state. [glibenclamie] an tolbutamie), use in the treatment Acetoacetic an 3-hyroxybutyric acis are both moer- of Type 2 iabetes meitus, reuce fatty aci oxiation an, atey strong acis an are buffere when present in boo or therefore, hypergycemia by inhibiting CPT-I. other tissues. However, their continua excretion in quantity Inherite efects in the enzymes of β-oxiation an keto- progressivey epetes the akai reserve, causing ketoaciosis. genesis aso ea to nonketotic hypogycemia, coma, an fatty This may be fata in uncontroe iabetes mellitus. iver. Defects have been ientifie in ong- an short-chain 3-hyroxyacy-CoA ehyrogenase (eficiency of the ong- chain enzyme may be a cause of acute fatty liver of pregnancy). SUMMARY 3-Ketoacyl-CoA thiolase an HMG-CoA lyase eficiency Fatty aci oxiation in mitochonria eas to the generation aso affect the egraation of eucine, a ketogenic amino aci of arge quantities of ATP by a process cae β-oxiation that (see Chapter 29). ceaves acety-CoA units sequentiay from fatty acy chains. Jamaican vomiting sickness is cause by eating the unripe The acety-CoA is oxiize in the citric aci cyce, generating fruit of the akee tree, which contains the toxin hypoglycin. further ATP. This inactivates meium- an short-chain acy-CoA ehy- The ketone boies (acetoacetate, 3-hyroxybutyrate, an rogenase, inhibiting β-oxiation an causing hypogycemia. acetone) are forme in hepatic mitochonria when there is a Dicarboxylic aciuria is characterize by the excretion of high rate of fatty aci oxiation. The pathway of ketogenesis C6—C10 ω-icarboxyic acis an by nonketotic hypogycemia, invoves synthesis an breakown of HMG-CoA by two key enzymes: HMG-CoA synthase an HMG-CoA yase. an is cause by a ack of mitochonria meium-chain acyl- CoA ehyrogenase. Refsum isease is a rare neuroogic Ketone boies are important fues in extrahepatic tissues. isorer cause by a metaboic efect that resuts in the accu- Ketogenesis is reguate at three crucia steps: (1) contro muation of phytanic aci, which is foun in airy proucts of FFA mobiization from aipose tissue; (2) the activity of an ruminant fat an meat. Phytanic aci is thought to have carnitine pamitoytransferase-I in iver, which etermines the pathoogic effects on membrane function, protein preny- proportion of the fatty aci fux that is oxiize rather than esterifie; an (3) partition of acety-CoA between the pathway ation, an gene expression. Zellweger (cerebrohepatorenal) of ketogenesis an the citric aci cyce. synrome occurs in iniviuas with a rare inherite absence of peroxisomes in a tissues. They accumuate C26—C38 poy- Diseases associate with impairment of fatty aci oxiation ea to hypogycemia, fatty infitration of organs, an enoic acis in brain tissue an aso exhibit a generaize oss of hypoketonemia. peroxisoma functions. The isease causes severe neuroogic symptoms, an most patients ie in the first year of ife. Ketosis is mi in starvation but severe in iabetes meitus an ruminant ketosis. Ketoacidosis Results From Prolonged Ketosis REFERENCES Higher than norma quantities of ketone boies present in Ejami AS: Lipid Biochemistry: For Medical Sciences. iUniverse, the boo or urine constitute ketonemia (hyperketonemia) or 2015. ketonuria, respectivey. The overa conition is cae ketosis. Gurr MI, Harwoo JL, Frayn KN, et a: Lipids, Biochemistry, The basic form of ketosis occurs in starvation an invoves Biotechnology and Health. Wiey-Backwe 2016.