Chapter 17 - Fatty acid catabolism..pdf

chapter 17 FATTY ACID CATABOLISM 17.1 Digestion, Mobilization, and Transport that make them espec...

chapter 17 FATTY ACID CATABOLISM 17.1 Digestion, Mobilization, and Transport that make them especially suitable as storage fuels. The of Fats 632 long alkyl chains of their constituent fatty acids are es- 17.2 Oxidation of Fatty Acids 637 sentially hydrocarbons, highly reduced structures with an energy of complete oxidation (~38 kJ/g) more than 17.3 Ketone Bodies 650 twice that for the same weight of carbohydrate or pro- tein. This advantage is compounded by the extreme insolubility of lipids in water; cellular triacylglycerols Jack Sprat could eat no fat, aggregate in lipid droplets, which do not raise the His wife could eat no lean, osmolarity of the cytosol, and they are unsolvated. (In And so between them both you see, storage polysaccharides, by contrast, water of solvation They licked the platter clean. can account for two-thirds of the overall weight of the —John Clarke, Paroemiologia Anglo-Latina stored molecules.) And because of their relative chem- (Proverbs English and Latin), 1639 ical inertness, triacylglycerols can be stored in large quantity in cells without the risk of undesired chemical reactions with other cellular constituents. he oxidation of long-chain fatty acids to acetyl-CoA T is a central energy-yielding pathway in many organ- isms and tissues. In mammalian heart and liver, for The properties that make triacylglycerols good stor- age compounds, however, present problems in their role as fuels. Because they are insoluble in water, ingested example, it provides as much as 80% of the energetic triacylglycerols must be emulsified before they can be needs under all physiological circumstances. The elec- digested by water-soluble enzymes in the intestine, and trons removed from fatty acids during oxidation pass triacylglycerols absorbed in the intestine or mobilized through the respiratory chain, driving ATP synthesis; from storage tissues must be carried in the blood bound the acetyl-CoA produced from the fatty acids may be to proteins that counteract their insolubility. To over- completely oxidized to CO2 in the citric acid cycle, re- come the relative stability of the COC bonds in a fatty sulting in further energy conservation. In some species acid, the carboxyl group at C-1 is activated by attach- and in some tissues, the acetyl-CoA has alternative fates. ment to coenzyme A, which allows stepwise oxidation In liver, acetyl-CoA may be converted to ketone bod- of the fatty acyl group at the C-3, or
, position—hence ies—water-soluble fuels exported to the brain and other the name
oxidation. tissues when glucose is not available. In higher plants, We begin this chapter with a brief discussion of the acetyl-CoA serves primarily as a biosynthetic precursor, sources of fatty acids and the routes by which they travel only secondarily as fuel. Although the biological role of to the site of their oxidation, with special emphasis on fatty acid oxidation differs from organism to organism, the process in vertebrates. We then describe the chem- the mechanism is essentially the same. The repetitive ical steps of fatty acid oxidation in mitochondria. The four-step process, called
oxidation, by which fatty complete oxidation of fatty acids to CO2 and H2O takes acids are converted into acetyl-CoA is the main topic of place in three stages: the oxidation of long-chain fatty this chapter. acids to two-carbon fragments, in the form of acetyl-CoA In Chapter 10 we described the properties of tria- (
oxidation); the oxidation of acetyl-CoA to CO2 in cylglycerols (also called triglycerides or neutral fats) the citric acid cycle (Chapter 16); and the transfer of 631 632 Chapter 17 Fatty Acid Catabolism electrons from reduced electron carriers to the mitochon- Micelle formation enormously increases the fraction of drial respiratory chain (Chapter 19). In this chapter we lipid molecules accessible to the action of water-soluble focus on the first of these stages. We begin our discus- lipases in the intestine, and lipase action converts tria- sion of
oxidation with the simple case in which a fully cylglycerols to monoacylglycerols (monoglycerides) and saturated fatty acid with an even number of carbon diacylglycerols (diglycerides), free fatty acids, and glyc- atoms is degraded to acetyl-CoA. We then look briefly erol (step 2 ). These products of lipase action diffuse at the extra transformations necessary for the degrada- into the epithelial cells lining the intestinal surface (the tion of unsaturated fatty acids and fatty acids with an intestinal mucosa) (step 3 ), where they are recon- odd number of carbons. Finally, we discuss variations verted to triacylglycerols and packaged with dietary on the
-oxidation theme in specialized organelles— cholesterol and specific proteins into lipoprotein aggre- peroxisomes and glyoxysomes—and two less common gates called chylomicrons (Fig. 17–2; see also Fig. pathways of fatty acid catabolism,  and  oxidation. The 17–1, step 4 ). chapter concludes with a description of an alternative Apolipoproteins are lipid-binding proteins in the fate for the acetyl-CoA formed by
oxidation in verte- blood, responsible for the transport of triacylglycerols, brates: the production of ketone bodies in the liver. phospholipids, cholesterol, and cholesteryl esters be- tween organs. Apolipoproteins (“apo” means “detached” or “separate,” designating the protein in its lipid-free 17.1 Digestion, Mobilization, and form) combine with lipids to form several classes of Transport of Fats lipoprotein particles, spherical aggregates with hy- drophobic lipids at the core and hydrophilic protein side Cells can obtain fatty acid fuels from three sources: fats chains and lipid head groups at the surface. Various consumed in the diet, fats stored in cells as lipid combinations of lipid and protein produce particles of droplets, and fats synthesized in one organ for export different densities, ranging from chylomicrons and very- to another. Some species use all three sources under low-density lipoproteins (VLDL) to very-high-density various circumstances, others use one or two. Verte- lipoproteins (VHDL), which can be separated by ultra- brates, for example, obtain fats in the diet, mobilize fats centrifugation. The structures of these lipoprotein par- stored in specialized tissue (adipose tissue, consisting ticles and their roles in lipid transport are detailed in of cells called adipocytes), and, in the liver, convert ex- Chapter 21. cess dietary carbohydrates to fats for export to other The protein moieties of lipoproteins are recognized tissues. On average, 40% or more of the daily energy re- by receptors on cell surfaces. In lipid uptake from the quirement of humans in highly industrialized countries intestine, chylomicrons, which contain apolipoprotein is supplied by dietary triacylglycerols (although most C-II (apoC-II), move from the intestinal mucosa into the nutritional guidelines recommend no more than 30% of lymphatic system, and then enter the blood, which car- daily caloric intake from fats). Triacylglycerols provide ries them to muscle and adipose tissue (Fig. 17–1, step more than half the energy requirements of some organs, 5 ). In the capillaries of these tissues, the extracellular particularly the liver, heart, and resting skeletal muscle. enzyme lipoprotein lipase, activated by apoC-II, hy- Stored triacylglycerols are virtually the sole source of drolyzes triacylglycerols to fatty acids and glycerol (step energy in hibernating animals and migrating birds. Pro- 6 ), which are taken up by cells in the target tissues tists obtain fats by consuming organisms lower in the (step 7 ). In muscle, the fatty acids are oxidized for en- food chain, and some also store fats as cytosolic lipid ergy; in adipose tissue, they are reesterified for storage droplets. Vascular plants mobilize fats stored in seeds as triacylglycerols (step 8 ). during germination, but do not otherwise depend on fats The remnants of chylomicrons, depleted of most of for energy. their triacylglycerols but still containing cholesterol and apolipoproteins, travel in the blood to the liver, where Dietary Fats Are Absorbed in the Small Intestine they are taken up by endocytosis, mediated by recep- In vertebrates, before ingested triacylglycerols can be tors for their apolipoproteins. Triacylglycerols that en- absorbed through the intestinal wall they must be con- ter the liver by this route may be oxidized to provide verted from insoluble macroscopic fat particles to finely energy or to provide precursors for the synthesis of ke- dispersed microscopic micelles. This solubilization is tone bodies, as described in Section 17.3. When the diet carried out by bile salts, such as taurocholic acid (p. contains more fatty acids than are needed immediately 355), which are synthesized from cholesterol in the liver, for fuel or as precursors, the liver converts them to stored in the gallbladder, and released into the small triacylglycerols, which are packaged with specific intestine after ingestion of a fatty meal. Bile salts are apolipoproteins into VLDLs. The VLDLs are transported amphipathic compounds that act as biological deter- in the blood to adipose tissues, where the triacylglyc- gents, converting dietary fats into mixed micelles erols are removed and stored in lipid droplets within of bile salts and triacylglycerols (Fig. 17–1, step 1 ). adipocytes.  17.1 Digestion, Mobilization, and Transport of Fats 633 Fats ingested in diet 8 Fatty acids are oxidized as fuel or reesterified for storage. Gallbladder Myocyte or adipocyte CO2 ATP Small intestine 7 Fatty acids enter cells. 1 Bile salts emulsify dietary fats in the small intestine, forming Lipoprotein lipase mixed micelles. 6 Lipoprotein lipase, activated by apoC-II in the capillary, 2 Intestinal lipases Capillary converts triacylglycerols degrade triacylglycerols. to fatty acids and glycerol. Intestinal mucosa 5 Chylomicrons move through the lymphatic system and bloodstream ApoC-II to tissues. 3 Fatty acids and other breakdown products are taken up by the Chylomicron intestinal mucosa and converted into triacylglycerols. 4 Triacylglycerols are incorporated, with cholesterol and apolipoproteins, into chylomicrons. FIGURE 17–1 Processing of dietary lipids in vertebrates. Digestion and absorption of dietary lipids occur in the small intestine, and the Apolipoproteins fatty acids released from triacylglycerols are packaged and delivered to muscle and adipose tissues. The eight steps are discussed in the text. B-48 C-III C-II FIGURE 17–2 Molecular structure of a chylomicron. The surface is a layer of phospholipids, with head groups facing the aqueous phase. Triacylglycerols sequestered in the interior (yellow) make up more than 80% of the mass. Several apolipoproteins that protrude from the sur- face (B-48, C-III, C-II) act as signals in the uptake and metabolism of Phospholipids Cholesterol chylomicron contents. The diameter of chylomicrons ranges from Triacylglycerols and about 100 to 500 nm. cholesteryl esters 634 Chapter 17 Fatty Acid Catabolism Hormones Trigger Mobilization acids can be oxidized for energy production. The hor- of Stored Triacylglycerols mones epinephrine and glucagon, secreted in response to low blood glucose levels, activate the enzyme adenylyl Neutral lipids are stored in adipocytes (and in steroid- cyclase in the adipocyte plasma membrane (Fig. 17–3), synthesizing cells of the adrenal cortex, ovary, and which produces the intracellular second messenger testes) in the form of lipid droplets, with a core of sterol cyclic AMP (cAMP; see Fig. 12–13). Cyclic AMP– esters and triacylglycerols surrounded by a monolayer dependent protein kinase (PKA) phosphorylates of phospholipids. The surface of these droplets is coated perilipin A, and the phosphorylated perilipin causes with perilipins, a family of proteins that restrict access hormone-sensitive lipase in the cytosol to move to to lipid droplets, preventing untimely lipid mobilization. the lipid droplet surface, where it can begin hydrolyz- When hormones signal the need for metabolic energy, ing triacylglycerols to free fatty acids and glycerol. PKA triacylglycerols stored in adipose tissue are mobilized also phosphorylates hormone-sensitive lipase, doubling (brought out of storage) and transported to tissues or tripling its activity, but the more than 50-fold increase (skeletal muscle, heart, and renal cortex) in which fatty in fat mobilization triggered by epinephrine is due pri- marily to perilipin phosphorylation. Cells with defective perilipin genes have almost no response to increases in Hormone Adenylyl cyclase cAMP concentration; their hormone-sensitive lipase 1 does not associate with lipid droplets. As hormone-sensitive lipase hydrolyzes triacylglyc- Receptor G5 erol in adipocytes, the fatty acids thus released (free 2 fatty acids, FFA) pass from the adipocyte into the ATP cAMP blood, where they bind to the blood protein serum al- bumin. This protein (Mr 66,000), which makes up about half of the total serum protein, noncovalently binds as Fatty acid many as 10 fatty acids per protein monomer. Bound to 4 transporter PKA this soluble protein, the otherwise insoluble fatty acids 3 are carried to tissues such as skeletal muscle, heart, and P Hormone- renal cortex. In these target tissues, fatty acids dissoci- 7 P P sensitive ate from albumin and are moved by plasma membrane P lipase b oxidation, transporters into cells to serve as fuel. Perilipin P citric acid cycle, respiratory chain About 95% of the biologically available energy of tri- P P 8 acylglycerols resides in their three long-chain fatty acids; Lipid ATP only 5% is contributed by the glycerol moiety. The glyc- droplet 6 CO2 erol released by lipase action is phosphorylated by glyc- 5 erol kinase (Fig. 17–4), and the resulting glycerol Serum Fatty acids albumin 3-phosphate is oxidized to dihydroxyacetone phosphate. Triacyl- The glycolytic enzyme triose phosphate isomerase con- glycerol Adipocyte Myocyte verts this compound to glyceraldehyde 3-phosphate, which is oxidized via glycolysis. Bloodstream Fatty Acids Are Activated and Transported FIGURE 17–3 Mobilization of triacylglycerols stored in adipose tis- into Mitochondria sue. When low levels of glucose in the blood trigger the release of The enzymes of fatty acid oxidation in animal cells are glucagon, 1 the hormone binds its receptor in the adipocyte mem- located in the mitochondrial matrix, as demonstrated in brane and thus 2 stimulates adenylyl cyclase, via a G protein, to 1948 by Eugene P. Kennedy and Albert Lehninger. The produce cAMP. This activates PKA, which phosphorylates 3 the hormone-sensitive lipase and 4 perilipin molecules on the surface fatty acids with chain lengths of 12 or fewer carbons of the lipid droplet. Phosphorylation of perilipin permits hormone- enter mitochondria without the help of membrane trans- sensitive lipase access to the surface of the lipid droplet, where 5 it porters. Those with 14 or more carbons, which consti- hydrolyzes triacylglycerols to free fatty acids. 6 Fatty acids leave the tute the majority of the FFA obtained in the diet or adipocyte, bind serum albumin in the blood, and are carried in the released from adipose tissue, cannot pass directly blood; they are released from the albumin and 7 enter a myocyte through the mitochondrial membranes—they must first via a specific fatty acid transporter. 8 In the myocyte, fatty acids are undergo the three enzymatic reactions of the carnitine oxidized to CO2, and the energy of oxidation is conserved in ATP, shuttle. The first reaction is catalyzed by a family of which fuels muscle contraction and other energy requiring metabo- isozymes (different isozymes specific for fatty acids hav- lism in the myocyte. ing short, intermediate, or long carbon chains) present  17.1 Digestion, Mobilization, and Transport of Fats 635 CH2OH HO C H Glycerol in the outer mitochondrial membrane, the acyl-CoA synthetases, which promote the general reaction CH2OH Fatty acid
CoA
ATP y8 8z fatty acyl–CoA
AMP
PPi ATP glycerol kinase Thus, acyl-CoA synthetases catalyze the formation of a ADP thioester linkage between the fatty acid carboxyl group CH2OH and the thiol group of coenzyme A to yield a fatty acyl–CoA, coupled to the cleavage of ATP to AMP and HO C H O L-Glycerol PPi. (Recall the description of this reaction in Chapter CH2 O P O 3-phosphate 13, to illustrate how the free energy released by cleav- O age of phosphoanhydride bonds in ATP could be cou- NAD
pled to the formation of a high-energy compound; p. glycerol 3-phosphate dehydrogenase XXX.) The reaction occurs in two steps and involves a NADH
H
fatty acyl–adenylate intermediate (Fig. 17–5). CH2OH Fatty acyl–CoAs, like acetyl-CoA, are high-energy compounds; their hydrolysis to FFA and CoA has a large, O C O Dihydroxyacetone negative standard free-energy change (G ≈ 31 CH2 O P O phosphate kJ/mol). The formation of a fatty acyl–CoA is made more O favorable by the hydrolysis of two high-energy bonds in triose phosphate ATP; the pyrophosphate formed in the activation reaction isomerase is immediately hydrolyzed by inorganic pyrophosphatase (left side of Fig. 17–5), which pulls the preceding activa- H O tion reaction in the direction of fatty acyl–CoA formation. C The overall reaction is D-Glyceraldehyde H C OH O 3-phosphate Fatty acid
CoA
ATP On CH2 O P O fatty acyl–CoA
AMP
2Pi (17–1) O G  34 kJ/mol Fatty acyl–CoA esters formed at the cytosolic side Glycolysis of the outer mitochondrial membrane can be trans- ported into the mitochondrion and oxidized to produce FIGURE 17–4 Entry of glycerol into the glycolytic pathway. ATP, or they can be used in the cytosol to synthesize O O O  O P O P O P O Adenosine ATP MECHANISM FIGURE 17–5    Conversion of a fatty acid to a fatty O O O acyl–CoA. The conversion is catalyzed O by fatty acyl–CoA synthetase and R C Fatty acid inorganic pyrophosphatase. Fatty acid O activation by formation of the fatty fatty acyl–CoA acyl–CoA derivative occurs in two 1 synthetase
steps. In step 1 , the carboxylate ion displaces the outer two (
and ) O phosphates of ATP to form a fatty O O O P O Adenosine acyl–adenylate, the mixed anhydride  O P O P O
R C O  Fatty acyl–adenylate of a carboxylic acid and a phosphoric O O O (enzyme-bound) acid. The other product is PPi, an Pyrophosphate CoA-SH excellent leaving group that is 2 immediately hydrolyzed to two Pi, fatty acyl–CoA inorganic synthetase AMP pulling the reaction in the forward pyrophosphatase
direction. In step 2 , the thiol group of O coenzyme A carries out nucleophilic 2Pi R C Fatty acyl–CoA attack on the enzyme-bound mixed S-CoA anhydride, displacing AMP and forming the thioester fatty acyl–CoA. The G  19 kJ/mol G  15 kJ/mol overall reaction is highly exergonic. (for the two-step process) 636 Chapter 17 Fatty Acid Catabolism Outer mitochondrial Inner mitochondrial membrane membrane Cytosol Intermembrane Matrix space Carnitine acyltransferase II O O R C R C S-CoA Carnitine Carnitine S-CoA O R C O Carnitine R C CoA-SH CoA-SH Carnitine Carnitine Transporter acyltransferase I FIGURE 17–6 Fatty acid entry into mitochondria via the acyl-carnitine/ A, freeing carnitine to return to the intermembrane space through the carnitine transporter. After fatty acyl–carnitine is formed at the outer same transporter. Acyltransferase I is inhibited by malonyl-CoA, the membrane or in the intermembrane space, it moves into the matrix first intermediate in fatty acid synthesis (see Fig. 21–1). This inhibition by facilitated diffusion through the transporter in the inner membrane. prevents the simultaneous synthesis and degradation of fatty acids. In the matrix, the acyl group is transferred to mitochondrial coenzyme membrane lipids. Fatty acids destined for mitochondrial This three-step process for transferring fatty acids oxidation are transiently attached to the hydroxyl group into the mitochondrion—esterification to CoA, transes- of carnitine to form fatty acyl–carnitine—the second terification to carnitine followed by transport, and trans- reaction of the shuttle. This transesterification is cat- esterification back to CoA—links two separate pools of alyzed by carnitine acyltransferase I (Mr 88,000), in coenzyme A and of fatty acyl–CoA, one in the cytosol, the outer membrane. Either the acyl-CoA passes the other in mitochondria. These pools have different through the outer membrane and is converted to the functions. Coenzyme A in the mitochondrial matrix is carnitine ester in the intermembrane space (Fig. 17–6), largely used in oxidative degradation of pyruvate, fatty or the carnitine ester is formed on the cytosolic face of acids, and some amino acids, whereas cytosolic coen- the outer membrane, then moved across the outer mem- zyme A is used in the biosynthesis of fatty acids (see brane to the intermembrane space—the current evi- Fig. 21–10). Fatty acyl–CoA in the cytosolic pool can be dence does not reveal which. In either case, passage into used for membrane lipid synthesis or can be moved into the intermembrane space (the space between the outer the mitochondrial matrix for oxidation and ATP pro- and inner membranes) occurs through large pores duction. Conversion to the carnitine ester commits the (formed by the protein porin) in the outer membrane. fatty acyl moiety to the oxidative fate. The fatty acyl–carnitine ester then enters the matrix by The carnitine-mediated entry process is the rate- facilitated diffusion through the acyl-carnitine/carni- limiting step for oxidation of fatty acids in mitochondria tine transporter of the inner mitochondrial membrane and, as discussed later, is a regulation point. Once in- (Fig. 17–6). side the mitochondrion, the fatty acyl–CoA is acted upon CH3 by a set of enzymes in the matrix. CH3 N
CH2 CH CH2 COO CH3 OH SUMMARY 17.1 Digestion, Mobilization, Carnitine and Transport of Fats In the third and final step of the carnitine shuttle, the fatty acyl group is enzymatically transferred from The fatty acids of triacylglycerols furnish a carnitine to intramitochondrial coenzyme A by carni- large fraction of the oxidative energy in tine acyltransferase II. This isozyme, located on the animals. Dietary triacylglycerols are emulsified inner face of the inner mitochondrial membrane, re- in the small intestine by bile salts, hydrolyzed generates fatty acyl–CoA and releases it, along with free by intestinal lipases, absorbed by intestinal carnitine, into the matrix (Fig. 17–6). Carnitine reen- epithelial cells, reconverted into ters the intermembrane space via the acyl-carnitine/car- triacylglycerols, then formed into chylomicrons nitine transporter. by combination with specific apolipoproteins.  17.2 Oxidation of Fatty Acids 637 Chylomicrons deliver triacylglycerols to tissues, Stage 1 Stage 2 where lipoprotein lipase releases free fatty CH3 acids for entry into cells. Triacylglycerols CH2 stored in adipose tissue are mobilized by a CH2  Oxidation 8 Acetyl-CoA hormone-sensitive triacylglycerol lipase. The CH2 released fatty acids bind to serum albumin and CH2 are carried in the blood to the heart, skeletal CH2 muscle, and other tissues that use fatty acids CH2 for fuel. e CH2 Once inside cells, fatty acids are activated at CH2 the outer mitochondrial membrane by CH2 Citric conversion to fatty acyl–CoA thioesters. Fatty CH2 acid cycle acyl–CoA to be oxidized enters mitochondria in CH2 three steps, via the carnitine shuttle. CH2 CH2 64e 16CO2 CH2 17.2 Oxidation of Fatty Acids C O As noted earlier, mitochondrial oxidation of fatty acids O takes place in three stages (Fig. 17–7). In the first stage—
oxidation—fatty acids undergo oxidative re- moval of successive two-carbon units in the form of NADH, FADH2 Stage 3 acetyl-CoA, starting from the carboxyl end of the fatty e acyl chain. For example, the 16-carbon palmitic acid
1 (palmitate at pH 7) undergoes seven passes through the 2H
2 O2 Respiratory oxidative sequence, in each pass losing two carbons as (electron-transfer) acetyl-CoA. At the end of seven cycles the last two car- chain H2O bons of palmitate (originally C-15 and C-16) remain as acetyl-CoA. The overall result is the conversion of the 16-carbon chain of palmitate to eight two-carbon acetyl ADP
Pi ATP groups of acetyl-CoA molecules. Formation of each acetyl-CoA requires removal of four hydrogen atoms FIGURE 17–7 Stages of fatty acid oxidation. Stage 1: A long-chain (two pairs of electrons and four H
) from the fatty acyl fatty acid is oxidized to yield acetyl residues in the form of acetyl- moiety by dehydrogenases. CoA. This process is called
oxidation. Stage 2: The acetyl groups are In the second stage of fatty acid oxidation, the oxidized to CO2 via the citric acid cycle. Stage 3: Electrons derived from the oxidations of stages 1 and 2 pass to O2 via the mitochon- acetyl groups of acetyl-CoA are oxidized to CO2 in the drial respiratory chain, providing the energy for ATP synthesis by citric acid cycle, which also takes place in the mito- oxidative phosphorylation. chondrial matrix. Acetyl-CoA derived from fatty acids thus enters a final common pathway of oxidation with the acetyl-CoA derived from glucose via glycolysis and The
Oxidation of Saturated Fatty Acids Has Four pyruvate oxidation (see Fig. 16–1). The first two stages Basic Steps of fatty acid oxidation produce the reduced electron car- riers NADH and FADH2, which in the third stage donate Four enzyme-catalyzed reactions make up the first stage electrons to the mitochondrial respiratory chain, of fatty acid oxidation (Fig. 17–8a). First, dehydro- through which the electrons pass to oxygen with the genation of fatty acyl–CoA produces a double bond concomitant phosphorylation of ADP to ATP (Fig. between the  and
carbon atoms (C-2 and C-3), yield- 17–7). The energy released by fatty acid oxidation is ing a trans-
2-enoyl-CoA (the symbol 2 designates thus conserved as ATP. the position of the double bond; you may want to re- We now take a closer look at the first stage of fatty view fatty acid nomenclature, p. 343.) Note that the new acid oxidation, beginning with the simple case of a sat- double bond has the trans configuration, whereas the urated fatty acyl chain with an even number of carbons, double bonds in naturally occurring unsaturated fatty then turning to the slightly more complicated cases of acids are normally in the cis configuration. We consider unsaturated and odd-number chains. We also consider the significance of this difference later. the regulation of fatty acid oxidation, the
-oxidative This first step is catalyzed by three isozymes of processes as they occur in organelles other than mito- acyl-CoA dehydrogenase, each specific for a range of chondria, and, finally, two less-general modes of fatty fatty-acyl chain lengths: very-long-chain acyl-CoA de- acid catabolism,  oxidation and  oxidation. hydrogenase (VLCAD), acting on fatty acids of 12 to 18 638 Chapter 17 Fatty Acid Catabolism carbons; medium-chain (MCAD), acting on fatty acids in the citric acid cycle (p. XXX); in both reactions the of 4 to 14 carbons; and short-chain (SCAD), acting on enzyme is bound to the inner membrane, a double bond fatty acids of 4 to 8 carbons. All three isozymes are flavo- is introduced into a carboxylic acid between the  and proteins with FAD (see Fig. 13–18) as a prosthetic
carbons, FAD is the electron acceptor, and electrons group. The electrons removed from the fatty acyl–CoA from the reaction ultimately enter the respiratory chain are transferred to FAD, and the reduced form of the de- and pass to O2, with the concomitant synthesis of about hydrogenase immediately donates its electrons to an 1.5 ATP molecules per electron pair. electron carrier of the mitochondrial respiratory chain, In the second step of the
-oxidation cycle (Fig. the electron-transferring flavoprotein (ETF) (see 17–8a), water is added to the double bond of the Fig. 19–8). The oxidation catalyzed by an acyl-CoA de- trans-2-enoyl-CoA to form the L stereoisomer of hydrogenase is analogous to succinate dehydrogenation
-hydroxyacyl-CoA (3-hydroxyacyl-CoA). This re- action, catalyzed by enoyl-CoA hydratase, is for- mally analogous to the fumarase reaction in the citric (a)  (C16) R CH2 CH2 CH2 C S-CoA acid cycle, in which H2O adds across an –
double bond (p. XXX). O Palmitoyl-CoA In the third step, L-
-hydroxyacyl-CoA is dehydro- acyl-CoA FAD genated to form
-ketoacyl-CoA, by the action of dehydrogenase
-hydroxyacyl-CoA dehydrogenase; NAD
is the FADH 2 electron acceptor. This enzyme is absolutely specific for H the L stereoisomer of hydroxyacyl-CoA. The NADH R CH2 C C C S-CoA formed in the reaction donates its electrons to NADH trans-2- dehydrogenase, an electron carrier of the respiratory H O chain, and ATP is formed from ADP as the electrons pass Enoyl-CoA H 2O to O2. The reaction catalyzed by
-hydroxyacyl-CoA de- enoyl-CoA hydratase hydrogenase is closely analogous to the malate dehy- drogenase reaction of the citric acid cycle (p. XXX). OH The fourth and last step of the
-oxidation cycle is catalyzed by acyl-CoA acetyltransferase, more com- R CH2 C CH2 C S-CoA monly called thiolase, which promotes reaction of
- L- -Hydroxy- H O ketoacyl-CoA with a molecule of free coenzyme A to acyl-CoA NAD
split off the carboxyl-terminal two-carbon fragment of  -hydroxyacyl-CoA dehydrogenase the original fatty acid as acetyl-CoA. The other product NADH
H
is the coenzyme A thioester of the fatty acid, now short- ened by two carbon atoms (Fig. 17–8a). This reaction R CH2 C CH2 C S-CoA is called thiolysis, by analogy with the process of hy- -Ketoacyl-CoA O O drolysis, because the
-ketoacyl-CoA is cleaved by re- acyl-CoA CoA-SH action with the thiol group of coenzyme A. acetyltransferase The last three steps of this four-step sequence are (thiolase) catalyzed by either of two sets of enzymes, with the en- zymes employed depending on the length of the fatty (C14) R CH2 C S-CoA
CH3 C S-CoA acyl chain. For fatty acyl chains of 12 or more carbons, O O the reactions are catalyzed by a multienzyme complex (C14) Acyl-CoA Acetyl -CoA associated with the inner mitochondrial membrane, the (myristoyl-CoA) trifunctional protein (TFP). TFP is a heterooctamer of 4
4 subunits. Each  subunit contains two activities, the enoyl-CoA hydratase and the
-hydroxyacyl-CoA dehydrogenase; the
subunits contain the thiolase ac- (b) tivity. This tight association of three enzymes may allow C14 Acetyl -CoA efficient substrate channeling from one active site to the C12 Acetyl -CoA C10 Acetyl -CoA FIGURE 17–8 The
-oxidation pathway. (a) In each pass through this C8 Acetyl -CoA 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— C6 Acetyl -CoA in this example palmitate (C16), which enters as palmitoyl-CoA. (b) Six C4 Acetyl -CoA more passes through the pathway yield seven more molecules of acetyl-CoA, the seventh arising from the last two carbon atoms of the Acetyl -CoA 16-carbon chain. Eight molecules of acetyl-CoA are formed in all.  17.2 Oxidation of Fatty Acids 639 next, without diffusion of the intermediates away from process. Transfer of electrons from NADH or FADH2 to the enzyme surface. When TFP has shortened the fatty O2 yields one H2O per electron pair. Reduction of O2 by acyl chain to 12 or fewer carbons, further oxidations are NADH also consumes one H
per NADH molecule: catalyzed by a set of four soluble enzymes in the matrix. NADH
H

12 O2 On NAD

H2O. In hibernating As noted earlier, the single bond between methyl- animals, fatty acid oxidation provides metabolic energy, ene (OCH2O) groups in fatty acids is relatively stable. heat, and water—all essential for survival of an animal The
-oxidation sequence is an elegant mechanism for that neither eats nor drinks for long periods (Box 17–1). destabilizing and breaking these bonds. The first three Camels obtain water to supplement the meager supply reactions of
oxidation create a much less stable COC available in their natural environment by oxidation of bond, in which the  carbon (C-2) is bonded to two car- fats stored in their hump. bonyl carbons (the
-ketoacyl-CoA intermediate). The The overall equation for the oxidation of palmitoyl- ketone function on the
carbon (C-3) makes it a good CoA to eight molecules of acetyl-CoA, including the target for nucleophilic attack by the OSH of coenzyme electron transfers and oxidative phosphorylations, is A, catalyzed by thiolase. The acidity of the  hydrogen Palmitoyl-CoA
7CoA
7O2
28Pi
28ADP On and the resonance stabilization of the carbanion gener- 8 acetyl-CoA
28ATP
7H2O (17–4) ated by the departure of this hydrogen make the termi- nal OCH2OCOOS-CoA a good leaving group, facilitating Acetyl-CoA Can Be Further Oxidized breakage of the –
bond. in the Citric Acid Cycle The Four
-Oxidation Steps Are Repeated to Yield The acetyl-CoA produced from the oxidation of fatty Acetyl-CoA and ATP acids can be oxidized to CO2 and H2O by the citric acid cycle. The following equation represents the balance In one pass through the
-oxidation sequence, one mol- sheet for the second stage in the oxidation of palmitoyl- ecule of acetyl-CoA, two pairs of electrons, and four pro- CoA, together with the coupled phosphorylations of the tons (H
) are removed from the long-chain fatty third stage: acyl–CoA, shortening it by two carbon atoms. The equa- tion for one pass, beginning with the coenzyme A ester 8 Acetyl-CoA
16O2
80Pi
80ADP On of our example, palmitate, is 8CoA
80ATP
16CO2
16H2O (17–5) Palmitoyl-CoA
CoA
FAD
NAD

H2O On Combining Equations 17–4 and 17–5, we obtain the myristoyl-CoA
acetyl-CoA
FADH2
NADH
H
overall equation for the complete oxidation of palmitoyl- (17–2) CoA to carbon dioxide and water: Following removal of one acetyl-CoA unit from palmitoyl- Palmitoyl-CoA
23O2
108Pi
108ADP On CoA, the coenzyme A thioester of the shortened fatty CoA
108ATP
16CO2
23H2O (17–6) acid (now the 14-carbon myristate) remains. The Table 17–1 summarizes the yields of NADH, FADH2, myristoyl-CoA can now go through another set of four and ATP in the successive steps of palmitoyl-CoA oxida-
-oxidation reactions, exactly analogous to the first, to tion. Note that because the activation of palmitate to yield a second molecule of acetyl-CoA and lauroyl-CoA, palmitoyl-CoA breaks both phosphoanhydride bonds in the coenzyme A thioester of the 12-carbon laurate. ATP (Fig. 17–5), the energetic cost of activating a fatty Altogether, seven passes through the
-oxidation acid is equivalent to two ATP, and the net gain per mol- sequence are required to oxidize one molecule of ecule of palmitate is 106 ATP. The standard free-energy palmitoyl-CoA to eight molecules of acetyl-CoA (Fig. change for the oxidation of palmitate to CO2 and H2O 17–8b). The overall equation is is about 9,800 kJ/mol. Under standard conditions, the Palmitoyl-CoA
7CoA
7FAD
7NAD

7H2O On energy recovered as the phosphate bond energy of ATP 8 acetyl-CoA
7FADH2
7NADH
7H
(17–3) is 106 30.5 kJ/mol  3,230 kJ/mol, about 33% of the theoretical maximum. However, when the free-energy Each molecule of FADH2 formed during oxidation of the changes are calculated from actual concentrations of re- fatty acid donates a pair of electrons to ETF of the res- actants and products under intracellular conditions (see piratory chain, and about 1.5 molecules of ATP are gen- Box 13–1), the free-energy recovery is more than 60%; erated during the ensuing transfer of each electron pair the energy conservation is remarkably efficient. to O2. Similarly, each molecule of NADH formed deliv- ers a pair of electrons to the mitochondrial NADH de- Oxidation of Unsaturated Fatty Acids Requires hydrogenase, and the subsequent transfer of each pair Two Additional Reactions of electrons to O2 results in formation of about 2.5 mol- ecules of ATP. Thus four molecules of ATP are formed The fatty acid oxidation sequence just described is typ- for each two-carbon unit removed in one pass through ical when the incoming fatty acid is saturated (that is, the sequence. Note that water is also produced in this has only single bonds in its carbon chain). However, 640 Chapter 17 Fatty Acid Catabolism BOX 17–1 THE WORLD OF BIOCHEMISTRY Fat Bears Carry Out
Oxidation in Their Sleep nating) level. Although expending about 25,000 kJ/day Many animals depend on fat stores for energy during (6,000 kcal/day), the bear does not eat, drink, urinate, hibernation, during migratory periods, and in other sit- or defecate for months at a time. uations involving radical metabolic adjustments. One Experimental studies have shown that hibernat- of the most pronounced adjustments of fat metabo- ing grizzly bears use body fat as their sole fuel. Fat lism occurs in hibernating grizzly bears. These animals oxidation yields sufficient energy for maintenance of remain in a continuous state of dormancy for periods body temperature, active synthesis of amino acids as long as seven months. Unlike most hibernating and proteins, and other energy-requiring activities, species, the bear maintains a body temperature of be- such as membrane transport. Fat oxidation also re- tween 32 and 35 C, close to the normal (nonhiber- leases large amounts of water, as described in the text, which replenishes water lost in breathing. The glyc- erol released by degradation of triacylglycerols is con- verted into blood glucose by gluconeogenesis. Urea formed during breakdown of amino acids is reab- sorbed in the kidneys and recycled, the amino groups reused to make new amino acids for maintaining body proteins. Bears store an enormous amount of body fat in preparation for their long sleep. An adult grizzly con- sumes about 38,000 kJ/day during the late spring and summer, but as winter approaches it feeds 20 hours a day, consuming up to 84,000 kJ daily. This change in feeding is a response to a seasonal change in hormone secretion. Large amounts of triacylglycerols are formed from the huge intake of carbohydrates during the fattening-up period. Other hibernating species, in- A grizzly bear prepares its hibernation nest, near the McNeil River cluding the tiny dormouse, also accumulate large in Canada. amounts of body fat. most of the fatty acids in the triacylglycerols and phos- the trans double bond of the 2-enoyl-CoA generated pholipids of animals and plants are unsaturated, having during
oxidation. Two auxiliary enzymes are needed one or more double bonds. These bonds are in the cis for
oxidation of the common unsaturated fatty acids: configuration and cannot be acted upon by enoyl-CoA an isomerase and a reductase. We illustrate these aux- hydratase, the enzyme catalyzing the addition of H2O to iliary reactions with two examples. TABLE 17–1 Yield of ATP during Oxidation of One Molecule of Palmitoyl-CoA to CO2 and H2O Number of NADH Number of ATP Enzyme catalyzing the oxidation step or FADH2 formed ultimately formed* Acyl-CoA dehydrogenase 7 FADH2 10.5
-Hydroxyacyl-CoA dehydrogenase 7 NADH 17.5 Isocitrate dehydrogenase 8 NADH 20 -Ketoglutarate dehydrogenase 8 NADH 20 Succinyl-CoA synthetase 8† Succinate dehydrogenase 8 FADH2 12 Malate dehydrogenase 8 NADH 20 Total 108 * These calculations assume that mitochondrial oxidative phosphorylation produces 1.5 ATP per FADH2 oxidized and 2.5 ATP per NADH oxidized. † GTP produced directly in this step yields ATP in the reaction catalyzed by nucleoside diphosphate kinase (p. XXX).  17.2 Oxidation of Fatty Acids 641 Oleate is an abundant 18-carbon monounsaturated 12 9 O 1 fatty acid with a cis double bond between C-9 and C-10 C (denoted 9). In the first step of oxidation, oleate is con- 18 S-CoA verted to oleoyl-CoA and, like the saturated fatty acids, b oxidation Linoleoyl-CoA (three cycles) 3 Acetyl-CoA cis-9,cis-12 enters the mitochondrial matrix via the carnitine shut- tle (Fig. 17–6). Oleoyl-CoA then undergoes three passes 6 4 3(b) O through the fatty acid oxidation cycle to yield three mol- C ecules of acetyl-CoA and the coenzyme A ester of a 3, 12 5 2(a) S-CoA cis-3,cis-6 12-carbon unsaturated fatty acid, cis-3-dodecenoyl- 3, 2-enoyl-CoA CoA (Fig. 17–9). This product cannot serve as a sub- isomerase strate for enoyl-CoA hydratase, which acts only on trans 6 4 2(a) S-CoA double bonds. The auxiliary enzyme
3,
2-enoyl-CoA C isomerase isomerizes the cis-3-enoyl-CoA to the 12 5 3(b) O trans-2, cis-6 trans-2-enoyl-CoA, which is converted by enoyl-CoA b oxidation hydratase into the corresponding L-
-hydroxyacyl-CoA (one cycle, and (trans-2-dodecenoyl-CoA). This intermediate is now first oxidation Acetyl-CoA acted upon by the remaining enzymes of
oxidation of second cycle) to yield acetyl-CoA and the coenzyme A ester of a 10- 5 4 2 S-CoA carbon saturated fatty acid, decanoyl-CoA. The latter 1 C undergoes four more passes through the pathway to 10 3 O trans-2, cis-4 yield five more molecules of acetyl-CoA. Altogether, nine acetyl-CoAs are produced from one molecule of the NADPH
H
2,4-dienoyl-CoA reductase 18-carbon oleate. NADP
The other auxiliary enzyme (a reductase) is re- quired for oxidation of polyunsaturated fatty acids—for O 5 3 1 C 10 4 2 S-CoA trans-3 O enoyl-CoA 9 isomerase 18 1 C S-CoA O 3 1 Oleoyl-CoA C 10 4 2 S-CoA trans-2  oxidation (three cycles) 3 Acetyl-CoA b oxidation (four cycles) H H O 5 Acetyl-CoA 12 C FIGURE 17–10 Oxidation of a polyunsaturated fatty acid. The S-CoA example here is linoleic acid, as linoleoyl-CoA (9,12). Oxidation re- cis-3- quires a second auxiliary enzyme in addition to enoyl-CoA isomerase: Dodecenoyl-CoA NADPH-dependent 2,4-dienoyl-CoA reductase. The combined action 3, 2-enoyl-CoA isomerase of these two enzymes converts a trans-2,cis-4-dienoyl-CoA inter- mediate to the trans-2-enoyl-CoA substrate necessary for
oxidation. H O C S-CoA 12 H example, the 18-carbon linoleate, which has a cis-9,cis- 2 trans- - 12 configuration (Fig. 17–10). Linoleoyl-CoA under- Dodecenoyl-CoA b oxidation goes three passes through the
-oxidation sequence to (five cycles) yield three molecules of acetyl-CoA and the coenzyme A ester of a 12-carbon unsaturated fatty acid with a cis- 3,cis-6 configuration. This intermediate cannot be 6 Acetyl-CoA used by the enzymes of the
-oxidation pathway; its FIGURE 17–9 Oxidation of a monounsaturated fatty acid. Oleic acid, double bonds are in the wrong position and have the as oleoyl-CoA (9), is the example used here. Oxidation requires an wrong configuration (cis, not trans). However, the com- additional enzyme, enoyl-CoA isomerase, to reposition the double bined action of enoyl-CoA isomerase and 2,4-dienoyl- bond, converting the cis isomer to a trans isomer, a normal interme- CoA reductase, as shown in Figure 17–10, allows reen- diate in
oxidation. try of this intermediate into the
-oxidation pathway 642 Chapter 17 Fatty Acid Catabolism and its degradation to six acetyl-CoAs. The overall re- H sult is conversion of linoleate to nine molecules of H C H acetyl-CoA. H C H Propionyl-CoA Complete Oxidation of Odd-Number Fatty Acids C Requires Three Extra Reactions CoA-S O Although most naturally occurring lipids contain fatty HCO 3 acids with an even number of carbon atoms, fatty acids propionyl-CoA ATP with an odd number of carbons are common in the lipids carboxylase biotin of many plants and some marine organisms. Cattle and ADP
Pi other ruminant animals form large amounts of the three- carbon propionate (CH3OCH2OCOO) during fer- H mentation of carbohydrates in the rumen. The propi-  H C H O onate is absorbed into the blood and oxidized by the C C H liver and other tissues. And small quantities of propi- D-Methylmalonyl-CoA O C onate are added as a mold inhibitor to some breads and cereals, thus entering the human diet. CoA-S O Long-chain odd-number fatty acids are oxidized in the same pathway as the even-number acids, beginning methylmalonyl-CoA at the carboxyl end of the chain. However, the substrate epimerase for the last pass through the
-oxidation sequence is a fatty acyl–CoA with a five-carbon fatty acid. When this is oxidized and cleaved, the products are acetyl-CoA and H H O propionyl-CoA. The acetyl-CoA can be oxidized in the H C H coenzyme C C H B12 citric acid cycle, of course, but propionyl-CoA enters a O CoA-S different pathway involving three enzymes. methyl- C C H malonyl-CoA H C H Propionyl-CoA is first carboxylated to form the D CoA-S mutase C C stereoisomer of methylmalonyl-CoA (Fig. 17–11) by   O O O O propionyl-CoA carboxylase, which contains the co- factor biotin. In this enzymatic reaction, as in the pyru- L-Methylmalonyl-CoA Succinyl-CoA vate carboxylase reaction (see Fig. 16–16), CO2 (or its hydrated ion, HCO 3 ) is activated by attachment to bi- FIGURE 17–11 Oxidation of propionyl-CoA produced by
oxida- otin before its transfer to the substrate, in this case the tion of odd-number fatty acids. The sequence involves the carboxy- propionate moiety. Formation of the carboxybiotin in- lation of propionyl-CoA to D-methylmalonyl-CoA and conversion of termediate requires energy, which is provided by the the latter to succinyl-CoA. This conversion requires epimerization of cleavage of ATP to ADP and Pi. The D-methylmalonyl- D- to L-methylmalonyl-CoA, followed by a remarkable reaction in CoA thus formed is enzymatically epimerized to its L which substituents on adjacent carbon atoms exchange positions (see stereoisomer by methylmalonyl-CoA epimerase (Fig. Box 17–2). 17–11). The L-methylmalonyl-CoA then undergoes an intramolecular rearrangement to form succinyl-CoA, transfer of long-chain fatty acyl–CoA into mitochondria. which can enter the citric acid cycle. This rearrange- The three-step process (carnitine shuttle) by which ment is catalyzed by methylmalonyl-CoA mutase, fatty acyl groups are carried from cytosolic fatty which requires as its coenzyme 5-deoxyadenosyl- acyl–CoA into the mitochondrial matrix (Fig. 17–6) is cobalamin, or coenzyme B12, which is derived from rate-limiting for fatty acid oxidation and is an important vitamin B12 (cobalamin). Box 17–2 describes the role of point of regulation. Once fatty acyl groups have entered coenzyme B12 in this remarkable exchange reaction. the mitochondrion, they are committed to oxidation to acetyl-CoA. Fatty Acid Oxidation Is Tightly Regulated Malonyl-CoA, the first intermediate in the cytoso- Oxidation of fatty acids consumes a precious fuel, and lic biosynthesis of long-chain fatty acids from acetyl-CoA it is regulated so as to occur only when the need for en- (see Fig. 21–1), increases in concentration whenever ergy requires it. In the liver, fatty acyl–CoA formed in the animal is well supplied with carbohydrate; excess the cytosol has two major pathways open to it: (1)
ox- glucose that cannot be oxidized or stored as glycogen idation by enzymes in mitochondria or (2) conversion is converted in the cytosol into fatty acids for storage into triacylglycerols and phospholipids by enzymes in as triacylglycerol. The inhibition of carnitine acyltrans- the cytosol. The pathway taken depends on the rate of ferase I by malonyl-CoA ensures that the oxidation of  17.2 Oxidation of Fatty Acids 643 fatty acids is inhibited whenever the liver is amply sup- frequency of carriers (individuals with this recessive plied with glucose as fuel and is actively making tria- mutation on one of the two homologous chromosomes) cylglycerols from excess glucose. is about 1 in 40, and about 1 individual in 10,000 has the disease—that is, has two copies of the mutant MCAD O allele and is unable to oxidize fatty acids of 6 to 12 car-  OOC CH2 C S-CoA bons. The disease is characterized by recurring episodes Malonyl-CoA of a syndrome that includes fat accumulation in the liver, Two of the enzymes of
oxidation are also regu- high blood levels of octanoic acid, low blood glucose lated by metabolites that signal energy sufficiency. (hypoglycemia), sleepiness, vomiting, and coma. The When the [NADH]/[NAD
] ratio is high,
-hydroxyacyl- pattern of organic acids in the urine helps in the diag- CoA dehydrogenase is inhibited; in addition, high con- nosis of this disease: the urine commonly contains high centrations of acetyl-CoA inhibit thiolase (Fig. 17–12). levels of 6-carbon to 10-carbon dicarboxylic acids (pro- duced by  oxidation) and low levels of urinary ketone Genetic Defects in Fatty Acyl–CoA Dehydrogenases bodies (we discuss  oxidation below and ketone bod- ies in Section 17.3). Although individuals may have no Cause Serious Disease symptoms between episodes, the episodes are very se- Stored triacylglycerols are typically the chief rious; mortality from this disease is 25% to 60% in early source of energy for muscle contraction, and an childhood. If the genetic defect is detected shortly inability to oxidize fatty acids from triacylglycerols has after birth, the infant can be started on a low-fat, high- serious consequences for health. The most common ge- carbohydrate diet. With early detection and careful man- netic defect in fatty acid catabolism in U.S. and north- agement of the diet—including avoiding long intervals ern European populations is due to a mutation in the between meals, to prevent the body from turning to its gene encoding the medium-chain acyl-CoA dehy- fat reserves for energy—the prognosis for these indi- drogenase (MCAD). Among northern Europeans, the viduals is good. Dietary High blood Low blood carbohydrate glucose glucose Fatty acyl– CoASH 1 Fatty carnitine acyl–CoA Insulin P Glucagon carnitine 2 5 acyl- Carnitine ACC transferase I 7 Inactive 4 Fatty phosphatase 6 PKA Fatty acyl– acyl–CoA carnitine Pi ACC FADH 3 8 Glucose Acetyl–CoA Malonyl-CoA b oxidation glycolysis, pyruvate multistep NADH dehydrogenase complex Fatty acids Acetyl-CoA Fatty acid Fatty acid synthesis b oxidation Mitochondrion FIGURE 17–12 Coordinated regulation of fatty acid synthesis and (the first intermediate of fatty acid synthesis), and 4 malonyl-CoA in- breakdown. When the diet provides a ready source of carbohydrate hibits carnitine acyltransferase I, thereby preventing fatty acid entry as fuel,
oxidation of fatty acids is unnecessary and is therefore down- into the mitochondrial matrix. regulated. Two enzymes are key to the coordination of fatty acid When blood glucose levels drop between meals, 5 glucagon re- metabolism: acetyl-CoA carboxylase (ACC), the first enzyme in the lease activates cAMP-dependent protein kinase (PKA), which 6 phos- synthesis of fatty acids (see Fig. 21–1 ), and carnitine acyl transferase I, phorylates and inactivates ACC. The concentration of malonyl-CoA which limits the transport of fatty acids into the mitochondrial matrix falls, the inhibition of fatty acid entry into mitochondria is relieved, for
oxidation (see Fig. 17–6). Ingestion of a high-carbohydrate meal and 7 fatty acids enter the mitochondrial matrix and 8 become the raises the blood glucose level and thus 1 triggers the release of in- major fuel. Because glucagon also triggers the mobilization of fatty sulin. 2 Insulin-dependent protein phosphatase dephosphorylates acids in adipose tissue, a supply of fatty acids begins arriving in the ACC, activating it. 3 ACC catalyzes the formation of malonyl-CoA blood.  BOX 17–2 WORKING IN BIOCHEMISTRY Coenzyme B12: A Radical Solution (a) H H O H H O coenzyme B12 to a Perplexing Problem H C C C H C C C In the methylmalonyl-CoA mutase reaction (see Fig. H C O methylmalonyl-CoA C H O mutase 17–11), the group OCOOS-CoA at C-2 of the original O S-CoA O S-CoA propionate exchanges position with a hydrogen atom at C-3 of the original propionate (Fig. 1a). Coenzyme L-Methylmalonyl-CoA Succinyl-CoA B12 is the cofactor for this reaction, as it is for almost (b) coenzyme B12 all enzymes that catalyze reactions of this general type C C C C (Fig. 1b). These coenzyme B12–dependent processes H X X H are among the very few enzymatic reactions in biol- ogy in which there is an exchange of an alkyl or sub- FIGURE 1 stituted alkyl group (X) with a hydrogen atom on an adjacent carbon, with no mixing of the transferred syl group (Fig. 2). This is a relatively weak bond; its hydrogen atom with the hydrogen of the solvent, bond dissociation energy is about 110 kJ/mol, com- H2O. How can the hydrogen atom move between two pared with 348 kJ/mol for a typical COC bond or 414 carbons without mixing with the enormous excess of kJ/mol for a COH bond. Merely illuminating the com- hydrogen atoms in the solvent? pound with visible light is enough to break this CoOC Coenzyme B12 is the cofactor form of vitamin B12, bond. (This extreme photolability probably accounts which is unique among all the vitamins in that it for the absence of vitamin B12 in plants.) Dissociation contains not only a complex organic molecule but an produces a 5-deoxyadenosyl radical and the Co2
essential trace element, cobalt. The com- O H H plex corrin ring system of vitamin B12 1 4 (colored blue in Fig. 2), to which cobalt OH HO (as Co3
) is coordinated, is chemically re- 2 3 lated to the porphyrin ring system of heme 5-Deoxy- H H and heme proteins (see Fig. 5–1). A fifth adenosine N N 5 coordination position of cobalt is filled CH2 O N by dimethylbenzimidazole ribonucleotide N C NH2 (shaded yellow), bound covalently by its NH2 CH2 3-phosphate group to a side chain of the O O corrin ring, through aminoisopropanol. CH2 C The formation of this complex cofactor oc- H2N C H CH3 CH2 NH2 curs in one of only two known reactions in CH2 CH3 which triphosphate is cleaved from ATP CH3 O Corrin CH3 N ring (Fig. 3); the other reaction is the forma- H C system tion of S-adenosylmethionine from ATP N H CH2 NH2 Co3
and methionine (see Fig. 18–18). CH2 N O CH3 H Vitamin B12 as usually isolated is called CH 2 N cyanocobalamin, because it contains a C CH3 NH2 H CH2 cyano group (picked up during purification) attached to cobalt in the sixth coordination CH 3 CH 3 CH2 CH2 position. In 5-deoxyadenosylcobalamin, O O C CH2 the cofactor for methylmalonyl-CoA mu-