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You are watching: __________ is the conversion of acetyl coa into ketone bodies.

Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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The β-oxidation pathway perfect the finish degradation the saturated fatty acids having actually an even variety of carbon atoms. Many fatty acids have such structures because of their mode of synthesis (Section 22.4.3). However, not all fatty acids are so simple. The oxidation of fat acids containing double bonds requires additional steps. Likewise, fat acids include an odd number of carbon atoms yield a propionyl CoA in ~ the final thiolysis action that have to be converted right into an easily usable form by extr enzyme reactions.

22.3.1. One Isomerase and also a Reductase Are compelled for the Oxidation of Unsaturated fat Acids

The oxidation of unsaturated fatty acids presents part difficulties, yet countless such fat acids are obtainable in the diet. Many of the reactions are the very same as those because that saturated fat acids. In fact, only two extr enzymes—an isomerase and a reductase—are needed to degrade a wide range of unsaturated fatty acids.

Consider the oxidation of palmitoleate. This C16 unsaturated fat acid, which has actually one twin bond between C-9 and C-10, is activated and also transported throughout the inside mitochondrial membrane in the same means as saturated fatty acids. Palmitoleoyl CoA then undergoes 3 cycles that degradation, i m sorry are lugged out by the exact same enzymes as in the oxidation that saturated fat acids. However, the cis-Δ3-enoyl CoA formed in the 3rd round is not a substrate because that acyl CoA dehydrogenase. The visibility of a twin bond in between C-3 and C-4 stays clear of the development of another twin bond between C-2 and C-3. This impasse is fixed by a brand-new reaction the shifts the position and also configuration the the cis-Δ3 twin bond. One isomerase converts this twin bond into a trans-Δ2double bond. The subsequent reactions space those the the saturated fatty mountain oxidation pathway, in which the trans-Δ2-enoyl CoA is a regular substrate.


Another problem arises with the oxidation the polyunsaturated fatty acids. Consider linoleate, a C18 polyunsaturated fat acid v cis-Δ9 and cis-Δ12 twin bonds (Figure 22.10). The cis-Δ3 dual bond developed after three rounds the β oxidation is converted into a trans-Δ2 double bond by the abovementioned isomerase. The acyl CoA created by one more round that β oxidation includes a cis-Δ4 dual bond. Dehydrogenation the this varieties by acyl CoA dehydrogenase yields a 2,4-dienoyl intermediate, i beg your pardon is no a substrate for the next enzyme in the β-oxidation pathway. This impasse is circumvented by 2,4-dienoyl CoA reductase, an enzyme that provides NADPH to reduce the 2,4-dienoyl intermediate to trans-Δ3-enoyl CoA. Cis-Δ3-Enoyl CoA isomerase climate converts trans-Δ3-enoyl CoA into the trans-Δ2 form, a customary intermediary in the β-oxidation pathway. These catalytic strategies are elegant and economical. Just two extra enzymes are needed for the oxidation of any kind of polyunsaturated fat acid. Odd-numbered double bonds are handled by the isomerase, and even-numbered ones by the reductase and the isomerase.


Figure 22.10

Oxidation that Linoleoyl CoA. The complete oxidation that the diunsaturated fatty acid linoleate is assisted in by the activity of enoyl CoA isomerase and 2,4-dienoyl CoA reductase.

22.3.2. Odd-Chain fat Acids productivity Propionyl Coenzyme A in the last Thiolysis Step

Fatty acids having an odd number of carbon atoms space minor species. They room oxidized in the same way as fatty acids having an also number, other than that propionyl CoA and also acetyl CoA, quite than two molecules that acetyl CoA, are developed in the last round the degradation. The set off three-carbon unit in propionyl CoA beginning the citric mountain cycle after ~ it has actually been converted into succinyl CoA.


22.3.3. Propionyl CoA Is Converted right into Succinyl CoA in a Reaction That requires Vitamin B12

The pathway from propionyl CoA come succinyl CoA is specifically interesting because it requires a rearrangement that requires vitamin B12 (also known as cobalamin). Propionyl CoA is carboxylated at the cost of the hydrolysis of one ATP to yield the d isomer the methylmalonyl CoA (Figure 22.11). This carboxylation reaction is catalyzed by propionyl CoA carboxylase, a biotin enzyme the is homologous to and has a catalytic mechanism like the of pyruvate carboxylase (Section 16.3.2). The d isomer the methylmalonyl CoA is racemized to the together isomer, the substrate because that a mutase that converts it right into succinyl CoA by an intramolecular rearrangement. The -CO-S-CoA team migrates from C-2 come C-3 in exchange because that a hydrogen atom. This very unusual isomerization is catalytic analysis by methylmalonyl CoA mutase, which has a derivative of vitamin B12, cobalamin, as its coenzyme.


Figure 22.11

Conversion the Propionyl CoA right into Succinyl CoA. Propionyl CoA, produced from fatty acids v an odd number of carbons as well as some amino acids, is converted into the citric acid cycle intermediate succinyl CoA.

Cobalamin enzymes, i m sorry are current in many organisms, catalyze three species of reactions: (1) intramolecular rearrangements; (2) methylations, as in the synthesis of methionine (Section 24.2.7); and (3) palliation of ribonucleotides come deoxyribonucleotides (Section 25.3). In mammals, the conversion of l-methylmalonyl CoA into succinyl CoA and the formation of methionine by methylation of homocysteine room the just reactions that are known to call for coenzyme B12. The latter reaction is especially important due to the fact that methionine is forced for the generation of coenzymes that take part in the synthetic of purines and thymine, i beg your pardon are required for nucleic acid synthesis.

The main point of cobalamin consists of a corrin ring v a central cobalt atom (Figure 22.12). The corrin ring, favor a porphyrin, has four pyrrole units. Two of lock are straight bonded to each other, vice versa, methene bridges, together in porphyrins, join the others. The corrin ring is more reduced than that the porphyrins and the substituents room different. A cobalt atom is bonded to the four pyrrole nitrogens. Attached to the corrin ring is a derivative of di-methylbenzimidazole that has ribose 3-phosphate and also aminoisopropanol. In free cobalamin, one of the nitrogen atoms of dimethylbenzimidazole is the 5th substituent linked to the cobalt atom. In coenzyme B12, the 6th substituent attached to the cobalt atom is a 5′-deoxyadenosyl unit. This place can likewise be inhabited by a cyano group, a methyl group, or various other ligands. In these compounds, the cobalt is in the +3 oxidation state.

Figure 22.12

Structure that Coenzyme B12 (5′-deoxyadenosylcobalamin). Substitution the cyano and methyl groups produce cyanocobalamin and methylcobalamin, respectively.

The rearrangement reactions catalyzed by coenzyme B12 space exchanges the two teams attached to nearby carbon atom (Figure 22.13). A hydrogen atom migrates native one carbon atom come the next, and an R team (such as the -CO-S-CoA group of methylmalonyl CoA) concomitantly moves in the turning back direction. The an initial step in these intramolecular rearrangements is the cleavage that the carbon-cobalt bond of 5′-deoxyadenosylcobalamin to kind coenzyme B12 (Co2+) and also a 5′-deoxyadenosyl radical, -CH2·) (Figure 22.14). In this homolytic cleavage reaction, one electron of the Co-C bond continues to be with Co (reducing it from the +3 come the +2 oxidation state) while the other stays v the carbon atom, generating a cost-free radical. In contrast, practically all various other cleavage reactions in organic systems space heterolytic—an electron pair is moved to among the 2 atoms that were external inspection together.

Figure 22.13

Rearrangement Reaction catalyzed by Cobalamin Enzymes. The R group can it is in an amino group, a hydroxyl group, or a substituted carbon.

Figure 22.14

Formation the a 5″-Deoxyadenosyl Radical. The methylmalonyl CoA mutase reaction begins with the homolytic cleavage the the shortcut joining Co3+ to a carbon the the ribose the the adenosene moiety. The cleavage generates a 5′-deoxyadenosyl radical (more...)

What is the function of this really unusual -CH2· radical? This highly reactive types abstracts a hydrogen atom native the substrate to kind 5′-deoxyadenosine and a substrate radical (Figure 22.15). This substrate radical spontaneously rearranges: the carbonyl CoA team migrates come the position previously occupied by H ~ above the neighboring carbon atom to produce a various radical. This product radical summary a hydrogen atom from the methyl team of 5′-deoxyadenosine to complete the rearrangement and also return the deoxyadenosyl unit come the radical form. The duty of coenzyme B12 in together intramolecular migrations is to serve as a resource of cost-free radicals for the abstraction that hydrogen atoms.

Figure 22.15

Formation of Succinyl CoA by a Rearrangement Reaction. A free radical abstracts a hydrogen atom in the rearrangement of methylmalonyl CoA come succinyl CoA.

An crucial property the coenzyme B12 is the weak of its cobalt-carbon bond, the facile cleavage of i beg your pardon generates a radical. To facilitate the cleavage that this bond, enzyme such as methylmalonyl CoA mutase displace the benzamidazole group from the cobalt and coordinate the cobalamin v a histidine residue (Figure 22.16). The steric crowding roughly the cobalt-carbon bond within the corrin ring mechanism contributes come the bond weakness.

Figure 22.16

Active website of Methylmalonyl CoA Mutase.

The arrangement of substrate and also coenzyme in the active site facilitates the cleavage of the cobalt-carbon bond and the succeeding abstraction the a hydrogen atom native the substrate.

22.3.4. Fatty Acids Are additionally Oxidized in Peroxisomes

Although many fatty acid oxidation takes place in mitochondria, part oxidation takes location in to move organelles dubbed peroxisomes (Figure 22.17). These organelles are defined by high concentration of the enzyme catalase, i beg your pardon catalyzes the dismutation the hydrogen peroxide into water and molecular oxygen (Section 18.3.6). Fatty mountain oxidation in these organelles, which halts at octanyl CoA, may serve come shorten lengthy chains to do them far better substrates of β oxidation in mitochondria. Peroxisomal oxidation different from β oxidation in the early dehydrogenation reaction (Figure 22.18). In peroxisomes, a flavoprotein dehydrogenase transfers electrons to O2 to yield H2O2 rather of catching the high-energy electrons as FADH2, as occurs in mitochondrial β oxidation. Catalase is needed to transform the hydrogen peroxide produced in the initial reaction into water and also oxygen. Subsequent actions are the same with your mitochondrial counterparts, although they are carried out by different isoforms of the enzymes.

Figure 22.17

Electron Micrograph the a Peroxisome in a Liver Cell. A crystal of urate oxidase is existing inside the organelle, which is bounded by a single bilayer membrane. The dark granular structures exterior the peroxisome room glycogen particles.
Figure 22.18

Initiation the Peroxisomal Fatty mountain Degradation. The an initial dehydration in the destruction of fatty acids in peroxisomes calls for a flavoprotein dehydrogenase the transfers electron to O2 to productivity H2O2.

Zellweger syndrome, which results from the lack of functional peroxisomes, is characterized by liver, kidney, and muscle abnormalities and usually results in fatality by age six. The syndrome is led to by a defect in the income of enzymes right into the peroxisomes. Right here we watch a pathological condition resulting indigenous an inappropriate cellular circulation of enzymes.

22.3.5. Ketone bodies Are formed from Acetyl Coenzyme A as soon as Fat malfunction Predominates

The acetyl CoA created in fatty acid oxidation beginning the citric mountain cycle just if fat and carbohydrate deterioration are as necessary balanced. The factor is the the entry of acetyl CoA right into the citric mountain cycle counts on the availability of oxaloacetate because that the development of citrate, yet the concentration that oxaloacetate is lower if carbohydrate is unavailable or improperly utilized. Recall the oxaloacetate is normally created from pyruvate, the product that glycolysis, by pyruvate carboxylase (Section 16.3.1). This is the molecular basis of the adage the fats burn in the fire of carbohydrates.

In fasting or diabetes, oxaloacetate is consumed to form glucose through the gluconeogenic pathway (Section 16.3.2) and hence is unavailable for condensation through acetyl CoA. Under these conditions, acetyl CoA is diverted to the formation of acetoacetate and also d-3-hydroxybutyrate. Acetoacetate, d-3-hydroxybutyrate, and acetone are often referred to together ketone bodies. Abnormally high level of ketone body are existing in the blood of untreated diabetics (Section 22.3.6).

Acetoacetate is developed from acetyl CoA in three measures (Figure 22.19). Two molecules that acetyl CoA condensation to type acetoacetyl CoA. This reaction, i beg your pardon is catalytic analysis by thiolase, is the turning back of the thiolysis action in the oxidation of fatty acids. Acetoacetyl CoA climate reacts v acetyl CoA and also water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA. This condensation resembles the one catalyzed by citrate synthase (Section 17.1.3). This reaction, which has a favorable equilibrium owing to the hydrolysis the a thioester linkage, compensates because that the unfavorable equilibrium in the development of acetoacetyl CoA. 3-Hydroxy-3-methylglutaryl CoA is climate cleaved come acetyl CoA and acetoacetate. The amount of these reactions is
Figure 22.19

Formation that Ketone Bodies. The Ketone bodies-acetoacetate, d-3-hydroxybutyrate, and acetone indigenous acetyl CoA—are developed primarily in the liver. Enzyme catalyzing these reactions space (1) 3-ketothiolase, (2) hydroxymethylglutaryl CoA synthase, (more...)

d-3-Hydroxybutyrate is created by the palliation of acetoacetate in the mitochondrial procession by d-3-hydroxybutyrate dehydrogenase. The ratio of hydroxybutyrate come acetoacetate depends on the NADH/NAD+ proportion inside mitochondria.

Because it is a β-ketoacid, acetoacetate likewise undergoes a slow, spontaneous decarboxylation to acetone. The odor of acetone may be detected in the breath the a human being who has a high level of acetoacetate in the blood.

22.3.6. Ketone Bodies room a major Fuel in some Tissues

The significant site of production of acetoacetate and also 3-hydroxybutyrate is the liver. These substances diffuse native the liver mitochondria into the blood and are transported to peripheral tissues. These ketone bodies were at first regarded as degradation assets of small physiological value. However, the results of studies by George Cahill and others revealed that these derivatives the acetyl CoA are essential molecules in energy metabolism. Acetoacetate and 3-hydroxybutyrate room normal fuels of respiration and also are quantitatively important as resources of energy. Indeed, love muscle and the renal cortex usage acetoacetate in preference to glucose. In contrast, glucose is the significant fuel for the brain and red blood cell in well-nourished human being on a well balanced diet. However, the mind adapts to the utilization of acetoacetate throughout starvation and also diabetes (Sections 30.3.1 and 30.3.2). In an extensive starvation, 75% that the fuel needs of the brain are met through ketone bodies.

3-Hydroxybutyrate is oxidized to create acetoacetate as well as NADH for usage in oxidative phosphorylation.

Acetoacetate deserve to be caused by the deliver of CoA native succinyl CoA in a reaction catalytic analysis by a specific CoA transferase. Acetoacetyl CoA is climate cleaved by thiolase to yield two molecules of acetyl CoA, which have the right to then enter the citric acid cycle (Figure 22.20). The liver has actually acetoacetate obtainable to supply to other organs because it lacks this certain CoA transferase.

Figure 22.20

Utilization the Acetoacetate as a Fuel. Acetoacetate have the right to be converted right into two molecules of acetyl CoA, which then get in the citric mountain cycle.

Ketone bodies can be concerned as a water-soluble, transportable kind of acetyl units. Fat acids room released by adipose tissue and also converted into acetyl units by the liver, which climate exports them as acetoacetate. As might be expected, acetoacetate likewise has a regulation role. High levels of acetoacetate in the blood signify wealth of acetyl units and lead come a to decrease in the rate of lipolysis in adipose tissue.

certain pathological conditions can result in a life-threatening climb in the blood levels of the ketone bodies. Most typical of these conditions is diabetic ketosis in patients with insulin-dependent diabetes mellitus. The absence of insulin has actually two significant biochemical consequences. First, the liver cannot absorb glucose and consequently cannot administer oxaloacetate to process fatty acid-derived acetyl CoA (Section 17.3.1). Second, insulin typically curtails fatty acid mobilization by adipose tissue. The liver therefore produces large amounts of ketone bodies, which room moderately solid acids. The result is significant acidosis. The to decrease in pH impairs organization function, most importantly in the central nervous system.

22.3.7. Pets Cannot transform Fatty Acids into Glucose

It is crucial to keep in mind that animals are unable to result the network synthesis of glucose from fat acids. Special, acetyl CoA cannot be converted into pyruvate or oxaloacetate in animals. The 2 carbon atom of the acetyl team of acetyl CoA enter the citric acid cycle, however two carbon atoms leave the bicycle in the decarboxylations catalytic analysis by isocitrate dehydrogenase and also α-ketoglutarate dehydrogenase. Consequently, oxaloacetate is regenerated, but it is not created de novo once the acetyl unit the acetyl CoA is oxidized by the citric acid cycle. In contrast, plants have actually two additional enzymes enabling them to convert the carbon atoms of acetyl CoA into oxaloacetate (Section 17.4.).

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