Fatty acid oxidative degradation

FIGURE 24.6 Fatty acids are degraded by repeated cycies of oxidation at the /3-carbon and cieavage of the bond to yieid... 

The acetyl-CoA derived from amino acid degradation is normally insufficient for fatty acid biosynthesis, and the acetyl-CoA produced by pyruvate dehydrogenase and by fatty acid oxidation cannot cross the mitochondrial membrane to participate directly in fatty acid synthesis. Instead, acetyl-CoA is linked with oxaloacetate to form citrate, which is transported from the mitochondrial matrix to the cytosol (Figure 25.1). Here it can be converted back into acetyl-CoA and oxaloacetate by ATP-citrate lyase. In this manner, mitochondrial acetyl-CoA becomes the substrate for cytosolic fatty acid synthesis. (Oxaloacetate returns to the mitochondria in the form of either pyruvate or malate, which is then reconverted to acetyl-CoA and oxaloacetate, respectively.)... 

The next three steps—reduction of the /3-carbonyl group to form a /3-alcohol, followed by dehydration and reduction to saturate the chain (Figure 25.7) — look very similar to the fatty acid degradation pathway in reverse. However, there are two crucial differences between fatty acid biosynthesis and fatty acid oxidation (besides the fact that different enzymes are involved) First, the alcohol formed in the first step has the D configuration rather than the L form seen in catabolism, and, second, the reducing coenzyme is NADPH, although NAD and FAD are the oxidants in the catabolic pathway. 

GLUCONEOGENESIS FATTY ACID OXIDATION PROTEIN DEGRADATION KETONE BODY FORMATION... 

GLYCOLYSIS FATTY ACID OXIDATION KETONE BODY USE PROTEIN DEGRADATION... 

Fatty acids are degraded by two-carbon units in a reverse manner analogous to their biosynthesis. The acyl-CoAs are first dehydrogenated to a,(3-unsaturated acyl-CoA, and then hydrated to (3-hydroxyacyl-CoA, followed by oxidation to (3-ketoacyl-CoA. The C-C bond between C-2 and C-3 of the latter compound is broken by a free CoA molecule via thiolysis to form an acyl-CoA that is two carbons shorter and acetyl-CoA. Unlike fatty acid biosynthesis, each step of the (3 oxidation of fatty acids is... 

Lynen had studied chemistry in Munich under Wieland his skill as a chemist led to the successful synthesis of a number of fatty acyl CoA derivatives which proved to be substrates in the catabolic pathway. Many of these C=0 or C=C compounds had characteristic UV absorption spectra so that enzyme reactions utilizing them could be followed spectrophotometrically. This technique was also used to identify and monitor the flavoprotein and pyridine nucleotide-dependent steps. Independent evidence for the pathway was provided by Barker, Stadtman and their colleagues using Clostridium kluyveri. Once the outline of the degradation had been proposed the individual steps of the reactions were analyzed very rapidly by Lynen, Green, and Ochoa s groups using in the main acetone-dried powders from mitochondria, which, when extracted with dilute salt solutions, contained all the enzymes of the fatty acid oxidation system. 

The situation is, however, different in starvation. In this condition, it is the degradation of muscle protein that provides the amino acids for gluconeo-genesis, so that all the oxo-acids generated (except those for lysine and lencine) are nsed to synthesise the glucose required for oxidation by the brain. Hence, a process other than amino acid oxidation mnst generate the ATP required by gluconeogenesis. This process is fatty acid oxidation. 

Initially the level of insulin decreases, favouring increased rates of lipolysis, fatty acid oxidation, muscle protein degradation, glycogenolysis and gluconeogenesis. It soon increases, however, as a result of insulin resistance, when the stimulation of the above processes will depend on the cytokine levels. For details of endocrine hormone effects, see Chapter 12. For details of cytokines see Chapter 17. 

Most fatty acids are saturated and even-numbered. They are broken down via p-oxidation (see p.l64). In addition, there are special pathways involving degradation of unsaturated fatty acids (A), degradation of fatty acids with an odd number of C atoms (B), a and ro oxidation of fatty acids, and degradation in peroxisomes. 

Energy yield from fatty acid oxidation The energy yield from ihe P-oxidation pathway is high. For example, the oxidation of a molecule of palmitoyl CoA to C02 and H20 yields 131 AIRs (Figure 16.19). A comparison of the processes of synthesis and degradation of saturated fatty acids with an even number of car bon atoms is provided in Figure 16.20. 

Figure 17-20 The interlocking pathways of glycolysis, gluconeogenesis, and fatty acid oxidation and synthesis with indications of some aspects of control in hepatic tissues. (— ) Reactions of glycolysis, fatty acid degradation, and oxidation by the citric acid cycle. ) Biosynthetic pathways. Some effects of insulin via indirect action on enzymes , 0, or on transcription 0/ 0. Effects of glucagon , .

The first data about the bioconversion of farnesol date back to the sixties its degradation pathway is similar to that of geraniol and nerol. Seubert [139] showed that the degradation of farnesol by Pseudomonas citronellolis proceeds through the oxidation of C-l to give famesic acid, followed by carboxylation of the -methyl group. Subsequently, the 2,3-double bond of the dicarboxylic acid is hydrated to a 3-hydroxy acid which is then acted upon by a lyase resulting in the formation of a /Tketo acid and acetic acid. The /Tketo acid readily enters the fatty acid oxidation pathway [29]. 

Fatty Acid Oxidation Yields Large Amounts of ATP Additional Enzymes Are Required for Oxidation of Unsaturated Fatty Acids in Mitochondria Ketone Bodies Formed in the Liver Are Used for Energy in Other Tissues Summary of Fatty Acid Degradation Biosynthesis of Saturated Fatty Acids... 

Recall that fatty acid chains nearly always contain an even number of carbon atoms (see chapter 17). Investigations into the mechanisms of fatty acid catabolism began around the turn of the century when Fritz Knoop reported experiments that indicated fatty acids were degraded by removal of two carbons at a time. The data indicated that carbon 3 of a fatty acid was oxidized with subsequent cleavage between carbons 2 and 3. 

The anaerobic metabolism of acrylate and 3-mercaptopropionate (3-MPA) was studied in slurries of coastal marine sediments. The rate of these compounds is important because they are derived from the algal osmolyte dimethylsulfoniopropionate (DMSP), which is a major organic sulfur compound in marine environments. Micromolar levels of acrylate were fermented rapidly in the slurries to a mixture of acetate and propionate (1 2 molar ratio). Sulfate-reducing bacteria subsequently removed the acetate and propionate. 3-MPA has only recently been detected in natural environments. In our experiments 3-MPA was formed by chemical addition of sulfide to aciylate and was then consumed by biological processes. 3-MPA is a known inhibitor of fatty acid oxidation in mammalian systems. In accord with this fact, high concentrations of 3-MPA caused acetate to accumulate in sediment slurries. At lower concentrations, however, 3-MPA was metabolized by anaerobic bacteria. We conclude that the degradation of DMSP may ultimately lead to the production of substrates which are readily metabolized by microbes in the sediments. 

Know pathways of triglyceride biosynthesis and catabolism, the /3-oxidative pathway, and pathways for the degradation of pro-pionyl-CoA, branched fatty acids, and unsaturated fatty acids identify cofactors required calculate ATP yields for fatty acid oxidation know the identity of key enzymes in each pathway. 

Fatty acid synthesis occurs in the cytoplasm, whereas fatty acid oxidation occurs in mitochondria. As mentioned previously, physicians are not so much interested in the intracellular localization of reactions as they are in the distribution of the reactions in the various organ systems. Lipids are such important components of cell membranes that the processes of lipid biosynthesis and degradation are near universal. Lipid" storage as triglycerides, however, is mainly a function of fat cells. 

Consider the oxidation of palmitoleate. This Cjg unsaturated fatty acid, which has one double bond between C-9 and C-10, is activated and transported across the inner mitochondrial membrane in the same way as saturated fatty acids. Palmitoleoyl CoA then undergoes three cycles of degradation, which are carried out by the same enzymes as in the oxidation of saturated fatty acids. However, the cis-A 3-enoyl CoA formed in the third round is not a substrate for acyl CoA dehydrogenase. The presence of a double bond between C-3 and C-4 prevents the formation of another double bond between C-2 and C-3. This impasse is resolved by a new reaction that shifts the position and configuration of the cis-A double bond. An isomerase converts this double bond into a trans- A double bond. The subsequent reactions are those of the saturated fatty acid oxidation pathway, in which the trans- A 2-enoyl CoA is a regular substrate. 

The acetyl CoA formed in fatty acid oxidation enters the citric acid cycle only if fat and carbohydrate degradation are appropriately balanced. The reason is that the entry of acetyl CoA into the citric acid cycle depends on the availability of oxaloacetate for the formation of citrate, but the concentration of oxaloacetate is lowered if carbohydrate is unavailable or improperly utilized. Recall that oxaloacetate is normally formed from pyruvate, the product of glycolysis, by pyruvate carboxylase (Section 16.3.1). This is the molecular basis of the adage that fats burn in the flame of carbohydrates. 

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