Fatty acids complete oxidation

Hydrocarbons yield more energy upon combustion than do most other organic compounds, and it is, therefore, not surprising that one important type of food reserve, the fats, is essentially hydrocarbon in nature. In terms of energy content the component fatty acids are the most important. Most aerobic cells can oxidize fatty acids completely to C02 and water, a process that takes place within many bacteria, in the matrix space of animal mitochondria, in the peroxisomes of most eukaryotic cells, and to a lesser extent in the endoplasmic reticulum. 

Fatty acid degradation and synthesis are relatively simple processes that are essentially the reverse of each other. The process of degradation converts an aliphatic compound into a set of activated acetyl units (acetyl CoA) that can be processed by the citric acid cycle (Figure 22.2). An activated fatty acid is oxidized to introduce a double bond the double bond is hydrated to introduce an oxygen the alcohol is oxidized to a ketone and, finally, the four carbon fragment is cleaved by coenzyme A to yield acetyl CoA and a fatty acid chain two carbons shorter. If the fatty acid has an even number of carbon atoms and is saturated, the process is simply repeated until the fatty acid is completely converted into acetyl CoA units. 

As we will see in Chapter 22, the citric acid cycle is an energy-harvesting pathway that completely oxidizes the acetyl group to two COj molecules. The electrons that are harvested in the process are used to produce large amounts of ATP. Coen-z)une A also serves to activate the acyl group of fatty acids during p-oxidation, the pathway by which fatty acids are oxidized to produce ATP. 

Fuel Oxidation. During fasting, glucose continues to be oxidized by glucose-dependent tissues such as the brain and red blood cells, and fatty acids are oxidized by tissues such as muscle and liver. Muscle and most other tissues oxidize fatty acids completely to CO2 and H2O. However, the liver partially oxidizes fatty acids to smaller molecules called ketone bodies, which are released into the blood. Muscle, kidney, and certain other tissues derive energy from completely oxidizing ketone bodies in the tricarboxylic acid (TCA) cycle. 

Fatty acids are used as fuels principally when they are released from adipose tissue triacylglycerols in response to hormones that signal fasting or increased demand. Many tissues, such as muscle and kidney, oxidize fatty acids completely to CO2 and H2O. In these tissues, the acetyl CoA produced by p-oxidation enters the TCA cycle. The FAD(2H) and the NADH from p-oxidation and the TCA cycle are... 

The immediate sources of energy for the body are the free fatty acids in the circulation liberated from adipose triglycerides by the enzyme lipase. These free fatty acids are oxidized or burned by a systematic process called betaoxidation, whereby 2-carbon fragments are successively cleaved from the fatty acid molecule to form acetyl CoA which releases energy upon completing the Krebs cycle (TG cycle). 

Peroxisomes appear to be capable of degrading long-chain, saturated, even-numbered fatty acids completely to their constituent acetyl units. Medium- and short-chain acyl-CoAs, intermediates in long-chain acyl-CoA oxidation, are oxidized by the acyl-CoA oxidase and serve as substrates for the overall in vitro 6-oxidation bv peroxisomes. However, storage triacylglycerols, the substrate source for 6-oxidation in fatty tissues, and membrane lipids, a possible substrate source for 6-oxidation in nonfatty tissues, contain unusual and unsaturated fatty acids. Additional enzyme reactions are required to link the catabolism of these fatty acids to the 6-oxidation sequence. 

FIGURE 9 Oxidation of fatty acids. Fats and oils are hydrolyzed to form glycerol and fatty acids. CoA derivatives of the fatty acids are oxidized in mitochondria by NAD+ and FAD to j0-oxo-derivatives. CoA cleaves these derivatives to yield acetyl CoA and a fatty acid CoA molecule that is two carbons shorter. The process continues until the fatty acid has been completely converted to acetyl CoA. The acetyl moiety is oxidized in the citric acid cycle to CO2 and water. The complete oxidation of a fatty acid of about the same molecular weight of glucose yields four times more ATP than that of glucose. 

Fatty acids are oxidized completely to CO2 and water by )8-oxidation and the citric acid cycle. Acetyl CoA is the end product of )8-oxidation of fatty acids and is the source of carbon for fatty acid biosynthesis. Yet, the pathways for fatty acid degradation and synthesis are so very different that they even occur within different compartments within cells. Fatty acid synthesis takes place in the cytoplasm of animal cells and in the plastids of plant cells, whereas )8-oxidation is located in mitochondria in both animal and plant cells. 

The TCA cycle can now be completed by converting succinate to oxaloacetate. This latter process represents a net oxidation. The TCA cycle breaks it down into (consecutively) an oxidation step, a hydration reaction, and a second oxidation step. The oxidation steps are accompanied by the reduction of an [FAD] and an NAD. The reduced coenzymes, [FADHg] and NADH, subsequently provide reducing power in the electron transport chain. (We see in Chapter 24 that virtually the same chemical strategy is used in /3-oxidation of fatty acids.)... 

In essence, this series of four reactions has yielded a fatty acid (as a CoA ester) that has been shortened by two carbons, and one molecule of acetyl-CoA. The shortened fatty acyl-CoA can now go through another /3-oxidation cycle, as shown in Figure 24.10. Repetition of this cycle with a fatty acid with an even number of carbons eventually yields two molecules of acetyl-CoA in the final step. As noted in the first reaction in Table 24.2, complete /3-oxidation of palmitic acid yields eight molecules of acetyl-CoA as well as seven molecules of FADHg and seven molecules of NADFI. The acetyl-CoA can be further metabolized in the TCA cycle (as we have already seen). Alternatively, acetyl-CoA can also be used as a substrate in amino acid biosynthesis (Chapter 26). As noted in Chapter 23, however, acetyl-CoA cannot be used as a substrate for gluco-neogenesis. 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

Figure 3. Mitochondrial fatty acid oxidation. Long-chain fatty acids are converted to their CoA-esters as described in the text, and their fatty-acyl-groups transferred to CoA in the matrix by the concerted action of CPT 1, the acylcarnitine/carnitine exchange carrier and CPT (A) as described in the text. Medium-chain and short-chain fatty acids (Cg or less) diffuse directly into the matrix where they are converted to their acyl-CoA esters by a acyl-CoA synthase. The mechanism of p-oxidation is shown below (B). Each cycle of P-oxidation removes -CH2-CH2- as an acetyl unit until the fatty acids are completely converted to acetyl-CoA. The enzymes catalyzing each stage of P-oxidation have different but overlapping specificities. In muscle mitochondria, most acetyl-CoA is oxidized to CO2 and H2O by the citrate cycle (Figure 4) some is converted to acylcamitine by carnitine acetyltransferase (associated with the inner face of the inner membrane) and exported from the matrix. Some acetyl-CoA (if in excess) is hydrolyzed to acetate and CoASH by acetyl-CoA hydrolase in the matrix. Enzymes ...

The citrate cycle is the final common pathway for the oxidation of acetyl-CoA derived from the metabolism of pyruvate, fatty acids, ketone bodies, and amino acids (Krebs, 1943 Greville, 1968). This is sometimes known as the Krebs or tricarboxylic acid cycle. Acetyl-CoA combines with oxaloacetate to form citrate which then undergoes a series of reactions involving the loss of two molecules of CO2 and four dehydrogenation steps. These reactions complete the cycle by regenerating oxaloacetate which can react with another molecule of acetyl-CoA (Figure 4). 

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