Regeneration Fatty acid synthesis

The reactions of fatty acid synthesis all take place in the cytosol, but acetyl-CoA is made in the mitochondria and can t cross the inner membrane. The Pyruvate-Malate Cycle (Citrate-Pyruvate Cycle) is used to take acetyl- groups to the cytosol while simultaneously providing a source of NADPH from NADH, and thus, coupling fatty acid synthesis to Glycolysis (Fig. 10.7). Note that the acetyl-CoA is first joined to oxaloacetate to make citrate which is readily transported out of the mitochondria using a co-transporter. The citrate is then cleaved to acetyl-CoA and oxaloacetate, a process requiring ATP to make it favourable (recall the condensation was spontaneous). Acetyl-CoA for fatty acid synthesis is now available in the cytosol, but oxaloacetate must be regenerated for the mitosol. 

The malic enzyme/citrate lyase pathway is shown in Figure 5.10. The 2-carbon units acetyl groups) for fatty acid synthesis are supplied by the activity of citrate lyase, which may be considered an enzyme of fatty acid biosynthesis. The reduced NADP is Supplied at the point of malic enzyme. Figure 5.10 reveals no net production or utilization of NAD in the cytoplasm. The NADPH + H generated in the cytoplasm is used for fatly acid synthesis, which regenerates NADP. One molecule of CO is produced in the cytoplasm. The diagram reveals no net production or utilization of CO in the mitochondrion. One molecule of NAD is... 

Tie reactions constitute a metabolic motif that we will see again in fatty acid synthesis and degradation as well as in the degradation of some amino acids. A methylene group (CH2) is converted into a carbonyl group (C=0) in three steps an oxidation, a hydration, and a second oxidation reaction, Oxaloacetate is thereby regenerated for another round of the cycle, and more energy is extracted in the form of FADH and NADH. 

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-... 

It is important to note that animals are unable to effect the net synthesis of glucose from fatty acids. Specifically, acetyl CoA cannot be converted into pyruvate or oxaloacetate in animals. The two carbon atoms of the acetyl group of acetyl CoA enter the citric acid cycle, but two carbon atoms leave the cycle in the decarboxylations catalyzed by isocitrate dehydrogenase and a-ketoglutarate dehydrogenase. Consequently, oxaloacetate is regenerated, but it is not formed de novo when the acetyl unit of acetyl CoA is oxidized by the citric acid cycle. In contrast, plants have two additional enzymes enabling them to convert the carbon atoms of acetyl CoA into oxaloacetate (Section 17.4.). 

Figure 36-3. Mobilization of fatty acids during times in which the hver is synthesizing glucose via the gluconeogenic pathway. The P-oxidation of fatty acids by the liver produces the energy needed for gluconeogenesis, but because the TCA cycle is slowed because of depletion of acids (used for glucose synthesis), ketone bodies (acetoacetate and P-hydroxybutyrate) are formed from acetyl-CoA to regenerate CoA for continued P-oxidation. The ketone bodies are exported to extrahepatic tissues, where they are used as an energy source.

Synthesis of most of the ATP generated in aerobic oxidation is coupled to the reoxidation of NADH and FADH2 by O2 In a stepwise process involving the respiratory chain, also called the electron transport chain. Even though molecular O2 is not involved in any reaction of the citric acid cycle, in the absence of O2 the cycle soon stops operating as the supply of NAD and FAD dwindles. Before considering electron transport and the coupled formation of ATP in detail, we discuss first how the supply of NAD in the cytosol is regenerated and then the oxidation of fatty acids to CO2. 

In vitamin B22 deficiency methyltetrahydrofolate cannot donate its methyl group to homocysteine to regenerate methionine. Because the synthesis of methyltetrahydrofolate is irreversible (text, p. 675), the cell s tetrahydrofolate ultimately will be converted into this form. No formyl or methylene tetrahydrofolate will be left for nucleotide synthesis. Pernicious anemia illustrates the intimate connection between amino acid metabolism and nucleotide metabolism. The metabolism of fatty acids that have odd numbers of carbons also will be affected because methylmalonyl-CoA mutase requires vitamin B22 for the production of succinyl-CoA. A further connection is that methylmalonyl-CoA mutase also is involved in the degradation of valine and isoleucine. 

Once the structure of acetyl CoA was known, a detailed chemical scheme of fatty-acid oxidation could be formulated, based on several experimental observations published in the literature. I presented it in my first publication on acetyl CoA i and called it later the fatty acid cycle .< The substrate is regenerated in this repeated reaction sequence, which thus resembles the citric acid cycle or the cyclic process in the synthesis of urea. In these other cyclic processes, however, identical substrates are formed after each cycle, whereas a shorter homologous chain is formed in each repetition of the fatty acid cycle . It would therefore be more appropriate to describe the oxidation of fatty acids by a spiral process rather than by a cycle. 

---