Metabolism Fatty acid degradation

Fatty acid metabolism Synthesis and degradation of ketone bodies... 

While MS-MS allows for unequivocal identification of most metabolites, there are a few exceptions. In particular, the short-chain acylcarnitines of 4 and 5 carbons represent more than one analyte. C4-Acylcarnitine is known to be a mixture of bu-tyrylcarnitine derived from fatty acid metabolism and isobutyrylcarnitine derived from the metabolism of valine (Fig. 3.2.3) [21, 58]. C5-Acylcarnitine is a mixture of isovalerylcarnitine and 2-methylbutyrylcarnitine derived from leucine and isoleucine degradation, respectively (Fig. 3.2.4) [20, 59]. Samples of patients treated with antibiotics containing pivalic acid may contain pivaloylcarnitine another C5 species... 

Ethanoic acid is activated for biosynthesis by combination with the thiol, coenzyme A (CoASH, Figure 18-7) to give the thioester, ethanoyl (acetyl) coenzyme A (CH3COSC0A). You may recall that the metabolic degradation of fats also involves this coenzyme (Section 18-8F) and it is tempting to assume that fatty acid biosynthesis is simply the reverse of fatty acid metabolism to CH3COSCoA. However, this is not quite the case. In fact, it is a general observation in biochemistry that primary metabolites are synthesized by different routes from those by which they are metabolized (for example, compare the pathways of carbon in photosynthesis and metabolism of carbohydrates, Sections 20-9,10). 

Before discussing the specific aspects of regulation of fatty acid metabolism, let us review the main steps in fatty acid synthesis and degradation. Figure 18.18 illustrates these processes in a way that emphasizes the parallels and differences. In both cases, two-carbon units are involved. However, different enzymes and coenzymes are utilized in the biosynthetic and degradative processes. Moreover, the processes take place in different compartments of the cell. The differences in the location of the two processes and in the... 

Before closing we should point out that, over an extended period, dietary conditions can alter the levels of enzymes involved in fatty acid metabolism. For example, the concentrations of fatty acid synthase and acetyl-CoA carboxylase in rat liver are reduced four- to fivefold after fasting. When a rat is fed a fat-free diet, the concentration of fatty acid synthase is 14-fold higher than in a rat maintained on standard rat chow diet. Current evidence indicates that the levels of these enzymes are governed by the rate of enzyme synthesis, not degradation. It appears that synthesis of the enzyme, in turn, is controlled by the rate of transcription of DNA into mRNA. A question of current interest is how this transcription of DNA is regulated. 

Many aroma compounds in fruits and plant materials are derived from lipid metabolism. Fatty acid biosynthesis and degradation and their connections with glycolysis, gluconeogenesis, TCA cycle, glyoxylate cycle and terpene metabolism have been described by Lynen (2) and Stumpf ( ). During fatty acid biosynthesis in the cytoplasm acetyl-CoA is transformed into malonyl-CoA. The de novo synthesis of palmitic acid by palmitoyl-ACP synthetase involves the sequential addition of C2-units by a series of reactions which have been well characterized. Palmitoyl-ACP is transformed into stearoyl-ACP and oleoyl-CoA in chloroplasts and plastides. During B-oxi-dation in mitochondria and microsomes the fatty acids are bound to CoASH. The B-oxidation pathway shows a similar reaction sequence compared to that of de novo synthesis. B-Oxidation and de novo synthesis possess differences in activation, coenzymes, enzymes and the intermediates (SM+)-3-hydroxyacyl-S-CoA (B-oxidation) and (R)-(-)-3-hydroxyacyl-ACP (de novo synthesis). The key enzyme for de novo synthesis (acetyl-CoA carboxylase) is inhibited by palmitoyl-S-CoA and plays an important role in fatty acid metabolism. 

Acetyl-CoA plays a central role in most lipid-related metabolic processes. For example, acetyl-CoA is used in the synthesis of fatty acids. When fatty acids are degraded to generate energy, acetyl-CoA is the product. 

In this chapter we attempted to review the transcriptional regulation of fatty acid metabolism in the liver. Many transcription factors are involved in this process. We chose to focus on PPARa and SREBP-lc because of their established regulatory roles in the control of transcriptional programs that govern fatty acid degradation and synthesis, respectively. Moreover, we thought their distinct activation processes and sensitivity to various stimuli make them very... 

Ide, T., Shimano, H., Yoshikawa, T., Yahagi, N., Amemiya-Kudo, M., Matsuzaka, T., Nakakuki, M., Yatoh, S., lizuka, Y., Tomita, S., et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. IF LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol Endocrinol 17 (2003) 1255-1267. 

Acyl-CoA thioesterase enzymes (EC 3.1.2.-), although their catalytic activity simply entails the hydrolysis of CoA and ACP thioesters to release the fatty acids and other carboxylic acids bound to them (Equation (19)), have wide and varied physiological functions that includes the regulation of fatty acid metabolism and playing a central role in the biosynthesis of polyketide and nonribosomal peptide-based metabolites (especially the macrocyclic versions) and the degradation of aromatic compounds. These enzymes are thoroughly discussed in several recent reviews as well as the relevant chapters of this series that include fatty acids, polyketides, and nonribosomal peptide biosynthesis ° ° (see Chapters 1.05,1.02, and 5.19) therefore, only a brief overview of the structural and mechanistic diversity of acyl-CoA and acyl-ACP thioesterases is provided in this section. 

In animal cells, fatty acids are degraded both in mitochondria and peroxisomes, whereas in lower eukaryotes, P-oxidation is confined to peroxisomes. Mitochondrial P-oxidation provides energy for oxidative phosphorylation and generates acetyl-CoA for ketogenesis in liver. The oxidation of fatty acids with odd numbers of carbon atoms also yields propi-onyl-CoA that is metabolized to succinate. 

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