Long chain fatty ketone

Acetyl-CoA is also used as the precursor for biosynthesis of long-chain fatty acids steroids, including cholesterol and ketone bodies. 

A summary of the sources and fates of fatty acids and ketone bodies is presented in Figure 7.1 and Table 7.1. A major problem with long-chain fatty acids and TAGs is their lack of solubility in the aqueous medium of the blood and interstitial fluid. How this is overcome for fatty acids is discussed in this chapter, and for triacylglycerol in Chapter 11. Unfortunately, the need to transport relatively large quantities of triacylglycerol in the blood can lead to pathological problems (Chapter 11). 

Figure 7.1 The sources and fates offatfueb. The fat fuels considered in this figure are the long-chain fatty acids and ketone bodies that are transported in the blood.

Although emphasis is usually placed on long-chain fatty acids (i.e. containing more than 14 carbon atoms) as a fat fuel, three others are also important short-chain (<6 carbon atoms), medium-chain (6-14 carbon atoms) and ketone bodies. Unless otherwise specified, the term fatty acids... 

Medium-chain acyl-CoA synthetase, which is present within the mitochondrial matrix of the liver, activates fatty acids containing from four to ten carbon atoms. Medium-chain length fatty acids are obtained mainly from triacylglycerols in dairy products. However, unlike long-chain fatty acids, they are not esterified in the epithelial cells of the intestine but enter the hepatic portal vein as fatty acids to be transported to the liver. Within the liver, they enter the mitochondria directly, where they are converted to acyl-CoA, which can be fully oxidised and/or converted into ketone bodies. The latter are released and can be taken up and oxidised by tissues. 

Each turn of the P-oxidation spiral splits off a molecule of acetyl-CoA. The process involves four enzymes catalysing, in turn, an oxidation (to form a double bond), a hydration, another oxidation (forming a ketone from a secondary alcohol) and the transfer of an acetyl group to coenzyme A (Figure 7.12). The process of P-oxidation operates as a multienzyme complex in which the intermediates are passed from one enzyme to the next, i.e. there are no free intermediates. The number of molecules of ATP generated from the oxidation of one molecule of the long-chain fatty acid pal-mitate (C18) is given in Table 7.4. Unsaturated fatty acids are also oxidised by the P-oxidation process but require modification before they enter the process (Appendix 7.3). 

Ketone bodies are produced in the liver by partial oxidation of long-chain fatty acids arising from the triacylglyc-erol stored in adipose tissue, so that the question arises, why should one lipid fuel be converted into another There are several reasons. 

There are two tissues that cannot use long-chain fatty acids, the small intestine and the brain. Both can, however, oxidise ketone bodies and therefore can restrict glucose utilisation. It is not known why these tissues do not oxidise fatty acids possibly the activity of the enzymes in oxidation is very low. 

The three fat fuels and their metabolism are involved directly or indirectly in diseases such as diabetes mellitus, syndrome X, obesity, atherosclerosis and coronary heart disease, which are discussed in other chapters in this book. This section considers the problems associated with high blood levels of ketone bodies and long-chain fatty acids. 

Several cycles are required for complete degradation of long-chain fatty acids—eight cycles in the case of stearyl-CoA (C18 0), for example. The acetyl CoA formed can then undergo further metabolism in the tricarboxylic acid cycle (see p. 136), or can be used for biosynthesis. When there is an excess of acetyl CoA, the liver can also form ketone bodies (see p. 312). 

Figure 7-1. Pathways of fuel metabolism and oxidative phosphorylation. Pyruvate may be reduced to lactate in the cytoplasm or may be transported into the mitochondria for anabolic reactions, such as gluconeogenesis, or for oxidation to acetyl-CoA by the pyruvate dehydrogenase complex (PDC). Long-chain fatty acids are transported into mitochondria, where they undergo [ -oxidation to ketone bodies (liver) or to acetyl-CoA (liver and other tissues). Reducing equivalents (NADH, FADII2) are generated by reactions catalyzed by the PDC and the tricarboxylic acid (TCA) cycle and donate electrons (e ) that enter the respiratory chain at NADH ubiquinone oxidoreductase (Complex 0 or at succinate ubiquinone oxidoreductase (Complex ID- Cytochrome c oxidase (Complex IV) catalyzes the reduction of molecular oxygen to water, and ATP synthase (Complex V) generates ATP fromADP Reprinted with permission from Stacpoole et al. (1997).

Excess acetate (C2) can be converted to the mobile ketone body energy source aceto-acetate (C4) and thence its reduced form hydroxybutyrate (C,) for transport throughout the body. Excess acetate can be carboxylated (via acetylCoA carboxylase) to form malonylCoA (C3), the donor for further C2 additions (with C02 elimination) in the anabolic synthesis of long chain fatty acids. Fatty acids are components of the phospholipids of cellular membranes and are also stored as triacylglycerols (triglycerides) for subsequent hydrolysis and catabolic fatty acid oxidation to yield reduced coenzymes and thence ATP (see Chapter 2). 

Fatty acids. Normal brain tissne does not take np or metabolise fatty acids (hence its dependence on glucose, or the switch to ketone body ntUisation). However, the arcnate nucleus converts fatty acids to long-chain fatty acyl-CoA intermediates. The exact mechanism of appetite control is unclear, bnt it is known that the long-chain fatty acyl-CoA intermediates formed in the arcuate nucleus dampen appetite and rednce food intake. 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

Paraffin followed by candelilla wax and microcrystalline waxes, and eventually by beeswax, are considered as the most effective moisture barriers derived from edible waxes (Morillon et al. 2002). There is no satisfactory chemical definition for the term wax which is used for a variety of products of mineral, botanical and animal origin that contain various kinds of fatty materials (Table 23.4). The term resins or lacs can also be used for plant or insect secretions that take place along resins ducts, often in response to injury or infection, and result in more acidic substances (Hernandez 1994). However, all waxes tend to contain wax esters as major components, that is, esters of long-chain fatty alcohols with long chain fatty acids. Depending on their source, they may additionally include hydrocarbons, sterol esters, aliphatic aldehydes, primary and secondary alcohols, diols, ketones, triacylglycerols, and so on. 

Carnitine is required for transport of longoxidative metabolism as well as in the formation of ketone bcidies, The concentration of free carnitine in muscle is about 4,0 mmol/kg. The concentration of carnitine bound to long-chain fatty adds (fatty acyl-camitine) is lower, about 0,2 mmol/kg. Short-chain fatty adds, including acetic, are also esterified to carnitine, but the functions of these complexes are not clear. There is some indication that keto forms of BCAAs (BCKAs) can also be esterified to carnitine. These complexes can then be transported into the mitochondria for complete oxidation of the BCKAs, The importance of this mode of BCKA transport is not dear (Takakura et ai., 1997). 

Pyrolysis products show a significant level of long aliphatic chain methyl ketones. These are probably generated by the mechanism suggested in the structure of the polymer. Long chain fatty acids also have been obtained in the pyrolysis of cuticular macromolecular constituents of Agave americana. 

Both the spores and the mycelium seem capable of producing methyl ketones from fatty acids (12, 13). Furthermore, both short chain and long chain fatty acids are metabolized, thereby giving rise to an homologous series of methyl ketones, the main ones being 2-pentanone, 2-heptanone and 2-nonanone (14). A number of processes have been developed and patented for producing blue cheese flavor via the fermentation of milk fat (15, 16). Usually the... 

Long-chain fatty acyl-CoA is at a crossroad of various metabolic pathways. Inside the mitochondrial matrix, fatty acyl-CoA is converted to acetyl-CoA, a compound that serves as substrate for aerobic energy production by concerted action of enzymes of the citric acid cycle and respiratory chain, and as precursor for ketone-body formation. The latter process is confined to the liver. The fatty acyl residue of acyl-CoA can also be incorporated into triacylglycerols and phospholipids (Figure 3). These anabolic processes occur in the extramitochondrial cytoplasmic space (see below). 

The first two A1—C bonds of the trialkyl alane react with oxygen appreciably faster than the third. Various side reactions may result (formation of ketones, dialkyl carbinols, etc.), and various modifications in the process for oxidizing the alane have therefore been proposed (16, 50,168). The preparative possibilities of autoxidation, and particularly the preparation of long-chain fatty alcohols by a combination of the ethylene synthesis reaction and oxidation of the trialkyl alanes has been reported in detail (SOI, 312). 

The liver is the main origin of ketones in laboratory animals, where the long chain fatty acids are released from plasma albumin and bound to fatty acid-binding proteins in the hepatocytes. The long chain fatty acids react with CoA and then can be used to synthesize triacylglycerol or undergo beta-oxidation to acetyl CoA. When the levels of plasma fatty acids are elevated, acetyl CoA can be metabolized to form acetoacetate and 3-hydroxybutyrate or enter the tricarboxylic acid cycle. In ketosis, the levels of acetone, acetoacetate, and 3-hydroxybutyrate (also known as beta-hydroxybutyrate) are increased in both plasma and urine these three compounds historically were collectively called ketone bodies. Urine test strips can be used to test for ketonuria, and there are several enzymatic assays for 3-hydroxybutyrate and acetoacetate. 

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