Biosynthesis long-chain fatty acids

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

Biosynthesis of unsatutated long-chain fatty acids is achieved by desaturase and elongase enzymes, which introduce double bonds and lengthen existing acyl chains, respectively. 

FIGURE 3-7 Pathways for the interconversion of brain fatty acids. Palmitic acid (16 0) is the main end product of brain fatty acid synthesis. It may then be elongated, desaturated, and/or P-oxidized to form different long chain fatty acids. The monoenes (18 1 A7, 18 1 A9, 24 1 A15) are the main unsaturated fatty acids formed de novo by A9 desaturation and chain elongation. As shown, the very long chain fatty acids are a-oxidized to form a-hydroxy and odd numbered fatty acids. The polyunsaturated fatty acids are formed mainly from exogenous dietary fatty acids, such as linoleic (18 2, n-6) and a-linoleic (18 2, n-3) acids by chain elongation and desaturation at A5 and A6, as shown. A A4 desaturase has also been proposed, but its existence has been questioned. Instead, it has been shown that unsaturation at the A4 position is effected by retroconversion i.e. A6 unsaturation in the endoplasmic reticulum, followed by one cycle of P-oxidation (-C2) in peroxisomes [11], This is illustrated in the biosynthesis of DHA (22 6, n-3) above. In severe essential fatty acid deficiency, the abnormal polyenes, such as 20 3, n-9 are also synthesized de novo to substitute for the normal polyunsaturated 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). 

Malonyl-CoA, the first intermediate in the cytosolic biosynthesis of long-chain fatty acids from acetyl-CoA (see Fig. 21-1), increases in concentration whenever the animal is well supplied with carbohydrate excess glucose that cannot be oxidized or stored as glycogen is converted in the cytosol into fatty acids for storage as triacylglycerol. The inhibition of carnitine acyltrans-ferase I by malonyl-CoA ensures that the oxidation of... 

Cholesterol, like long-chain fatty acids, is made from acetyl-CoA, but the assembly plan is quite different. In early experiments, animals were fed acetate labeled with 14C in either the methyl carbon or the carboxyl carbon. The pattern of labeling in the cholesterol isolated from the two groups of animals (Fig. 21-32) provided the blueprint for working out the enzymatic steps in cholesterol biosynthesis. 

Millar A. A. and Kunst L. (1997) Very-long-chain fatty acid biosynthesis is controlled through the expression and specificity of the condensing enzyme. Plant J. 12, 121-131. 

In insects, especially Diptera, several pioneer studies reviewed by Blomquist et al. (1987) established that long chain hydrocarbons, some of which play a pheromone role, were derived from very long chain fatty acids by reduction and decarboxylation. Thus, pheromone biosynthesis shares steps with those leading to basic lipid molecules and also with those of the well-known pheromones of Lepidoptera (Roelofs and Wolf, 1988). All often display several double bonds located in various positions while the volatile butterfly compounds bear functional groups (acetate, aldehyde or alcohol) and aliphatic chains with 12-16 carbons. Contact pheromones of flies have much longer chains (21C-39C) (Pennanec h et al., 1991). 

The biosynthesis of hydrocarbons occurs by the microsomal elongation of straight chain, methyl-branched and unsaturated fatty acids to produce very long-chain fatty acyl-CoAs (Figure 11.1). The very long chain fatty acids are then reduced to aldehydes and converted to hydrocarbon by loss of the carboxyl carbon. The mechanism of hydrocarbon formation has been controversial. Kolattukudy and coworkers have reported that for a plant, an algae, a vertebrate and an insect, the aliphatic aldehyde is decarbonylated to the hydrocarbon and carbon monoxide, and that this process does not require cofactors (Cheesbrough and Kolattukudy, 1984 1988 Dennis and Kolattukudy, 1991,1992 Yoder et al., 1992). In contrast, the Blomquist laboratory has presented evidence that the aldehyde is converted to hydrocarbon and carbon dioxide in a process that... 

The biosynthesis of polyketides is analogous to the formation of long-chain fatty acids catalyzed by the enzyme fatty acid synthase (FAS). These FASs are multi-enzyme complexes that contain numerous enzyme activities. The complexes condense coenzyme A (CoA) thioesters (usually acetyl, propionyl, or malonyl) followed by a ketoreduction, dehydration, and enoylreduction of the [3-keto moiety of the elongated carbon chain to form specific fatty acid products. These subsequent enzyme activities may or may not be present in the biosynthesis of polyketides. 

Tvrdik, P., Westerberg, R., Silve, S., Asadi, A., Jakobsson, A., Cannon, B., Loison, G. and Jacobsson, A. (2000). Role of a new mammalian gene family in the biosynthesis of very long chain fatty acids and sphingolipids../. Cell Biol., 149, 707-718. 

It is clear from this discussion that carnitine is required in humans for the oxidation of long-chain fatty acids. In humans, carnitine is derived from both dietary sources and endogenous biosynthesis. Meat products, particularly red meats, and dairy products are important dietary sources of carnitine. Since biosynthesis can meet all physiological requirements, carnitine is not an essential nutrient. Premature infants are an exception to this rule as they lack a mature biosynthetic system and have limited tissue carnitine stores. As many infant formulas, particularly those based on soy protein, are low in carnitine, premature infants receiving a significant part of their nutrition from such formulas may be susceptible to carnitine deficiency. 

The location (in base pairs) of the giant dptA, dptBC and dptD genes cloned on BAC pVCl which contains a 128 000 base pair insert.14 The dptA, dptBC and dptD genes encode five, six and two modules, respectively. The specificity of A domains is shown with amino acid subscripts. The C condensation domain differs from the others in that it couples the long chain fatty acids to the TV-terminus of Trp i to initiate daptomycin biosynthesis. Note that modules 2, 8 and 11 have CATE modules to incorporate D-amino acids. The Kyn13 module has a terminal Te (as CATTe) to cyclise and release the completed lipopeptide. 

An unusual structural feature from the inositol perspective is the derivatiza-tion of the 2-hydroxyl group of inositol by a long chain fatty acid (palmitic acid). In many mature GPI-proteins, the palmatoyl side chain is not present the palmatoyl chain is added during the biosynthesis of GPI and removed after the GPI anchor is attached to the protein during posttranslational modification. Although the wyo-isomer of inositol is the most prevalent form in GPI molecules, the presence of chiro-inositol has also been detected. 

Volatile fatty acids are by-products in the formation of long-chain fatty acids, which are required for cell membrane phospholipid biosynthesis. The biosynthesis of volatile fatty acids is generally controlled by the same factors that control the formation of ethyl fatty acid esters, that is, oxygen, ergosterol and various insoluble solids (grape solids, clarification solids, yeast hulls) tends to suppress production whereas sugar concentration and clarification are stimulatory (Bardi et al. 1999 Delfini et al. 1992, 1993 Edwards et al. 1990 Houtman et al. 1980). 

This is the second key enzyme needed to produce high amounts of hpid as the reaction catalysed simultaneously produces the necessary reducing equivalent, NADPH, by which the growing long acyl chain, derived from acetyl-coenzyme A (see above), is reduced to the final long-chain fatty acid. Fatty acid biosynthesis, and consequently lipid accumulation, requires both a continous supply of acetyl-CoA and reducing power (NADPH), and these are provided by the key reactions mentioned above. 

The KQ is influenced by the net rate of fatty acid biosynthesis. Fatty acid synthesis involves the conversion of carbohydrate, via the acetyJ-CoA intermediate, to long-chain fatty acids. The synthesis of fatty acids requires reduced NADP as a co/ac-tor. It involves the consumption of two molecules of NADPH + H+ for each 2-carbon unit incorporated into the fatty acid. The NADPH + H is supplied by two separate pathways the pentose phosphate pathway (PPP) and the malic enzyme/citrate Lyase pathway. 

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in long-chain fatty acid biosynthesis (see Chapter 7.11). The overall reaction is catalyzed in two sequential reactions (Scheme 3). First, the biotin carboxylase domain catalyzes the ATP-dependent carboxylation of biotin (which is attached to a carrier protein) using bicarbonate as a CO2 donor. In the second reaction, the carboxyl group is transferred from biotin to acetyl-CoA to form malonyl-CoA. In mammals, both reactions are catalyzed by a single protein, but in Escherichia coli and other bacteria, the activity is catalyzed by two separate proteins, a biotin carboxylase and a carboxytransferase. Due to its role in fatty acid synthesis, inhibitors of the overall ACC reaction are proposed to be useful as antiobesity drugs in mammals as well as novel antibiotics against bacteria. 

See also Fatty Acids, Table 10.1, Synthesis of Long Chain Fatty Acids, Fatty Acid Desaturation, Palmitate Synthesis from Acetyl-CoA, Biosynthesis of Sphingolipids, 3-Ketosphinganine... 

See also Palmitate Biosynthesis from Acetyl-CoA, Fatty Acid Biosynthesis Strategy, Synthesis of Long Chain Fatty Acids, Figure 18.29, Figure 18.30, Fatty Acids... 

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