Chain elongation of palmitate

Further chain elongation of palmitic acid occurs by reactions similar to those just described, but CoA rather than ACP is the carrier group, ancl separate enzymes are needed for each step rather than a multienzyme synthase complex. 

The net effect of these eight steps is to take two acetyl groups and combine them into a single four-carbon butyryl group. Further condensation of butyryl synthase with another malonyl ACP yields a six-carbon unit, and still further repetitions of the pathway add two more carbon atoms to the chain each time until the 16-carbon palmitic acid is reached. Further chain elongation of palmitic acid occurs by reactions similar to those just described, but acetyl CoA itself rather than malonyl ACP is the two-carbon donor. 

Chain Elongation of Palmitate (long chain fatty acids)... 

The end-product of this process is the C-16 saturated fatty acid, palmitate. The elongation of palmitate to longer-chain fatty acids involves another system (see below). 

After the extraction of lipid and nonlipid components from the leaves of mandarin orange Citrus reticulata, the lipid fraction was further separated by PTLC to determine different lipid classes that affect the chemical deterrence of C. reticulata to the leaf cutting ecat Acromyrmex octopinosus. These lipids seem to be less attractive to the ants [81a]. The metabolism of palmitate in the peripheral nerves of normal and Trembler mice was studied, and the polar lipid fraction purified by PTLC was used to determine the fatty acid composition. It was found that the fatty acid composition of the polar fraction was abnormal, correlating with the decreased overall palmitate elongation and severely decreased synthesis of saturated long-chain fatty acids (in mutant nerves) [81b]. 

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. 

The elongation of the fatty acid by fatty acid synthase concludes at Cie, and the product, palmitate (16 0), is released. Unsaturated fatty acids and long-chain fatty acids can arise from palmitate in subsequent reactions. Fats are finally synthesized from activated fatty acids (acyl CoA) and glycerol 3-phosphate (see p. 170). To supply peripheral tissues, fats are packed by the hepatocytes into lipoprotein complexes of the VLDL type and released into the blood in this form (see p. 278). 

Seven cycles of condensation and reduction produce the 16-carbon saturated palmitoyl group, still bound to ACP. For reasons not well understood, chain elongation by the synthase complex generally stops at this point and free palmitate is released from the ACP by a hydrolytic activity in the complex. Small amounts of longer fatty acids such as stearate (18 0) are also formed. In certain plants (coconut and palm, for example) chain termination occurs earlier up to 90% of the fatty acids in the oils of these plants are between 8 and 14 carbons long. 

The pathway The first committed step in fatty acid biosynthesis is the carboxylation of acetyl CoA to form malonyl CoA which is catalyzed by the biotin-containing enzyme acetyl CoA carboxylase. Acetyl CoA and malonyl CoA are then converted into their ACP derivatives. The elongation cycle in fatty acid synthesis involves four reactions condensation of acetyl-ACP and malonyl-ACP to form acetoacetyl-ACP releasing free ACP and C02, then reduction by NADPH to form D-3-hydroxybutyryl-ACP, followed by dehydration to crotonyl-ACP, and finally reduction by NADPH to form butyryl-ACP. Further rounds of elongation add more two-carbon units from malonyl-ACP on to the growing hydrocarbon chain, until the C16 palmitate is formed. Further elongation of fatty acids takes place on the cytosolic surface of the smooth endoplasmic reticulum (SER). 

Palmitate can serve as a precursor for both longer and unsaturated fatty adds. Chain elongation takes place in both the endoplasmic reticulum and mitochondria. In the latter, this is a simple reversal of the /3-oxidation reaction sequence, except that the step that would normally require FADH2 requires NADPH instead. This system is designed for the elongation of short-chain acids. There is no activity with palmitate. 

Palmitic acid may be converted to stearic acid (C1K 0) by elongation of the carbon chain. Desaturation of stearic acid produces oleic acid (C18 1 A9). Linoleic acid (Ci8 2A9,12), however, cannot be synthesized in mammalian tissues. Therefore, it is an essential fatty acid for animals and must be obtained from the diet it has two important metabolic roles. One is to maintain the fluid state of membrane lipids, lipoproteins, and storage lipids. The other role is as a precursor of arachidonic acid, which has a specialized role in the formation of prostaglandins (Sec. 13.9). 

A number of plants and phytochemicals have attracted attention for their ability to reduce many of the risk factors associated with cardiovascular disease. Research into these diseases has shown the relationship between lesions, fatty streaking and plaque formation in blood vessels and the development of strokes and myocardial infarctions. These effects are linked to levels of plasma lipids which comprise triglycerides, cholesterol and other fat substances. It is known that the biosynthesis of lipids involves the condensation of several molecules of acetylcoenzyme A and malonylcoenzyme A in a gradual process of elongation of the fatty acid chain involving the sequential addition of two carbon units giving rise to fatty acids such as lauric acid (12 carbons) and eventually to palmitic acid (16 carbons). Palmitic acid is the precursor... 

Fig. 2.13 Biosynthesis of saturated fatty acids in plants and animals. Palmitate is formed by successive additions of malonyl coenzyme A to the enzyme-bound chain, with C02 being lost at each addition.This results in chain elongation by a (CH2)2 unit at each step. Details of the formation of butyryl (C4) from acetyl (C2) are shown, while the subsequent six further additions, terminating in palmitate, proceed similarly.

We found the principal FAs upon infection to be oleic acid (18 1) and saturated FAs. The most characteristic increases in FAs were in palmitic (16 0), which went from 19% to 28%, stearic (18 0) from 10% to 14% and oleic (18 1) from 18% to 28%. The relative paucity of polyunsaturates in PLs led us to suggest that there were defects in appropriate desaturases, chain elongation systems and acylation enzymes and we concluded that the malaria parasite, though it may have no capacity for de novo biosynthesis of lipids from acetate, can regulate its use of host cell lipids and lipid precursors in such a manner as to establish and maintain a lipid composition distinct in many respects from that of the erythrocyte (Beach et al., 1977). 

After fatty acid synthesis, downstream enzymes can further modify palmi-tate for various cellular functions. In the endoplasmic reticulum, the 16 carbon fatty acid can be modified to fatty acids with eighteen or more carbons known as very long chain fatty acids (VLCFA), such as stearate (18 0) by a family of elongase enzymes called elongation of very long chain fatty acids (ELOVLl-6) (Jakobsson et ah, 2006). Palmitate and stearate can also be desaturated by stearoyl-CoA desaturase-1 (SCDl) at the cis-9 carbon to palmitoleate (16 1) and oleate (18 1), respectively (Sampath and Ntambi,... 

Most mammalian cells have the capacity to synthesize fatty acids from glucose de novo in a pathway that uses products from glycolysis and two key cytosolic enzymes, acetyl-CoA carboxylase and fatty acid synthase (Chapter 6). This pathway generates long-chain SFA, mainly palmitate (16 0). The de novo synthesized palmitate and the palmitate derived from dietary sources are transported to the ER membranes. In the membranes, two major fatty acid enzymatic modifications of chain elongation and desaturation occur to yield longer chain SFA and unsaturated fatty acids of the n - 9 series. The n - 3 and n - 6 series of PUFA can be synthesized only from dietary fats, as animal cells do not have the... 

As shown in Figure 22.22 on page 619 of the text, acetyl-ACP and malonyl-ACP condense to form acetoacetyl-ACP. Carbons 4 and 3 of acetoacetyl-ACP are not labeled, because they are derived from acetyl CoA. These two carbons vdll become carbons 15 and 16 of palmitate. Only C-2 of acetoacetyl-ACP will be labeled because it is derived from the methylene carbon of malonyl-ACP. When the second round of synthesis begins, butyryl-ACP condenses with a second molecule of methylene-labeled malonyl-ACP, which contributes C-1 and C-2 of the newly formed six-carbon ACP derivative. In this compound, C-2 and C-4 will be labeled. Chain elongation continues until palmitoyl-ACP is formed. Each even-numbered carbon atom, except for carbon 16 (at the co end), will be labeled. 

Bicarbonate is a source of carbon dioxide for the reaction catalyzed by acetyl CoA carboxylase, in which malonyl CoA is formed. Malonyl CoA is then used as a source of two-carbon units for fatty acyl chain elongation, and the carbon atom derived originally from bicarbonate is released as CO2. Carbon dioxide is then rapidly converted to bicarbonate, which is used again for the synthesis of another molecule of malonyl CoA. Thus, the carbon atom derived from bicarbonate can be used many times for the production of malonyl CoA, but it is never incorporated into the growing acyl chain, so it does not appear in palmitate. 

The biogenesis of n-alkanes in plants presents two points of considerable and novel interest firstly, chain construction. Alkyl chains are built up in plants, animals and microorganisms by sequential condensation of C2 units of acetate to yield fatty acid and related polyketides, but the fatty acid synthetase complexes involved rarely, if at all, catalyse chain elongation beyond compounds thus typically stearic acid CH3(CH2)i6COOH is the end product although palmitic acid (C ) is usually the... 

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