Synthesis of long-chain fatty acids

The synthesis of fatty acids in humans takes place in the liver and adipose tissue. The rates of synthesis are normally relatively low in adults in developed countries, probably because the normal diet contains such a high proportion of fat which reduces the activities of enzymes involved in fatty acid synthesis by decreasing expression 

Functional Biochemistry in Health and Disease by Eric Newsholme and Tony Leech 2010 John Wiley Sons Ltd 

CH 11 SYNTHESIS OF FATTY ACIDS, TRIACYLGLYCEROL, PHOSPHOLIPIDS AND FATTY MESSENGERS 

Citrate has a similar role in proliferating (including tumour) cells and in neurones. Acetyl-CoA is a precursor for many compounds in the former and for formation of acetylcholine in neurones (see Appendix 9.4). 

Conversion of 2-carbon units to a 16-carbon fatty acid 

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FGA and carbonyl strategy the synthesis of long chain fatty acids such as (16) can be achieved in a few steps by suitable FGA. Adding a carbonyl group in a 1,6 relationship allows reconnection to (17) and hence the disconnection of the six carbon atoms in the ring. Analysis... 

The synthesis of long-chain fatty acids (lipogenesis) is carried out by two enzyme systems acetyl-CoA carboxylase and fatty acid synthase. 

The synthesis of long-chain fatty acid esters of carbohydrates is inherently more demanding. It was found that glucose did not react with vinyl laurate in a pure ionic liquid medium, but in biphasic tert-butyl alcohol/[BMIm][PF6], glucose could be acylated by the vinyl esters of O, 2-Cu, fatty acids. The best results were obtained with CaLB, which was twice as active as TIL, and the selectivity for acylation at C-6 was high [114]. The esterification of glucose with palmitic acid, which is, in an industrial context, to be preferred over transesterification, has recently been demonstrated in tert-butyl alcohol/[BMIm][PF6] medium [115]. 

Kwatra, H., Caruthers, J., Tao, B. Synthesis of long chain fatty acids esterified onto cellulose via the vacuum-acid chloride process. Ind. Eng. Chem. Res. 31 2647-2651 (1992). 

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). 

Cunnane. SC, Williams SCR, Bell JD, Brookes S, Craig K, lies RA, etal. Utilization of [U- C]-polyunsatu-rated fatty acids in the synthesis of long chain fatty acids and cholesterol accumulating in the neonatal rat brain. J Neurochem 1994 62 2429. 

See also Fatty Acids, Table 10.1, Synthesis of Long Chain Fatty Acids, Fatty Acid Desaturation, Fatty Acid Synthase, Palmitate Synthesis from Acetyl-CoA... 

Table 10.1, Synthesis of Long Chain Fatty Acids,...

Synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA involves a number of sequential reactions (Fig. 11.1). Acyl groups are attached to the 4 -phosphopantetheine prosthetic group of acyl carrier protein (ACP) during modification by fatty acid synthetase. 

Kusumoto, S., M. Inage, T. Shiba. I. Azuma, and Y. Yamamura Synthesis of long chain fatty acid esters of N-acetyl-muramyl-L-alanyl-D-isoglulamine in relation to anti-tumor activity. Tetrahedron Lett. 4895 (1978). 

There is compelling evidence to support the latter mechanism [16-25], and it is the generally accepted pathway for generating extramito-chrondial acetyl-CoA. Acetyl-CoA formed by citrate cleavage is utilized for the synthesis of long-chain fatty acids, as illustrated in Fig. 1. 

Gibson, D. M., Titchener, E. B. and Wakil, S. J. (1958) Studies on the mechanism of fatty acid synthesis. V. Bicarbonate requirement for the synthesis of long chain fatty acids. Biochim. Biophys. Acta, 30, 376-383. 

After the basic mechanism of fatty acid oxidation was established, it was generally assumed that fatty acid synthesis would occur by a reversal of the oxidative pathway, except of course for those steps concerned with the transfer of electrons to molecular oxygen. This assumption was readily verified in the case of C. kluyveri where the synthesis of butyrate occurs by reversal of those steps shown in Fig. 1. However, subsequent studies in the laboratories of Wakil, Lynen, Brady and Vagelos demonstrated that the synthesis of long-chain fatty acids occurs by a different mechanism in which malonyl-CoA rather... 

Table VIII summarizes some of the results obtained with isotopic carbon compounds in the synthesis of long-chain fatty acids. Several examples are given below to indicate the role of 2-carbon fragments in the formation of the fatty acids. (Hydrogen atoms have been omitted in order to focus attention on the path of the carbon atoms, and intermediate steps have been omitted.)...

Brady and Gurin have observed the synthesis of long-chain fatty acids in a water-soluble system prepared from pigeon liver. The conversion of acetate-C or acetyl-C CoA to fatty acids proceeds aerobically, or anaerobically with only a slight depression in rate. The process is stimulated aerobically by Mg++, DPN+, and cytochrome c. Ca++ and F are inhibitory to this system. The synthesis of long-chain fatty adds from acetylrC CoA provides unequivocal evidence for the existence of a common intermediate among fatty adds, acetoacetate, and citrate, as shown in Fig. 2. 

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