Fatty acid biosynthesis, in brain

SATURATED AND MONO-UN SATURATED FATTY ACID BIOSYNTHESIS IN BRAIN RELATION TO DEVELOPMENT IN NORMAL AND DYSMYELINATING MUTANT MICE... 

Methylmalonyl-CoA may participate in fatty acid biosynthesis in place of malonyl-CoA, with the formation of methyl-branched long-chain (C17) fatty acids, and these acids have been isolated from glycerolipids of brain, spinal cord and sciatic nerve of a patient with methylmalonic aciduria and homo-cystinuria (Kishimoto et al., 1973). Odd-carbon-number straight-chain fatty acids (Ci5 and C17), due presumably to the accumulation of propionyl-CoA and the utilization of this substrate in fatty acid biosynthesis (Section 11.1), have also been observed in the central nervous system tissues of this patient (Kishimoto et aL, 1973), and another (the fourth described. Section 11.2.3) also with combined methylmalonic aciduria and homocystinuria (Dayan and Ramsay, 1974). It is relevant that methylmalonic acid may be utilized for the... 

The basic pathways for fatty acid biosynthesis and palmitic acid biosynthesis have already been discussed. But the biosynthesis of fatty acid in brain raises special problems, especially with respect to the biosynthesis of long-chain, even- and odd-numbered saturated or unsaturated fatty acids. 

Fatty Acid Synthesis. In human fatty acids synthesis is highly active in liver, mammary glands and brain. Fatty acid biosynthesis occurs in the cytosol through a series of reactions where acetyl-CoA (synthesized from pyruvate, the end product of glucose metabolism) and Malonyl-CoA are linked to form palmitoyl-CoA. During this elongation process, NADPH supplies electrons to Malonyl-CoA [20, 23]. 

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. 

Burstein and Hunter (1995) observed that THC stimulated the biosynthesis of anandamide in neuroblastoma cells employing either ethanolamine or arachidonic acid as the label. Anandamide bios5mthesis has also been shown to occur in primary cultures of rat brain neurons labelled with [H]-ethanolamine when stimulated with ionomycin, a Ca ionophore (Di Marzo et al. 1994). These authors proposed an alternate model for the biosynthesis of anandamide in which N-arachidonoyl phosphatidyl ethanolamine is cleaved by a phospholipase D activity to yield phosphatidic acid and ararchidonoylethanolamide. This model is based upon extensive studies undertaken by Schmid and collaborators (1990), who have shown that fatty acid ethanolamide formation results from the N-acylation of phosphatidyl ethanolamine by a transacylase to form N-acyl phosphatidylethanolamine. Possibly resulting from postmortem changes, this compound is subsequently hydrolyzed to the fatty acid ethanolamide and the corresponding phosphatide by a phosphodiesterase, phospholipase D. 

Several investigators have described plausible mechanisms for the production of DHA in the CNS. Moore and co-workers described the biosynthesis of DHA and transport of fatty acids through microcapillary cerebral endothelial cells, astrocytes, and neurons (Moore et al., 1991 Moore, 1993). In this model, microcapillary endothelial cells produce DP An-3 from LNA, which is turned over to the astrocytes to be synthesized into DHA. The astrocytes then release DHA, which is taken up by neurons. In contrast, Delton-Vandenbroucke and co-workers found that cerebral vascular cells produced appreciable amounts of labcled-DH A from DP An-3 (Delton-V andenbroucke et al., 1997). They theorize that cerebral endothelial cells will convert circulating DP An-3 into DHA, which is then taken up into the brain. These reports suggest that in the CNS, unlike the liver in which biosynthesis of DHA from LNA takes place entirely within the hepatocyte. 

Fig. 1. A schematic representation of the biosynthesis and accretion of DHA into the CNS of felines. Dietary n-3 fatty acids (LNA) are taken up into the liver and synthesized into DPAn-3 (22 5n-3). DPAn-3 is released from the liver and can ied on lipoproteins in the blood to the nervous system. The synthesis ofDHA is completed in the brain from DPAn-3.

Dhopeshwarkar GA, Subramanian C. Biosynthesis of polyunsaturated fatty acids in the developing brain 1. Metabolic transformations of intracraniaUy administered 1- C linolenic acid. Lipids 1976 11 67-71. 

CiaHJ3Oa mol wl 304.46. C 78.89%. H 10.60%, O 10.51%. An essential fatty acid, q.v, and a precursor m the biosynthesis of prostaglandins, thromboxanes, and leukotrienes, q.q. v. Structure Mo wry et al.. J. Biol. Chem. 142, 679 (1942) Arcus, Smedley-Maclean. Biochem- J. 37, 1 (1943). Occurs in liver, brain, glandular organs, and depot fats of animals, in small amounts in human depot fats, and is a constituent of animal phospha tides. Isolation from Liver lipids Brown, J, Biol. Chem. 80, 455 (1928) from beef... 

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