Fatty acid very long chain

Fatty acid transport proteins (FATPs) are an evolutionary conserved family of integral membrane proteins found at the plasma membrane and on internal membranes. FATPs facilitate the unidirectional uptake and/ or intracellular activation of unesterified long-chain and very long-chain fatty acids (LCFAs) into a variety of lipid-metabolizing cells and tissues. 

In vitro and ex vivo studies have shown that FATPs transport LCFAs and very long-chain fatty acids (VLCFAs) but no medium-chain fatty acids, fatty acid esters, or lipid-soluble vitamins [4]. LCFA transport is inhibited by prior protease treatment. Synthetic substrates for FATPs include 14C-labeled fatty acids and the fluorescently labeled fatty acid analogue C1 -BODEP Y-Cl 2. Using the latter substrate, differences in fatty acid uptake kinetics between FATP expressing 3T3 LI adipocytes and 3T3 LI fibroblasts, which are devoid of FATPs, can be readily appreciated (Fig. 2). 

Long-chain fatty acids (LCFAs) are aliphatic compounds with a terminal carboxyl group and with a chain length greater than 12 carbon atoms (e.g., lauric acid). Very long-chain fatty acids are fatty acids with more than 18 carbon atoms (e.g., stearic acid). 

Peroxisomes Oxidize Very Long Chain Fatty Acids... 

A modified form of P-oxidation is found in peroxisomes and leads to the formation of acetyl-CoA and H2O2 (from the flavoprotein-linked dehydrogenase step), which is broken down by catalase. Thus, this dehydrogenation in peroxisomes is not linked directly to phosphorylation and the generation of ATP. The system facilitates the oxidation of very long chain fatty acids (eg, Cjq, C22). These enzymes are induced by... 

Interest in import of proteins into peroxisomes has been stimulated by studies on Zellweger syndrome. This condition is apparent at birth and is characterized by profound neurologic impairment, victims often dying within a year. The number of peroxisomes can vary from being almost normal to being virtually absent in some patients. Biochemical findings include an accumulation of very long chain fatty acids, abnormalities of... 

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. 

Adrenoleukodystrophy is an X-linked dysmyelinative disorder caused by mutations in the ABCD1 gene, which encodes the peroxisomal integral membrane ALD protein, a member of the ATP binding cassette transporter family. These mutations result in impaired clearance of plasma very-long-chain fatty acids. Affected males may present with symmetrical distal axonal polyneuropathy, adrenocortical insufficiency or CNS demyelination, while occasional heterozygous women demonstrate deficits suggestive of multiple sclerosis [56]. Manipulation of dietary fatty acid intake has some minimal therapeutic effect, while bone marrow transplantation has diminished deficits in a few patients. (See in Ch. 41.)... 

Adrenoleukodystrophy X-linked Peroxisomal membrane protein in the ABC transporter family Decreased peroxidation of saturated, very-long-chain fatty acids, causing their accumulation in brain, adrenals and other tissues variable phenotypes with regard to hypomyelination see text 1,26, Ch. 40... 

Alkyl PAT, alkyl-dihydroxy phosphate synthase Bif, bifunctional enzyme DHAPAT, dihydroxyphosphate acyltransferase deficiency DHCA, dihydroxycholestanoic acid N, normal nd, not determined Ox, acyl-CoA oxidase Rac, 2-methylacyl-CoA racemase RCDP, rhizomelic chondrodysplasia punctata Ref, Refsum s disease THCA, trihydroxycholestanoic acid VLCFA, very-long-chain fatty acid. 

A separate very long-chain-acyl-CoA synthetase is present in peroxisomes for the activation of very long-chain fatty acids, such as arachidonate (20 carbon atoms). These fatty acids are degraded exclusively in the peroxisomes. 

Peroxisomes are organelles which are bounded by a single membrane. They are present in the Uver where very long-chain fatty acids are oxidised by P-oxidation in peroxisomes, which is different from mitochondrial oxidation. 

The capacity of P-oxidation in about 10% of that in the mitochondria but it plays an important role in oxidising unusual fatty acids for example, very long-chain fatty acids, polyunsaturated fatty acids, dicarbox-ylic fatty acids. 

F. Oxidation of very long-chain fatty acids (VLCFAs), ie, fatty acids having >22 carbons, requires special enzymes located in the peroxisome. 

Gamez, R., I. Rodeiro, I. Fernandez, and P.C. Acosta. Preliminary evaluation of the cytotoxic and genotoxic potential of D-003 mixture of very long chain fatty acids. Teratog Car-cinog Mutagen 2002 22(3) 175-181. Menendez, R., R. Mas, A. M. Amor, et al. Inhibition of rat lipoprotein lipid... 

The conversion of fatty acids into very long chain fatty acids is specifically inhibited by the thiocarbamate herbicides such as EPTC and triallate (Figure 2.19). These compounds are used pre-plant incorporated for the control of grass and some small seeded broad-leaved weeds in crops such as maize and small grain cereals. 

VLCFA very-long-chain fatty acids... 

In contrast to the general peroxisome biogenesis defects, patients with X-linked adrenoleucodystrophy, whose very-long-chain fatty acid oxidation is impaired as a result of an uptake defect, show minimal abnormalities of their DHA levels. 

Table 3.4.1 Levels of very-long-chain fatty acids (VLCFA), pristanic acid and phytanic acid in the different peroxisomal disorders. AMACR 2-methyl acyl-CoA racemase, N normal, RCDP rhizomelic chondrodysplasia punctata, SCP-x sterol carrier protein, ZSDs Zellweger spectrum disorders,...

Kemp S, Valianpour F, Denis S, Ofman R, Sanders RJ, Mooyer P, Barth PG, Wanders RJ (2005) Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy. Mol Genet Metab 84 144-151... 

Moser AB, Kreiter N, Bezman L, Lu S, Raymond G V, Naidu S, Moser HW (1999) Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 45 100-110... 

Stellaard F, ten Brink HJ, Kok RM, van den Heuvel L, Jakobs C (1990) Stable isotope dilution analysis of very long chain fatty acids in plasma, urine and amniotic fluid by electron capture negative ion mass fragmentography. Clin Chim Acta 192 33-144... 

Valianpour F, Selhorst JJ, van Lint LE, Van Gennip AH, Wanders RJA, Kemp S (2003) Analysis of very long-chain fatty acids using electrospray ionization mass spectrometry. Mol Genet Metab 79 189-196... 

Vreken P, Van Lint AEM, Bootsma AH, Overmars H, Wanders RJA, Van Gennip AH (1998) Rapid stable isotope dilution analysis of very-long-chain fatty acids, pristanic acid and phytanic acid using gas chromatography-electron impact mass spectrometry. J Chromatogr 713 281-287... 

A second important difference between mitochondrial and peroxisomal fi oxidation in mammals is in the specificity for fatty acyl-CoAs the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26 0) and on branched-chain fatty acids such as phytanic acid and pristanic acid (see Fig. 17-17). These less-common fatty acids are obtained in the diet from dairy products, the fat of ruminant animals, meat, and fish. Their catabolism in the peroxisome involves several auxiliary enzymes unique to this organelle. The inability to oxidize these compounds is responsible for several serious human diseases. Individuals with Zellweger syndrome are unable to make peroxisomes and therefore lack all the metabolism unique to that organelle. In X-linked adrenoleukodystrophy (XALD), peroxisomes fail to... 

Although palmitate, a 16-carbon, fully saturated LCFA (16 0), is to primary end-product of fatty acid synthase activity, it can be further I elongated by the addition of two-carbon units in the endoplasmic] reticulum (ER) and the mitochondria. These organelles use separate enzymic processes. The brain has additional elongation capabilities, allowing it to produce the very-long-chain fatty acids (up to 24 car bons) that are required for synthesis of brain lipids. 

In mitochondria, there are four fatty acyl CoA dehydrogenase species, each of which has a specificity for either short-, mediurr-long-, or very-long-chain fatty acids. MCAD deficiency, an autos mal, recessive disorder, is one of the most common inborn errors of metabolism, and the most common inborn error of fatty add oxidation, being found in 1 in 12,000 births in the west, and 1 in 40,000 worldwide. It causes a decrease in fatty acid oxidation and severe hypoglycemia (because the tissues cannot obtain full ener getic benefit from fatty acids and, therefore, must now rely on glu cose). Treatment includes a carbohydrate-rich diet. [Note Infants are particularly affected by MCAD deficiency, because they rely for their nourishment on milk, which contains primarily MCADs. 

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