Cytosol fatty acids

The acetyl-CoA derived from amino acid degradation is normally insufficient for fatty acid biosynthesis, and the acetyl-CoA produced by pyruvate dehydrogenase and by fatty acid oxidation cannot cross the mitochondrial membrane to participate directly in fatty acid synthesis. Instead, acetyl-CoA is linked with oxaloacetate to form citrate, which is transported from the mitochondrial matrix to the cytosol (Figure 25.1). Here it can be converted back into acetyl-CoA and oxaloacetate by ATP-citrate lyase. In this manner, mitochondrial acetyl-CoA becomes the substrate for cytosolic fatty acid synthesis. (Oxaloacetate returns to the mitochondria in the form of either pyruvate or malate, which is then reconverted to acetyl-CoA and oxaloacetate, respectively.)... 

Scott, J.C., Kennedy, M.W. and McManus, D.P. (2000) Molecular and immunological characterisation of a polymorphic cytosolic fatty acid binding protein from the human blood fluke Schistosoma japonicum. Biochimica et Biophysica Acta 1517, 53-62. 

The rate limiting step in fatty acid synthesis is catalyzed by acetyl-CoA carboxylase to produce malonyl-CoA at the expense of one ATP.31 Malonate and acetate are transferred from CoA to acyl carrier protein in the cytosolic fatty acid synthetase complex, where chain extension leads to the production of palmitate. Palmitate can then be transferred back to CoA, and the chain can be extended two carbons at a time through the action of a fatty acid elongase system located in the endoplasmic reticulum. The >-hydroxylation that produces the >-hydroxyacids of the acylceramides is thought to be mediated by a cytochrome p450 just when the fatty acid is long enough to span the endoplasmic reticular membrane. 

Fatty acids are predominantly formed in the liver and adipose tissne, as well as the mammary glands during lactation. Fatty acid synthesis occurs in the cytosol (fatty acid oxidation occurs in the mitochondria compartmentalisation of the two pathways allows for distinct regulation of each). Oxidation or synthesis of fats utilises an activated two-carbon intermediate, acetyl-CoA, but the acetyl-CoA in fat synthesis exists temporarily bound to the enzyme complex as malonyl-CoA. Acetyl-CoA is mostly produced from pyruvate (pyruvate dehydrogenase) in the mitochondria it is condensed with oxaloacetate to form citrate, which is then transported into the cytosol and broken down to yield acetyl-CoA and oxaloacetate (ATP citrate lyase). 

This transport is accomplished by carnitine (L-jS-hydroxy-y-trimethylammonium butyrate), which is required in catalytic amounts for the oxidation of fatty acids (Figure 18-1). Carnitine also participates in the transport of acetyl-CoA for cytosolic fatty acid synthesis. Two carnitine acyl-transferases are involved in acyl-CoA transport carnitine palmitoyltransferase I (CPTI), located on the outer surface of the inner mitochondrial membrane, and carnitine palmitoyltransferase II (CPTII), located on the inner surface. 

The end product of cytosol fatty acid synthetase in humans is... 

Several additional reactions are required for the elongation of fatty-acid chains and the introduction of double bonds. When mammals produce fatty acids with longer chains than that of pahnitate, the reaction does not involve cytosolic fatty-acid synthase. There are two sites for the chain-lengthening reactions the endoplasmic reticulum (ER) and the mitochondrion. In the chain-lengthening reactions in the mitochondrion, the intermediates are of the acyl-GoA type rather than the acyl-AGP type. In other words, the chainlengthening reactions in the mitochondrion are the reverse of the catabolic reactions of fatty acids, with acetyl-GoA as the source of added carbon atoms this is a difference between the main pathway of fatty-acid biosynthesis and these modification reactions. In the ER, the source of additional carbon atoms... 

A9, 18 2A9,12 and 18 3A9,12,15. Several mutants in the fatty acid biosynthetic pathway exist. One such mutant is cd, which requires fatty acid supplementation for growth. 100 LIM 16 0 is sufficient to restore wild-type growth rates [1]. The defect in cel is in the cytosolic fatty acid synthase. The enzyme complex has only 2% of the wild-type level of phosphopantetheine [2]. The cd mutant was used to show that some fatty acids are synthesized in mitochondria [3]. 

The high level of polyunsaturates in may result from its increased ability to convert exogenous 16 0 to unsaturates, compared to wild type. When grown from the time of inoculation in the presence of [2H]16 0, on average more than 70% of its fatty acids are derived from the supplement. The remaining fatty acids are presumably synthesized by a combination of residual activity of cytosolic fatty acid synthase, and mitochondrial fatty acid synthase. 

The end-product of cytosolic fatty acid synthesis is palmitate (C16 0) longer-chain fatty acids (up to C24) and unsaturated fatty acids are synthesized from palmitate in the endoplasmic reticulum and mitochondria. 

A glance at current knowledge of regulation of lipogenesis will be useful to point out problems that need to be examined in vascular tissue. Regulation of the cytosol fatty acid synthetic machinery has been excellently reviewed in Advances in Lipid Research in 1967 by Majerus and Vagelos, and other fine reviews too numerous to cite are available. The following discussion is not intended, therefore, as an exhaustive review. 

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