Cytosol fatty acid synthetase

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. 

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

The fatty acid-synthetase complex is located in the cytosol of the... 

Gu P., Welch W. H., Guo L., Schegg K. M. and Blomquist G. J. (1997) Characterization of a novel microsomal fatty acid synthetase (FAS) compared to a cytosolic FAS in the housefly, Musca domestica. Comparative Biochem. Physiol. 118B, 447-456. 

Keon, B.H., Ghosal, D., Keenan, T.W. 1993. Association of cytosolic lipids with fatty acid synthetase from lactating mammary gland, bit. J. Biochem. 25, 533-543. 

Although fatty acid 8-oxidation is catalyzed by a series of intramitochon-drial enzymes, and the fatty acyl chain is carried by CoA, fatty acid synthesis is catalyzed by a cytosolic-multienzyme complex in which the growing fatty acyl chain is bound by thioester linkage to an enzyme-bound 4 -phosphopantetheine residue. This component of the fatty acid synthetase complex is ACP. 

The answer is d. (Murray, pp 230-267. Scriver, pp 2297-2326. Sack, pp 121-138. Wihon, pp 287-320.) In humans, the end product of fatty acid synthesis in the cytosol is palmitic acid. The specilicity of cytosolic multienzyme, single-protein fatty acid synthetase is such that once the C16 chain length is reached, a thioesterase clips off the fatty acid. Elongation as well as desaturation of de novo palmitate and fatty acids obtained from the diet occur by the action of enzymes in the membranes of the endoplasmic reticulum. 

In prokaryotic cells fatty acid synthesis occurs in the cytosolic compartment. However, it has been observed that ACP in E. coli appears to be somewhat loosely associated with the inner face of the plasma membrane of the cell (van den Bosch et al., 1970). Nevertheless, all the activities associated with the synthesis of palmitic acid from acetyl-CoA can be readily separated and assigned to individual proteins which have been purified and their molecular and kinetic characteristics examined in considerable detail (Vagelos, 1974). In yeast and animal cells, the fatty acid synthetase responsible for the formation of palmitic acid is always associated with the cytosolic compartment as a dimer of a polyfunctional polypeptide (ibid.). 

Howard (1968b) studied fatty acid synthetic systems in cell-free preparations from squirrel monkey aortas, and the data were similar to those for the rabbit aorta with regard to the mitochondrial system. Acetate or acetyl-CoA was a more efficient precursor than malonyl-CoA, and the Schmidt degradation data indicated that it was primarily an elongation system. The cytosol or HSS was examined, and malonyl-CoA was found to be incorporated into fatty acids 55-200 times more actively than acetyl-CoA, a finding that had been noted previously in liver HSS by Abraham et al. (1962a). Majerus and Lastra (1967) noted that malonyl-CoA was incorporated into fatty acids six or seven times as fast as acetyl-CoA by human leukocytes. The latter authors were unable to find any acetyl-CoA carboxylase activity in leukocytes and reasoned that these cells possess only the fatty acid synthetase. As they pointed out, in the absence of any acetyl-CoA carboxylase, the synthetase alone uses 1 mole of acetyl-CoA plus 7 moles of malonyl-CoA to make 1 mole of palmitate (Wakil... 

The very slow incorporation of acetyl-CoA by the cytosol pathway raises doubts about the activity and amount of acetyl-CoA carboxylase (ACC) present in aorta. Fatty acid synthetase (FAS) is abundant... 

Fig. 1. The above pathways for fatty acid synthesis have been demonstrated to be present in the aorta. The thickness of the arrows denotes the author s interpretation of the relative contribution to total synthesis made by the three intracellular sites. The mitochondrial pathway has the largest capacity to utilize acetate for the elongation of available acyl units. The latter are derived from plasma free fatty acid (FFA) and lipolysis of tissue triglyceride (TG). The cytosol has a limited capacity to synthesize fatty acids from acetate because of minimal acetyl-CoA carboxylase (ACC) activity. The significance of fatty acid synthetase (FAS) activity is dubious in the absence of a source of malonyl-CoA. A microsomal elongation-desaturation pathway can synthesize a spectrum of saturated (SAT) and unsaturated (UNSAT) long-chain fatty acids, similar to the products of the mitochondrial system.

X0, 4-0X0, and 5-oxo esters [78]. The S enzyme had a molecular weight of 48,000 and reduced 3-oxo esters, 4-oxo, and 5-oxo acids and esters enantioselectively to -hydroxy compounds in the presence of NADPH. This enzyme may be located in the mitochondrial fraction. The R enzyme, which had a molecular weight of 800,000 and contained subunits having molecular weights of 200,000 and 210,000, specifically reduced 3-oxo esters to R-hydroxy esters, using NADPH as coenzyme. The R enzyme, which occurs in the cytosol, was considered to be identical with a subunit of file fatty acid synthetase complex. 

Short-chain acyl-CoA synthetase activates short-chain fatty acids, acetic, butyric and propionic acid. The enzyme is present in both the cytosol and in the mitochondrial matrix of most tissues the activity is especially high in the liver and the colon. 

After a LCFA enters a cell, it is converted to the CoA derivative by long-chain fatty acyl CoA synthetase (thiokinase) in the cytosol (see p. 174). Because 0-oxidation occurs in the mitochondrial matrix, the fatty acid must be transported across the mitochon drial inner membrane. Therefore, a specialized carrier transports the long-chain acyl group from the cytosol into the mitochondrial matrix. This carrier is carnitine, and the transport process is called the carnitine shuttle (Figure 16.16). 

Answer The transport of fatty acid molecules into mitochondria requires a shuttle system involving a fatty acyl-carnitine intermediate. Fatty acids are first converted to fatty acyl-CoA molecules in the cytosol (by the action of acyl-CoA synthetases) then, at the outer mitochondrial membrane, the fatty acyl group is transferred to carnitine (by the action of carnitine acyl-transferase I). After transport of fatty acyl-carnitine through the inner membrane, the fatty acyl group is transferred to mitochondrial CoA. The cytosolic and mitochondrial pools of CoA are thus kept separate, and no labeled CoA from the cytosolic pool enters the mitochondrion. 

Cytosol Glycolysis, glycogenesis and glycogenolysis, hexose monophosphate pathway, fatty acid synthesis, purine and pyrimidine catabolism, aminoacyl-tRNA synthetases... 

The synthesis of triacylglycerol takes place in the endoplasmic reticulum (ER). In liver and adipose tissue, fatty adds in the cytosol obtained from the diet or from de novo synthesis of palmitic add become inserted into the ER membrane. The reactions are shown in Fig. 13-10. Membrane-bound acyl-CoA synthetase activates two fatty acids, and membrane-bound acyl-CoA transferase esterifies them with glycerol 3-phosphate, to form phosphatidic acid. Phosphatidic acid phosphatase releases phosphate, and in the membrane, 1,2-diacylglycerol is esterified with a third molecule of fatty acid. 

Long chain fatty acids are are bound to Fatty acid binding protein for transport within the cytosol. They are impermeable to the inner mitochondrial membrane. They are thus esterified in the cytosol by microsomal Fatty acyl CoA synthetase in a reaction identical to the one shown above. Again the reaction is driven by the hydrolysis of pyrophosphate. The enzyme involves an acyl AMP intermediate ... 

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