Fatty acid-synthetase complex

Biosynthesis of coen2yme A (CoA) ia mammalian cells incorporates pantothenic acid. Coen2yme A, an acyl group carrier, is a cofactor for various en2ymatic reactions and serves as either a hydrogen donor or an acceptor. Pantothenic acid is also a stmctural component of acyl carrier protein (AGP). AGP is an essential component of the fatty acid synthetase complex, and is therefore requited for fatty acid synthesis. Free pantothenic acid is isolated from hver, and is a pale yeUow, viscous, and hygroscopic oil. 

The synthesis of fatty acids for incorporation into milk fat within the mammary gland is similar to that seen in other tissues. There are two basic reactions the conversion of acetyl-coenzyme A (CoA) to malonyl-CoA, followed by incorporation of the latter into a growing acyl chain via the action of the fatty acid-synthetase complex. However, the product of these reactions in lactating mammary tissue from many species is short and medium chain fatty acids. In most other tissues the product is palmitate. For more complete details see Moore and Christie, (1978), Bauman and Davis (1974), and Patton and Jensen (1976). 

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

Grunnet, I. and Knudsen, J. 1978. Medium chain acyl-thioester hydrolase activity in goat and rabbit mammary fatty acid synthetase complexes. Biochem. Biophys. Res. Commun. 80, 745-749. 

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 pathway from acetate to palmitic acid (actually a palmitic acid-acyl carrier protein complex) involves at least nine enzymes acetyl CoA synthetase, acetyl CoA carboxylase, and the seven enzyme fatty acid synthetase complex. We chose first to test the effect of these compounds on acetyl CoA carboxylase (ACCase) activity. There were several reasons to select ACCase as the... 

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. 

If the Fatty Acid Synthetase Complex only makes palmitate where do the rest of the fatty acids come from Of course palmitate can be shortened by P-oxidation. For longer fatty acids there is a fatty acid elongation system localized on the ER. The same reactions occur as in the S)mthetase, but now have individual enzymes. Palmitate is first activated to palmitoyl-CoA. The enzymes prefer C-16 or less as... 

Using the malonyl CoA, palmitate is then synthesized by seven cycles of the fatty acid synthetase complex, whose stoichiometry is summarized below ... 

Fatty acid synthetase Complex of enzymes that catalyzes the biosynthesis of fatty acids from acetate. 

The biogenesis of n-alkanes in plants presents two points of considerable and novel interest firstly, chain construction. Alkyl chains are built up in plants, animals and microorganisms by sequential condensation of C2 units of acetate to yield fatty acid and related polyketides, but the fatty acid synthetase complexes involved rarely, if at all, catalyse chain elongation beyond compounds thus typically stearic acid CH3(CH2)i6COOH is the end product although palmitic acid (C ) is usually the... 

Biochemical function in human metabolism. Activation of metabolites by coenzyme A while a thioester as a high-energy compound is generated. Examples acetyl CoA, succinyl-CoA, acyl-CoA-derivates. The acyl-carrier protein is a component of the fatty acid-synthetase complex. Both coenzymes transfer acyl groups. 

The phosphopantetheine prosthetic group of ACP, fatty acid synthetase complexes, and presumably other enzyme systems, turn over rapidly, possibly as part of a cellular control mechanism. A specific phosphodiesterase cleaves holo-ACP to 4 -phosphopantetheine and the apoprotein ... 

The molecular mechanism of fatty acid synthesis can best be understood if the anabolism of fatty acid is first examined in bacteria. The fatty acid synthetase complex of bacteria presents two major advantages it is readily solubilized, and it can be resolved into separate protein components. Three major stages of fatty acid synthesis can be described. First, acetyl-CoA reacts with an SH protein to yield bound acetyl derivatives and free CoA. This reaction is catalyzed by a fatty acid transacylase. Second, the acetyl 5 -protein... 

Elovson, J. (1975) Purification and properties of the fatty acid synthetase complex from Neurospora crassa. and the nature of the fM- mutation. J. Bacteriology 124 524-533... 

Acetyl-CoA produced from citrate is the primer for fatty acid biosynthesis via acetyl-CoA carboxylase (to give malonyl-CoA) and the fatty acid synthetase complex. However, for fatty acid biosynthesis to occur, reducing equivalents in the form of NADPH are also required. These are produced in whole or in part by the subsequent metabolism of oxaloacetate also arising from citrate cleavage (see reaction (9.4)). 

Fatty acid biosynthesis utilizes acetyl CoA. Radioactive acetate is the common experimental substitute, but in the developing seed sucrose from the mother plant is the initial source of substrate. Biosynthesis is a multi-step process (Fig. 3.14) which firstly involves the formation of malonyl CoA by carboxylation of acetyl CoA with carbon dioxide. This malonyl CoA is then accepted by acyl carrier protein (ACP) which is part of a multienzyme complex called the ACP fatty acid synthetase complex. The malonyl CoA is then condensed with... 

A very active fatty acid synthetase complex, an expression for which are the investigated parameters listed above. 

Two antibiotics inhibit enzymes of the fatty-acid synthetase-complex cerulenin and thiolactomycin. 

The two ketoacyl-synthetases present in the fatty-acid synthetase complexes of higher plants exhibit differential sensitivities against cerulenin. In plants the B-ketoacyl-synthetase I (de novo fatty acid synthesis) is affected by cerulenin, whereas the B-ketoacylsynthetase II, which catalyzes the elongation from 16 0 to 18 0 is relatively insensitive (Jaworski et al. 1974). The B-ketoacylsynthetase of Cephalosporium caerulens, which produces cerulenin, is much less sensitive than the yeast enzyme (Kawaguchi et al. 1979) and in Escherichia coli two sensitive and one insensitive synthetase were described (Jackowski and Rock 1987). 

The cyclohexane-1,3-dione and aryloxyphenoxypropionic acid-type herbicides are used as selective grass herbicides in several economical important crop cultures. They are known to block de novo fatty acid synthesis in the chloroplasts of sensitive grasses (Poaceae). These herbicides have been suggested to be inhibitors of an enzyme of the fatty acid synthetase complex, because they block the incorporation of labelled malonic acid into the fatty acid fraction. The aim of this work was to identify the single target enzyme of this herbicides. 

The incorporation of [2- C]-pyruvate into the total fatty acid fraction of isolated oat chloroplasts and etioplasts was inhibited by AMPI in a dose-dependent manner and increased during preincubation of plastids with the inhibitor (Figure 2). For isolated oat etioplasts the IsQ-values were 10 pM without and 4.5 pM after a 15 min preincubation time of plastids with the inhibitor. For oat chloroplasts. where only a very low pPDHC activity remains, the IgQ-values were much higher 130 pM without and 80 pM after a 15 min preincubation with AMPI. The 150-value for isolated etioplasts is similar to that determined for mitochondrial PDHC of pea (10 pM after 10 min preincubation) [8]. The results indicate that both mPDHC and pPDHC are inhibeted by AMPI. In contrast, the Incorporation of [ C]-acetate was not inhibited by,AMPI, demonstrating that the other enzymes of fatty acid biosynthesis ACS, ACCase (acetyl-CoA carboxylase) and FAS (fatty acid synthetase complex) were not affected by this inhibitor. 

Kater MM, Koningstein GM, Nijkamp HJJ and Stuitje AR. The use of a Hybrid Genetic System to Study the Functional Relationship between Prokaryotic and Plant Multi-Enzyme Fatty Acid Synthetase Complexes. Plant Mol Biol 1994 in press. 

The questions of when and how much the actual level of acetyl-CoA carboxylase present in a tissue regulates the rate of fetty acid synthesis in that tissue has only recently been satisfectorily answered. It had been observed by Allmann et al. (1965) that the stimulation of fatty acid synthesis that occurs upon refeeding fasted animals is prevented by puromycin and actinomycin injection at the time of refeeding. The latter agents prevented new protein (i.e., enzyme) synthesis. Later, Butterworth et al. (1966) reported that the quantity of purified enzyme protein (fatty acid synthetase complex) was reduced in the livers of fasted pigeons and returned to near control levels following refeeding. 

Qureshi, A. A., Lomitzo, F. A., and Porter, J. W., 1974, The isolation of acyl carrier protein from the pigeon liver fatty acid synthetase complex II, Biochem. Biophys. Res. Commun. 60 158. 

Attention has been directed also at fatty acid synthetase as a control site for the regulation of fatty acid synthesis. This multienzyme complex mediates the synthesis of saturated fatty acids from malonyl-CoA in a reaction requiring acetyl-CoA and NADPH. Details of the enzyme complex and reaction sequence have been reviewed recently (Volpe and Vagelos, 1976 Katiyar and Porter, 1977 Block and Vance, 1977). All available data suggest that while modulation of acetyl-CoA carboxylase activity represents the essential site of short-term control of fatty acid synthesis, long-term control of fatty acid synthesis may rest with the rate of de novo synthesis of the fatty acid synthetase complex. 

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. 

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