Fatty acids synthetase system

L Kuhn, H Castorph, E Schweizer. Gene linkage and gene-enzyme relations in the fatty-acid-synthetase system of Saccharomyces cerevisiae. Eur J Biochem 24 492-497, 1972. 

Thus, the lipid biosynthetic enzyme system evolved in extreme halophiles to utilize the (halophilic) mevalonate pathway for synthesis of virtually all of its hydrocarbon (isoprenoid/isopranoid) chains, rather than the (non-halophilic) fatty-acid synthetase system which was retained only for synthesis of normal fatty acid chains required for incorporation into proteins of the red membrane (Pugh and Kates, unpublished data). Starting from acetate and involving lysine, which provides the branch-methyl and methine carbons [88]), the mevalonate pathway proceeds to geranylgeranyl-PP (GG-PP) [13,15,89] as follows ... 

It is assumed that the coenzyme A ester (CoA-ester) of the R(-)-enantiomer acts as a substrate for the fatty acid deshydrogenase, thus eliminating the chiral center. The next step may, or may not, take place, depending whether or not the CoA-ester must be transferred to an acyl-carrier protein or another site in the fatty acid synthetase system, so that a stereoselective reduction by an enoykeductase can take place. Thus the nature of X is unknown. Similar epimerization reactions were also described for some other arylpropionic acids such as benoxaprofen, carprofen, and isopropyl-indanyl-propionic acid. ° It was demonstrated that the configural inversion does not take place in the liver, and that the responsible enzyme, R-(-)-aryIpro-... 

Fatty acid synthesis occurs by way of a rather complex series of reactions catalyzed by a multienzyme complex called the fatty acid synthetase system. This system is made up of six enzymes and an additional protein, acyl carrier protein (ACP), to which all intermediates are attached. 

A separate fatty acid synthetase system for Cig and Cig fatty acids as well as for the shorter-chain fatty acids. 

I. Caughey and R. G. O. Kekwick, Characteristics of some components of the fatty acid synthetase system of plastids from the mesocarp of avocado (Persea americana) fruit, Eur. 3. Biochem. 123 553 (1982). 

Several interesting features of the plant fatty acid synthetase systems can be highlighted. Firstly, several species of ACP have been found in different plants e.g. which may carry out different... 

R. Lessire and P.K. Stumpf, Nature of the fatty acid synthetase systems in parenchymal and epidermal cells of Allium porrum L. leaves. Plant Physiol. 73 614 (1983). 

Caughey, L. and Kekwlck, R.G.O. 1982. The characteristics of some components of fatty acid synthetase system in the plastlds from the meso-carp of avocado (Persea Americana) fruit. Eur.J.Biochem., 123 553-561. 

Knudsen and Grunnet (1982) have proposed an interesting system for the control of medium-chain fatty acid synthesis by ruminant mammary tissue. Their proposal is based on their observations that ruminant mammary tissue fatty acid-synthetase exhibits both medium-chain thioesterase (Grunnet and Knudsen 1978) and transacylase (Knudsen and Grunnet 1980) activity and that medium-chain fatty acids synthesized de novo can be incorporated into TG without an intermediate activation step (Grunnet and Knudsen 1981). They proposed that the synthesis of the medium-chain fatty acids is controlled by their incorporation into TG (Grunnet and Knudsen 1981). Further work will be needed to substantiate transacylation as a chain-termination mechanism in fatty acid synthesis by ruminant mammary tissue. 

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 ER elongation system works similarly to the fatty acid synthetase sequence, except that individual enzymes (gene products) are involved palmitoyl-CoA reacts with malonyl-CoA to give C02 and /3-ketooctadecanoyl-CoA. The... 

Fatty acid transport protein 1 (FATPl) and long chain acyl-CoA synthetase 1 (ASCLl) were identified as components of a fatty acid transport system in expression cloning experiments, which specifically targeted cellular fatty acid uptake (15). As both FATP and ACSLl were selected in these experiments, it was suggested that fatty acid transport occurred by a coupled transport-activation (15). This mechanism was first shown to occur in gram-negative bacteria and is referred to as vectorial acylation (3). Six different isoforms of FATP have subsequently been identified experimentally in mice, rats, and humans (e.g., in mice, mmFATPl-6). 

The observation that the fatty acid synthetase (FAS) in H. cutirubrum is strongly inhibited by high salt concentration while the mevalonate enzyme system for isoprenoid biosynthesis has an absolute requirement for high salt concentration (see section 4.1) may offer a clue to the mechanism of evolution of extreme halophiles from non-halophilic, or moderately halophilic precursors, and possibly also for the evolution of the methanogens and extreme thermophiles. The following hypothetical scenarios are offered for discussion (see ref [107] and Figs. 9, 14) ... 

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... 

Sohby, C. (1979). Regulation of fatty acid synthetase activity.. Biol. Chem. 254,8561-8566. TahiRani, A. G, and Neely,). R. (1987). A transport system for coenzyme A in isolated heart mitochondria. /. Biot. Otm. 262, 11607-11610,... 

Figure 11.2 A comparative picture of the fatty acid synthetase (FAS) systems in yeast, animal, bacterial and plant cells. fi-KS, -ketoacyl AGP synthetase P-KR, A-ketoacyl AGP reductase DH, -OH acyl-AGP dehydrase ER, enoyl AGP reductase AT, acetyl transacylase MT, malonyl transacylase TE, thioesterase AGP, acyl carrier protein. See Shimakata and Stumpf (19S2a,b) and Wakil etal, (1983) for details.

The end product of the Type II fatty acid synthetase of plants is palmitoyl-ACP (Stumpf, 1980) which then serves as the substrate for the elongation system (palmitate elongase). Palmitate elongase has been studied in a number of soluble and membrane-bound subcellular fractions from plants (cf. Harwood, 1979). The enzyme is sensitive to arsenite in contrast to the Type II synthetase which is inhibited by cerulenin. These selective inhibitions seem to be related to the properties of the )8-ketoacyl-ACP synthetase. Two of these enzymes have been purified from spinach leaves (Shimakata and Stumpf, 19826). One will condense a broad range of primer units (up to C14) and is sensitive to cerulenin whereas the second is specific for palmitoyl-ACP and is inhibited by arsenite. The latter enzyme can, therefore, be regarded as a key part of the Type III synthetase, palmitate elongase. 

Fatty acids in plants are synthesized by a series of reactions similar to those for fatty acid biosynthesis in animals, yeasts, bacteria, and other organisms. The synthetases of prokaryotic cytoplasmic systems are freely soluble and readily separable as discrete proteins those in mammalian systems are localized in the cytoplasm as large soluble synthetase complexes. The exact nature of association of the enzymes in plants is unknown (Ohlrogge et al., 1993). The reactions of plant fatty acid biosynthesis are catalyzed by individual polypeptides (Somerville and Browse, 1991) once organelles are disrupted, the enzymes also are soluble and may be isolated (Somerville and Browse, 1991 Stumpf, 1976). In contrast to mammalian systems, plant fatty acid synthetases are plastid localized. 

Few areas of natural products chemistry have seen as many major advances in the study of biosynthetic pathways as have occurred in polyketide compounds. Birch and Donovan (1953) demonstrated that a wide range of structural types are derived from acetate (later shown to be acetate and malonate). In experiments witfi deuterated precursors, acetate serves preferentially as a starter unit for the formation of 6-methylsalicylic acid in Penicillium griseofulvum (Simpson, 1983). Thus, polyketides are derived from the same precursors as fatty acids and the initial step seems to be similar (Fig. 5.1). Extensive purifrcation of 6-methylsalicylate synthetase from Penicillium patulum has been performed. This enzyme system is distinct and separable from the co-occurring fatty acid synthetase and has a molecular weight approximately half that of the former enzyme. NADPH is required as a coenzyme for methylsalicylate synthetase from this source (O Hagan, 1990 Packter, 1980). 

With spinach chloroplast stroma as the source of the fatty acid synthetase assay system. 

There was no evidence for a shorter-chain fatty acid synthetase in the coconut system. The products of the de novo synthesis by this system were essentially Ci and Cig fatty acids, as well as medium-chain fatty acids. 

A further close link between cis-dehydratase activity and aromatic and fatty acid synthetases became apparent when it was observed that chloro-plasts, isolated from etiolated barley leaves that had been partially greened, formed 6-methylsalicylate at the expense of fatty acids (Kannangara et al., 1971). The requirement for NADPH would be met in this system from endogenous sources. Mature chloroplasts and etioplasts do not possess this capacity for phenol production and presumably lack the ability to make the synthetase responsible. 

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 ... 

With the resolution of the hepatic fatty acid synthetic system from the soluble cell fraction into two components [1-5] and their subsequent indentification as acetyl-CoA carboxylase [6,7] and fatty acid synthetase [7-9], the nature of the cytoplasmic conversion of acetyl-CoA into... 

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