Acyl chains, elongation

Fig. 3. Cycles of fatty acyl chain elongation. All intermediates in fatty acid synthesis are shuttled through the cytosol as thioesters of the acyl carrier protein (ACP). (1) P-Ketoacyl-ACP reductase (FabG), (2) P-hydroxyacyl-ACP dehyrase (FabA or FabZ), (3) trani-2-enoyl-ACP reductase I (FabI), (4) P-ketoacyl-ACP synthase I or II (FabB or FabF).

An unusual sphingolipid contains a 22-carbon, polyunsaturated fatty acid called du-panodonic acid, or 7,10,13,16,19-docosapentaenoic acid. In mammals, both the mitochondrial and endoplasmic reticular acyl-chain elongation and desaturation systems can synthesize clupanodonate from linolenate. 

Bicarbonate is a source of carbon dioxide for the reaction catalyzed by acetyl CoA carboxylase, in which malonyl CoA is formed. Malonyl CoA is then used as a source of two-carbon units for fatty acyl chain elongation, and the carbon atom derived originally from bicarbonate is released as CO2. Carbon dioxide is then rapidly converted to bicarbonate, which is used again for the synthesis of another molecule of malonyl CoA. Thus, the carbon atom derived from bicarbonate can be used many times for the production of malonyl CoA, but it is never incorporated into the growing acyl chain, so it does not appear in palmitate. 

As a third production pathway, acyl chain elongation has been reported for PHA production during growth of P. putida KT2442 on hexanoic acid (Huijberts et al. 1995). This is a rather unconventional process and may take place only under special growth conditions. 

Figure 7. Enzymatic steps in long-chain fatty acid elongation. Enzymatic steps of microsomal fatty acyl chain elongation. ELOVL, elongation of very-long-chain fatty acids KAR, 3-ketoacyl-CoA reductase HADC, 3-hydroxyacyl-CoA dehydratase TER, /rowi-2,3-enoyl-CoA reductase [108].

Ford, D. A., Han, X., Homer, C. C. and Gross, R. W. (1996) Accumulation of unsaturated acylcamitine molecular species during acute myocardial ischemia metabolic compartmenta-lization of products of fatty acyl chain elongation in the acylcamitine pool. Biochemistry, 35, 7903-9. 

Agrawal, V.P. and Stumpf, P.K. (1985) Characterization and solubilization of an acyl chain elongation system in microsomes of... 

Further desaturation and acyl chain elongation of fatty acids are generally accepted to involve cytosolic membranous systems associated with the endoplasmic reticulum (Stumpf, 1989). A critical importance, therefore, would appear to exist for a detailed understanding of the mechanics by which the fatty acids are exported from the plastid. At present, there is little available information on the precise transport system or its regulation. Although fatty acids are presumed to be released on hydrolysis of acyl-ACPs by specific thioesterases, it is not known whether an initial formation of acyl-CoA is required prior to transport across the plastidic membrane in association with carnitine or some other system. A direct transacylation between ACP and CoA or some carrier system would be less expensive energetically than a process involving hydrolysis and synthesis. 

Acyl Chain Elongation Drives Ketosynthase Substrate Specificity in Polyketide Biosynthesis... 

Figure 3.7 Model of intermolecular fatty acid synthetase mechanism in the a2 2 protomer of yeast. A, acetyl transferase E, enoyl reductase D, dehydratase P, palmitoyl transferase M, malonyl transferase C, 5-ketoacyl synthase R. )5-ketoacyl reductase ACP, acyl carrier protein. Dotted lines and arrows delineate the route taken by intermediates when sequentially processed on different FAS domains. Numbers indicate the reaction sequence. Catalytically active dohnains, at a specific moment, are marked by bold lines. Shaded areas on E and P domains potentially interact by hydrophobic attraction in the presence of palmitate (b). On the protomer depicted in (a) fatty acyl chain elongation occurs in one half of the a2 2 protomer. In (b) chain termination is induced by hydrophobic interaction between E> bound palmitate and P. Subsequently, palmitate Is transferred to Its O-ester binding site on P. Inactivation of the left half of simultaneously activates its right half (b). Redrawn from Schweizer (1984) with permission of the author and Elsevier Science Publishers, BV. From Fatty Acid Metabolism and its Regulation (1984) (ed. S. Numa), p. 73, Figure 7.

Of great importance for porphyrin chemistry is the introduction of carbon substituents by Vilsmeier formylation100 or Friedel-Crafts acylation.100 The introduced substituents allow further carbon-chain elongations and other transformations so that interesting porphyrin derivatives can be synthesized. The Vilsmeier formylation of copper octaethylporphyrin (5) takes place at themethine position. The copper can then be easily removed by treatment with acid.105... 

There s a lot of shuffling of acyl groups between the pantetheine thiol and the thiol of a cysteine residue of the enzyme. They re shown in the correct position for all the reactions, so you have to do an acyl transfer at the end of each cycle to put the growing acyl chain back on the cysteine residues. The elongation step takes place with the growing acyl chain on cysteine and the malonyl-CoA on the pantetheine. At the end of the condensation reaction, the elongated chain is on the pantetheine. 

With the C-terminal residue introduced as part of the BAL anchor and the penultimate residue incorporated successfully by the optimized acylation conditions just described, further stepwise chain elongation by addition of Fmoc-amino acids generally proceeded normally by any of a variety of peptide synthesis protocols. 

All polyketides use the same general mechanism for chain elongation. Acetyl coenzyme A provides acetate (C2) units, which are condensed by a ketosynthase (KS). This in turn catalyzes condensation of the growing chain onto an acyl carrier protein (ACP), as generalized in Fig. 1.4. Enzymes such as ketoreductase (KR), enoyl reductase (ER), and dehydratase (DH) establish the oxidation state of caibon during translation, imparting structural diversity. Successive translation of each module leads to a chain of the required length that is eventually passed to thioeste-rase (TE), which releases the chain as a free acid or lactone. 

Acetogenins. Acetogenins are produced upon chain elongation with activated acetate units (or malonate followed by loss of carbon dioxide). A simplified sketch of this sequence is given in Fig. 1. During the first steps, a Claisen-type condensation of two acyl precursors yields a (3-ketoacyl intermediate A. Upon reduction to B and dehydration to C, followed by hydrogenation to D and hydrolysis, the chain elongated fatty acid E is produced. The next cycle will add another two carbons to the chain. Similarly, a reversed sequence leads to chain... 

Due to the low reactivity of the nitrogen, incorporation of the pyroglutamic acid into endo-positions by stepwise chain elongation is difficult (see reft49 and refs cited therein). It may be achieved using suitably protected aminoacyl-pyroglutamic acid derivatives as dipeptide synthons. These are accessible in satisfactory yields, e.g. by acylation of pGlu-OBzl with N-protected amino acid pentafluorophenyl esters in the presence of NaH or LiHMDS. 49 ... 

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