Phosphopantetheinylated acyl carrier protein

Several catalytic elements are required for the biosynthetic process acyltransferases that load the primer and extender substrates onto the FAS complex a posttranslationally phosphopantetheinylated acyl carrier protein (ACP) that translocates the various thioester intermediates between catalytic sites a P-ketoacyl synthase (KS) that performs the condensation reaction the p-ketoacylreductase, dehydrase, and enoylreductase enzymes that are responsible for the beta-carbon-processing reactions and a chain-terminating enzyme... 

We next examine the coordinated functioning of the mammalian fatty acid synthase. Fatty acid synthesis begins with the transfer of the acetyl group of acetyl CoA first to a serine residue in the active site of acetyl transferase and then to the sulfur atom of a cysteine residue in the active site of the condensing enzyme on one chain of the dimeric enzyme. Similarly, the malonyl group is transferred from malonyl CoA first to a serine residue in the active site of malonyl transferase and then to the sulfur atom of the phosphopantetheinyl group of the acyl carrier protein on the other chain in the dimer. Domain 1 of each chain of this dimer interacts with domains 2 and 3 of the other chain. Thus, each of the two functional units of the synthase consists of domains formed by different chains. Indeed, the arenas of catalytic action are... 

Figure 22.23. Schematic Representation of Animal Fatty Acid Synthase. Each of the identical chains in the dimer contains three domains. Domain 1 (blue) contains acetyl transferase (AT), malonyl transferase (MT), and condensing enzyme (CE). Domain 2 (yellow) contains acyl carrier protein (ACP), P-ketoacyl reductase (KR), dehydratase (DH), and enoyl reductase (ER). Domain 3 (red) contains thioesterase (TE). The flexible phosphopantetheinyl group (green) carries the fatty acyl chain from one catalytic site on a chain to another, as well as between chains in the dimer. [After Y. Tsukamoto, H. Wong, J. S. Mattick, and S. J. Wakil. J. Biol. Chem. 258(1983) 15312.]...

ACP, acyl carrier protein AT, acyltransferase DH, dehydratase KR, ketoreductase KS, ketoacyl synthase TD, terminal domain that most likely encodes a phosphopantetheinyl transferase. 

Fig. 33.12. Phosphopantetheinyl residue of the fatty acid synthase complex. The portion derived from the vitamin, pantothenic acid, is indicated. Phosphopantetheine is covalently linked to a serine residue of the acyl carrier protein (ACP) segment of the enzyme. The sulfhydryl group reacts with malonyl CoA to form a thioester.

Fig. 3. Phosphopantetheinylation of the acyl carrier protein (AGP) domain of a polyketide synthase. In order to be active, polyketide synthases must be post-translationally modified by a family of enzymes called phosphopantetheine transferases (PPTases). These enzymes transfer the 4 -phospho-pantetheine arm of Coenzyme A to an active site serine residue in the AGP...

Despite the structural diversity of polyketides, the building blocks of these compounds are simple acyl-CoAs, and the biosynthetic logic is closely associated with that of fatty acid synthases (FASs) [9, 10]. In both polyketide and fatty acid biosynthesis, the growing chain is covalently tethered to an acyl carrier protein (ACP) via a phosphopantetheine (PPant) moiety. The PPant chain, derived from CoA, is attached post-translationaUy to a conserved serine residue on the npo-ACP by a phosphopantetheinyl transferase (PPTase), yielding the mature to-ACP (Scheme 1.1) [11,12],... 

Some enzymes are nonfunctional until posttranslationally modified. Examples of these enzymes include the acyl- and carboxyltransferases. While lipoate and phosphopantetheine are necessary for acyl transfer chemistry, tethered biotin is used in carboxyl transfer chemistry. Biotin and lipoate tethering occur under a similar mechanism the natural small molecule is activated with ATP to form biotinyl-AMP or lipoyl-AMP (Scheme 20). A lysine from the target protein then attacks the activated acid and transfers the group to the protein. The phosphopantetheine moiety is transferred using its own enzyme, the phosphopantetheinyltrans-ferase (PPTase). The PPTase uses a nucleophilic hydroxy-containing amino acid, serine, to attach the phosphopantetheinyl (Ppant) arm found in coenzyme A to convert the apo (inactive) carrier protein to its holo (active) form. The reaction is Mg -dependent. 

Figure 5 Fatty acid biosynthesis catalyzed by fatty acid synthases. The growing acyl chain is tethered to the phosphopantetheinylated ACP domain, which enabies it to undergo cycles of condensation, ketone reduction, dehydration, and enol reduction catalyzed by different domains. AT, acyltransferase ACP, acyi-carrier protein KS, ketosynthase KR, ketoreductase DH, dehydratase ER, enoyireductase.

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