4 -phosphopantetheine prosthetic group

Synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA involves a number of sequential reactions (Fig. 11.1). Acyl groups are attached to the 4 -phosphopantetheine prosthetic group of acyl carrier protein (ACP) during modification by fatty acid synthetase. 

In vivo both enzymes have been demonstrated in E. coli and in mammalian synthetases the turnover of the 4 -phosphopantetheine prosthetic group is an order of magnitude faster than the rest of the synthetase, implying the presence of holo-ACP synthetase and ACP hydrolase. In plants, also, the holo-ACP synthetase has been detected. 

FIGURE 25.6 Fatty acids are conjugated both to coenzyme A and to acyl carrier protein through the sulfliydryl of phosphopantetheine prosthetic groups. 

Polyketide synthases, fatty acid synthases, and non-ribosomal peptide synthetases are a structurally and mechanistically related class of enzymes that catalyze the synthesis of biopolymers in the absence of a nucleic acid or other template. These enzymes utilize the common mechanistic feature of activating monomers for condensation via covalently-bound thioesters of phosphopantetheine prosthetic groups. The information for the sequence and length of the resulting polymer appears to be encoded entirely within the responsible proteins. 

The second, ACP2, binds the growing fatty acyl chain during the condensation and reduction reactions of the cycle. In this case the acyl group is carried on a long phosphopantetheine prosthetic group. This... 

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 ... 

FIGURE 21-4 Acyl carrier protein (ACP). The prosthetic group is 4 -phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP. Phosphopantetheine contains the B vitamin pantothenic acid, also found in the coenzyme A molecule. Its —SH group is the site of entry of malonyl groups during fatty acid synthesis. 

CoA to form malonyl CoA using C02 in the form of bicarbonate HC03 (Fig. 2). This reaction is catalyzed by the enzyme acetyl CoA carboxylase which has biotin as a prosthetic group, a common feature in C02-binding enzymes. One molecule of ATP is hydrolyzed in the reaction, which is irreversible. The elongation steps of fatty acid synthesis all involve intermediates linked to the terminal sulfhydryl group of the phosphopantetheine reactive unit in ACP phosphopantetheine is also the reactive unit in CoA. Therefore, the next steps are the formation of acetyl-ACP and malonyl-ACP by the enzymes acetyl transacylase and malonyl transacylase, respectively (Fig. 2). (For the synthesis of fatty acids with an odd number of carbon atoms the three-carbon propionyl-ACP is the starting point instead of malonyl-ACP.)... 

There is a rapid turnover of phosphopantetheine between AGP and CoA, in response to the metabolic state, and the need for fatty acid synthesis (and thus AGP in the fed state) or fatty acid oxidation (and thus GoAin the fasting state). Apo-AGP has a half-life of 6 to 7 days, whereas the prosthetic group turns over with a half-life of a few hours (Tweto and Larrabee, 1972 Volpe and Vagelos, 1973). 

Once the hexameric structure of the yeast FAS was established, the number of functional active sites still remained to be determined. Earlier studies had shown that the functional complex contains approximately six equivalents each of two prosthetic groups 4 -phosphopantetheine [60,63], necessary for the AGP functionality, and flavin mononucleotide [64], an essential component of the enoyl reductase activity. These studies provided an early indication that each of the six active sites in the complex has a full set of the chemical groups necessary for fatty acid synthesis. Nevertheless, conflicting reports appeared in the literature as to the competence of six active sites. Whereas some reports suggested the possibility of half-sites reactivity (only three of the six sites are catalytically competent) [65, 66], others proposed that all six active sites could synthesize fatty acids [62]. Subsequent active site titration experiments were performed which quantitated the amount of fatty acyl products formed in the absence of turnover [67]. Single-turnover conditions were achieved through the use of... 

Pantothenic acid is of ubiquitous occurrence in nature, where it is synthesized by most microorganisms and plants fi-om pantoic acid (D-2,4-dihydroxy-3,3-dimethylbutyric acid) derived from L-vafine, and p-alanine derived from L-aspartate. Addition of cysteamine at the C-terminal end and phosphorylation at C4 of pantoic acid forms 4 -phosphopantetheine, which serves as a covalently attached prosthetic group of acyl carrier proteins, and, when attached... 

The answer is c. (Murray, pp 627-661. Scriver, pp 3897-3964. Sack, pp 121—138. Wilson, pp 287-320.1 The almost universal carrier of acyl groups is coenzyme A (CoA). However, acyl carrier protein (ACP) also functions as a carrier ol acyl groups. In fatty acid synthesis, ACP carries the acyl intermediates. The reactive prosthetic group of both ACP and CoA is a phosphopantetheine sulfhiydryl. In ACP, the phosphopantetheine group is attached to the 77-residue polypeptide chain via a serine hydroxyl. In CoA, the phosphopantetheine is linked to the 5 -phosphate of adenosine that is phosphorylated in its 3 -hydroxyl. 

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