Condensation reactions, chain elongation

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. 

CHS orchestrates the condensation, cyclization, and aromatization of one p-coumaroyl-CoA and three malonyl-CoA molecules to produce chalcone (Fig. 12.2).22 Transfer of the p-coumaroyl moiety from the CoA-linked starter molecule to Cys 164 within the active site initiates the reaction sequence. Next, the sequential condensation of three acetate units, derived from malonyl-CoA, with the enzyme-bound coumaroyl moiety forms a tetraketide intermediate. Inherent in the condensation reaction is decarboxylation of malonyl-CoA to an acetyl-CoA carbanion that serves as a nucleophile during the successive chain elongation... 

Polycarboxylic acid synthases. Several enzymes, including citrate synthase, the key enzyme which catalyzes the first step of the citric acid cycle, promote condensations of acetyl-CoA with ketones (Eq. 13-38). An a-oxo acid is most often the second substrate, and a thioester intermediate (Eq. 13-38) undergoes hydrolysis to release coenzyme A.199 Because the substrate acetyl-CoA is a thioester, the reaction is often described as a Claisen condensation. The same enzyme that catalyzes the condensation of acetyl-CoA with a ketone also catalyzes the second step, the hydrolysis of the CoA thioester. These polycarboxylic acid synthases are important in biosynthesis. They carry out the initial steps in a general chain elongation process (Fig. 17-18). While one function of the thioester group in acetyl-CoA is to activate the methyl hydrogens toward the aldol condensation, the subsequent hydrolysis of the thioester linkage provides for overall irreversibility and "drives" the synthetic reaction. 

The Michael addition represents an extremely efficient synthetic method for achieving chain elongation by adding a three (or more) carbon fragment electrophile to a nucleophilic moiety. Notice that the typical Michael electrophiles (e.g. 90) are products of condensation of carbonyl compounds and can be easily formed via the aldol-like condensation, the Wittig reaction (with ylides like 81), the Perkin reaction, or the Mannich reaction (see below). 

This section presents some basic condensation reactions that result in the chain elongation of sugars. The examples presented here are historically important to the general field of carbohydrate chemistry, and include the cyanohydrin chain extension and the nitromethane condensation. 

The net effect of these eight steps is to take two acetyl groups and combine them into a single four-carbon butyryl group. Further condensation of butyryl synthase with another malonyl ACP yields a six-carbon unit, and still further repetitions of the pathway add two more carbon atoms to the chain each time until the 16-carbon palmitic acid is reached. Further chain elongation of palmitic acid occurs by reactions similar to those just described, but acetyl CoA itself rather than malonyl ACP is the two-carbon donor. 

ER fatty acid chain elongation, which uses two-carbon units provided by mal-onyl-CoA, is a cycle of condensation, reduction, dehydration, and reduction reactions similar to those observed in cytoplasmic fatty acid synthesis. In contrast to the cytoplasmic process, the intermediates in the ER elongation process are CoA esters. These reactions can lengthen both saturated and unsaturated fatty acids. Reducing equivalents are provided by NADPH. 

---