Coenzyme A esters

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

The degradation of vinyl chloride and ethene has been examined in Mycobacterium sp. strain JS 60 (Coleman and Spain 2003) and in Nocardioides sp. strain JS614 (Mattes et al. 2005). For both substrates, the initially formed epoxides underwent reaction with reduced coenzyme M and, after dehydrogenation and formation of the coenzyme A esters, reductive loss of coenzyme M acetate resulted in the production of 5-acetyl-coenzyme A. The reductive fission is formally analogous to that in the glutathione-mediated reaction. 

The degradation of pimelate is initiated by formation of the coenzyme A ester and is followed by a series of steps with the production of glutaryl-CoA that is decarboxylated to crotonyl-CoA... 

In view of this finding, it was proposed (135-138) (Scheme 22) that in the case of cocaine (98) the ornithine (201) is incorporated through free putrescine (202), which is a symmetrical intermediate and therefore would afford the pyrrolinium salt 206 equally labeled at C-2 and C-5. As above, condensation of the (V-methyl-A1 -pyrrolinium salt (206) with acetyl coenzyme A leads to the coenzyme A ester of hygrine-1 -carboxylic acid (207), which by transester-... 

A series of subsequent reactions after PAL first introduces a hydroxyl at the 4-position of the ring of cinnamic acid to form p- or 4-coumaric acid (i.e., 4-hydroxycinnamic acid). Addition of a second hydroxyl at the 3-position yields caffeic acid, whereas O-methylation of this hydroxyl group produces ferulic acid (see Fig. 3.3). Two additional enzymatic reactions are necessary to produce sinapic acid. These hy-drocinnamic acids are not found in significant amounts in plant tissue because they are rapidly converted to coenzyme A esters, or glucose esters. These activated intermediates form an important branch point because they can participate in a wide range of subsequent reactions. 

Hahlbrock K, Grisebach H (1970) Formation of coenzyme a esters of cinnamic acids with an enzyme preparation from cell suspension cultures of parsley. FEBS Lett ll(l) 62-64... 

The leaving group is the enolate anion of acetyl-CoA, and the reaction thus cleaves off a two-carbon fragment from the original fatty acyl-CoA. Since the nucleophile is coenzyme A, the other product is also a coenzyme A ester. In fact, the reaction generates a new fatty acyl-CoA, shorter by two carbons, which can re-enter the P-oxidation cycle. Most natural fatty acids have an even number of carbons, so the process continues until the original fatty acid chain is cleaved completely to acetyl-CoA fragments. 

The fatty acid synthase protein is known to contain an acyl carrier protein (ACP) binding site, and also an active-site cysteine residue in the P-ketoacyl synthase domain. Acetyl and malonyl gronps are successively transferred from coenzyme A esters and attached to the thiol groups of Cys and ACP. 

Table I. Phenolic Acid Esters Formed via Intermediate Acyl-Coenzyme A Esters...

Proanthocyanidins and Procyanidins - In a classical study Bate-Smith ( ) used the patterns of distribution of the three principal classes of phenolic metabolites, which are found in the leaves of plants, as a basis for classification. The biosynthesis of these phenols - (i) proanthocyanidins (ii) glycosylated flavonols and (iii) hydroxycinnamoyl esters - is believed to be associated with the development in plants of the capacity to synthesise the structural polymer lignin by the diversion from protein synthesis of the amino-acids L-phenylalanine and L-tyro-sine. Vascular plants thus employ one or more of the p-hydroxy-cinnarayl alcohols (2,3, and 4), which are derived by enzymic reduction (NADH) of the coenzyme A esters of the corresponding hydroxycinnamic acids, as precursors to lignin. The same coenzyme A esters also form the points of biosynthetic departure for the three groups of phenolic metabolites (i, ii, iii), Figure 1. 

The VLCFA as well as the branched-chain fatty acids phytanic acid and pristanic acid are extremely hydrophobic and practically insoluble in water. Their intracellular presence is in the form of coenzyme A esters. These acids are usually stored in lipid-containing tissues such as adipose tissue, but they may also be constituents of various physiologically important lipids such as myelin. In this respect, the VLCFA and the branched-chain fatty acids are abundant in many tissues/organs. 

In one pass through the /3-oxidation sequence, one molecule of acetyl-CoA, two pairs of electrons, and four protons (HT) are removed from the long-chain fatty acyl-CoA, shortening it by two carbon atoms. The equation for one pass, beginning with the coenzyme A ester of our example, palmitate, is... 

In extraliepatic tissues, d-/3-hydroxybutyrate is oxidized to acetoacetate by o-/3-hydroxybutyrate dehydrogenase (Fig. 17-19). The acetoacetate is activated to its coenzyme A ester by transfer of CoA from suc-cinyl-CoA, an intermediate of the citric acid cycle (see Fig. 16-7), in a reaction catalyzed by P-ketoacyl-CoA transferase. The acetoacetyl-CoA is then cleaved by thiolase to yield two acetyl-CoAs, which enter the citric acid cycle. Thus the ketone bodies are used as fuels. 

Fatty acids are converted to their coenzyme A esters in a reversible reaction catalyzed by acyl-CoA synthetase ... 

Some of the pathways of animal and bacterial metabolism of aromatic amino acids also are used in plants. However, quantitatively more important are the reactions of the phenylpropanoid pathway,173-1743 which is initiated by phenylalanine ammonia-lyase (Eq. 14-45).175 As is shown at the top of Fig. 25-8, the initial product from phenylalanine is trails-cinnam-ate. After hydroxylation to 4-hydroxycinnamate (p-coumarate) and conversion to a coenzyme A ester,1753 the resulting p-coumaryl-CoA is converted into mono-, di-, and trihydroxy derivatives including anthocyanins (Box 21-E) and other flavonoid compounds.176 The dihydroxy and trihydroxy methylated products are the starting materials for formation of lignins and for a large series of other plant products, many of which impart characteristic fragrances. Some of these are illustrated in Fig. 25-8. 

The biosynthesis of the polyketide moiety is thought to involve the condensation of coenzyme A esters of acetic acid with malonyl coenzyme A to give thiol esters of 3-keto acids. Further Claisen condensations with malonyl coenzyme A add further ketone units, leading to 3,5-diketo, 3,5,7-triketo acids and so on as their thiol esters. Intramolecular condensations subsequently afford heterocyclic or aromatic structures (Scheme 275). 

The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by species of Streptomyces, and several natural and semi-synthetic members are used clinically. They contain a linear tetracyclic skeleton of polyketide origin in which the starter group is malonamyl-CoA (Figure 3.54), i.e. the coenzyme A ester of malonate semi-amide. Thus, in contrast to most acetate-derived compounds, malonate supplies all carbon atoms of the tetracycline skeleton, the starter group as well as the chain extenders. The main features of the pathway (Figure 3.54) were deduced from extensive studies of mutant strains of Streptomyces aureofaciens with genetic blocks... 

A detailed study of amino acid sequences and mechanistic similarities in various polyketide synthase (PKS) enzymes has led to two main types being distinguished. Type I enzymes consist of one or more large multifunctional proteins that possess a distinct active site for every enzyme-catalysed step. On the other hand, Type II enzymes are multienzyme complexes that carry out a single set of repeating activities. Like fatty acid synthases, PKSs catalyse the condensation of coenzyme A esters of simple carboxylic acids. However, the variability at each step in... 

The polyketide synthases responsible for chain extension of cinnamoyl-CoA starter units leading to flavonoids and stilbenes, and of anthraniloyl-CoA leading to quinoline and acridine alkaloids (see page 377) do not fall into either of the above categories and have now been termed Type TTT PKSs. These enzymes differ from the other examples in that they are homodimeric proteins, they utilize coenzyme A esters rather than acyl carrier proteins, and they employ a single active site to perform a series of decarboxylation, condensation, cyclization, and aromatization reactions. 

Cinnamic acids, as their coenzyme A esters, may also function as starter units for chain extension with malonyl-CoA units, thus combining elements of the shikimate and acetate pathways (see page 80). Most commonly, three C2 units are added via malonate giving rise to flavonoids and stilbenes, as described in the next section (page 149). However, there are several examples of products formed from a cinnamoyl-CoA starter... 

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