Aromatic synthetases

The 3-keto reductase step is equivalent to that found in fatty acid synthesis, although it occurs late (and only once) in this process. Indeed, thiol-bound acetoacetate proved inactive as a substrate for the aromatic complex, whereas it was reduced by fatty acid synthetase (Dimrothe/a/., 1972). Thus, the carbonyl group adjacent to the terminal methyl position is not susceptible to reduction by the aromatic synthetase, despite the apparent presence of a suitable reductase, possibly because it is held on the enzyme surface in an inappropriate enolic configuration (Packter, 1973). If so, it may not prove acceptable, since the 3-ketoacyl-acyl carrier protein (ACP) reductase from Escherichia coli only accepts keto substrates and does not react with or bind to the enol form of 3-ketoacyl derivatives (Schulz and Wakil, 1971). 

Since fatty acid and aromatic synthetases have many properties in common, it is interesting to consider the effect of omitting NADPH from incubations catalyzed by these enzymes and to examine the consequences. In all cases studied from animal (Bressler and Wakil, 1%2 Nixon et al., 1%8), yeast (Yalpani et al., 1969), and bacterial origin (Brock and Bloch, 1966), fatty acid synthesis is naturally abolished, but a Q compound, triacetic acid lactone (4-hydroxy-6-methyl-2-pyrone) (VII), is formed instead. This product is also made when the NADPH-requiring 6-methylsalicylate synthetase is deprived of this nucleotide (Dimroth et al., 1972), but the relative rate of synthesis is considerably greater than that produced by fatty acid synthetase in P. patulum (Yalpani et al., 1%9). However, Scott et al. (1971) have reported that triacetic acid lactone is also formed by 6-methylsalicylate synthetase, albeit at a reduced rate, even in the presence of NADPH. 

Scheme 6. Pathway for the biosynthesis of gliorosein (XXV) in G. roseum. EnzSH, Aromatic synthetase.

The oxidation state of thiazolines and oxazolines can be adjusted by additional tailoring enzymes. For instance, oxidation domains (Ox) composed of approximately 250 amino acids utilize the cofactor FMN (flavin mononucleotide) to form aromatic oxazoles and thiazoles from oxazolines and thiazolines, respectively. Such domains are likely utilized in the biosynthesis of the disorazoles, " diazonimides, bleomycin, and epothiolone. The typical domain organization for a synthetase containing an oxidation domain is Cy-A-PCP-Ox however, in myxothiazol biosynthesis one oxidation domain is incorporated into an A domain. Alternatively, NRPSs can utilize NAD(P)H reductase domains to convert thiazolines and oxazolines into thiazolidines and oxazolidines, respectively. For instance, PchC is a reductase domain from the pyochelin biosynthetic pathway that acts in trans to reduce a thiazolyinyl-Y-PCP-bound intermediate to the corresponding thiazolidynyl-Y-PCP. ... 

Deoxy-D-araZu o-heptulosonate-7-phosphate synthetase (DAHPS) is the initial enzyme in the pathway responsible for the synthesis of aromatic compounds in microorganisms and plants. It catalyses the reaction shown in Equation (4) ... 

Roberts, D.R. (1983) Summary Report NIOSH-EPA Interagency Agreement for the Assessment of Human Health Effects from Exposure to Di-2-(Ethylhexyl) Phthalate, Cincinnati, OH, National Institute for Occupational Safety and Health Robertson, I.G.C., Sivarajah, K., Eling, T.E. Zeiger, E. (1983) Activation of some aromatic amines to mutagenic products by prostaglandin endoperoxide synthetase. Cancer Res., 43, 476-480... 

The conversion of androstenedione to estrone is catalyzed by aromatase. Inhibition of aromatase (human estrogen synthetase) by several naturally occurring flavonoids, including quercetin, chrysin, and apigenin, has been described. The synthetic flavone 7,8-benzoflavone was most active. Aromatization of androstenedione was affected by several flavonoids, of which 7-hydroxy-flavone and 7,4-dihydroxyflavone were the most potent. 

Beauvericin is a structural homolog of enniatins in which the branched-chain L-amino acid is substituted by the aromatic amino acid L-phenylalanine. Beauvericin synthetase, which has been isolated from the fungus Beauveria bassiana [54] and various strains of Fusaria [55], strongly resembles Esyn with respect to its molecular size and the reaction mechanism. In contrast to Esyn, which is only able to incorporate aliphatic amino acids, beauvericin synthetase exhibits high substrate specificity for aromatic amino acids such as phenylalanine. This capability is obviously caused by mutational alterations in the adenylation domain of this enzyme. 

Reductions Aromatic nitro compounds, azo dyes, nitrosamines, A-oxides, sulfoxides Prostaglandin Synthetase (PGS) Cooxidation... 

The quinone ring is derived from isochorismic acid, formed by isomerization of chorismic acid, an intermediate in the shikirnic acid pathway for synthesis of the aromatic amino acids. The first intermediate unique to menaquinone formation is o-succinyl benzoate, which is formed by a thiamin pyrophosphate-dependent condensation between 2-oxoglutarate and chorismic acid. The reaction catalyzed by o-succinylbenzoate synthetase is a complex one, involving initially the formation of the succinic semialdehyde-thiamin diphosphate complex by decarboxylation of 2-oxoglutarate, then addition of the succinyl moiety to isochorismate, followed by removal of the pyruvoyl side chain and the hydroxyl group of isochorismate. 

Example DHAP synthetase (of aromatic amino acid biosynthetic pathway)... 

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