Natural Diels-Alderase

Since we reported the enzymatic activity of SPS in 1995 as the first Diels-Alderase, two additional Diels-Alderases, lovastatin nonaketide synthase (LNKS) and macrophomate synthase (MPS), have been purified and characterized. Two of these catalyze intramolecular Diels-Alder reactions while the third catalyzes an intermolecular Diels-Alder reaction. We have recently reported the detailed reaction pathway ° ° of MPS and its catalytic mechanism based on the crystal structure. " In this section, we describe three natural Diels-Alderases and discuss the mechanism of their catalysis. 

Oxidative-pericydic processes, and in particular the oxidative/Diels-Alder reaction, are quite common in nature. The so-called Diels-Alderase is usually an oxidizing enzyme, which induces, for example, the formation of a suitable dienophile such as an enone from an allylic alcohol [49]. 

The library of natural catalysts has very little to offer for the catalysis of Diels-Alder (and the reverse) reactions (Diels-Alderases)[139]. For this reason one of the intriguing areas of biomimickry, namely the formation and use of antibodies exhibiting catalytic activity, has focused on [4 + 2] reactions to try to furnish proteins possessing useful catalytic properties. Thus in early studies a polyclonal catalytic antibody raised to hapten (57)[140] showed a modest rate enhancement for the reaction depicted in Scheme 48. 

Recently a number of Diels-Alder type natural products has been isolated from living things. Biomimetic syntheses of these natural products provide not only effective synthetic method but also useful intermediates labeled with isotopes for feeding experiments. As the results, many Diels-Alderases will be discovered from natural sources in the near fiiture [4-7, 89, 90], since the Diels-Alder type natural products have been discovered continuously every year. 

Diels-Alderase, a novel C-C bond-formation enzyme involving natural products biosynthesis 04YGK778. 

In many cases, it is difficult to predict that a target molecule is actually biosynthesized by a Diels-Alderase based only on its structure. Demonstration of the skeletal construction of natural products with a biomimetic Diels-Alder reaction is an effective way to confirm the involvement of Diels-Alder reactions in their biosynthesis. This section describes putative [4 + 2] adducts enzymatically biosynthesized in addition to nonenzymatic [4 + 2] adducts. The biomimetic synthesis not only provides information on the feasibility of the Diels-Alder reaction but also provides diastereomer ratio and detailed reaction conditions to afford adducts. 

Involvement of the Diels-Alderases in the biosynthesis of natural products 05BCJ537. 

The participation of enzymes in Diels-Alder reactions (Fig. 5.157) was postulated for more than 100 natural products. [381,383] However, the structure of Diels-Alderases, and therefore the mechanism of the biocatalysed [4 -i- 2]Other enzyme-catalysed electrocyclic reactions, like the Cope rearrangement of chorismic acid into prephenic acid by chorismate-mutase, were aiready known for a while and are well investigated. 

The existence of Diels—Alderases has been debated for some time in relation to several natural products,... 

There are reports of Diels-Alderase enzymes in the biosynthesis of certain natural products, but their existence is somewhat controversial. For that reason, this discussion has been limited to the sigmatropic rearrangement example cited. 

H.J. Kim, M.W. Ruszczycky, H.W. Liu, Current developments and challenges in the search for a naturally selected Diels-Alderase, Curr. Opin. Chem. Biol. 16 (2012) 124-131. 

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