A model study of ergot alkaloid biosynthesis

Wenkert, Ernest; Sliwa, H.

doi:10.1016/0045-2068(77)90043-8

Cited by 19 publications

(18 citation statements)

References 9 publications

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“…They suggested that the reaction catalyzed by the wild-type enzyme proceeds in two steps, reverse alkylation at C3 followed by a Cope rearrangement and deprotonation to form the normal C4 prenylation product, as originally proposed by Wenkert and Silwa. 32 The multiplicity of products we observe when C4 is blocked, including normal and reverse alkylation at C3, do not support the Cope mechanism. While a Cope rearrangement is consistent with reverse alkylation at C3 and normal alkylation at N1, it does not account for the concurrent normal prenylation at both C5 and C7.…”

Section: Discussionmentioning

confidence: 64%

Multisite Prenylation of 4-Substituted Tryptophans by Dimethylallyltryptophan Synthase

2013

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The aromatic prenyltransferase dimethylallyltryptophan synthase in Claviceps purpurea catalyzes the normal prenylation of tryptophan at C4 of the indole nucleus in the first committed step of ergot alkaloid biosynthesis. 4-Methyltryptophan is a competitive inhibitor of the enzyme that has been used in kinetic studies. Upon investigation of background activity during incubations of 4-methyltryptophan with dimethylallyl diphosphate, we found that the analogue was an alternate substrate, which gave four products. The structures of three of these compounds were established by 1H NMR and 2D NMR studies and revealed that dimethylallyltryptophan synthase catalyzed both normal and reverse prenylation at C3 of the indole ring and normal prenylation of N1. Similarly, 4-methoxytryptophan was an alternate substrate, giving normal prenylation at C5 as the major product. 4-Aminotryptophan, another alternate substrate, gave normal prenylation at C5 and C7. The ability of dimethylallyltryptophan synthase to prenylate at five different sites on the indole nucleus, with normal and reverse prenylation at one of the sites, is consistent with a dissociative electrophilic alkylation of the indole ring where orientation of the substrates within the active site and substituent electronic effects determine the position and type of prenylation. These results suggest a common mechanism for prenylation of tryptophan by all of the members of the structurally related dimethylallyltryptophan synthase family.

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Section: Discussionmentioning

confidence: 64%

Multisite Prenylation of 4-Substituted Tryptophans by Dimethylallyltryptophan Synthase

2013

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“…This mechanism had previously been considered as a way to explain how prenylation is directed to the poorly nucleophilic position of the indole ring (C-4), but was eventually discounted due to lack of non-enzymatic precedence for the key rearrangement. [46][47][48] This mechanism involves an initial reverse prenylation at the C-3 position of the indole (Fig. 9).…”

Section: -Dimethylallyltryptophan Synthase (4-dmats or Fgapt2)mentioning

confidence: 99%

Mechanistic studies on the indole prenyltransferases

2015

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Covering: up to 2014. Prenylated indole alkaloids comprise a large and structurally diverse family of natural products that often display potent biological activities. In recent years a large family of prenyltransferases that install prenyl groups onto the indole core have been discovered. While the vast majority of these enzymes are evolutionarily related and share a common protein fold, they are remarkably versatile in their ability to catalyze reverse and normal prenylations at all positions on the indole ring. This highlight article will focus on recent studies of the mechanisms utilized by indole prenyltransferases. While all of the prenylation reactions may follow a direct electrophilic aromatic substitution mechanism, studies of structure and reactivity suggest that in some cases prenylation may first occur at the nucleophilic C-3 position, and subsequent rearrangements then generate the final product.

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“…In this perception, reverse prenylation of 6 at position 3 of the indole would set the stage for cyclization via the side chain NH function of a suitably protected tryptophan. This general concept, in various modalities, had been inherent in several previous approaches toward the construction of the pyrroloindoles. − Its success would depend, in the first instance, on introduction of a functional carbon electrophile, capable in some way of progression to a reverse prenyl group. Included under this formalism would be the special case where the electrophile (E + ) corresponded to the intact reverse prenyl group.…”

Section: Synthetic Planningmentioning

confidence: 99%

Total Synthesis of 5-N-Acetylardeemin and Amauromine: Practical Routes to Potential MDR Reversal Agents

et al. 1999

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The total synthesis of the title compounds has been accomplished. The key step involves the kinetic stereoselective conversion of 19 → 20. The synthesis of 20 represents for the first time a direct method for constructing exo-pyrroloindoles from protected tryptophans in a highly diastereoselective manner. This step was followed by reverse prenylation (see conversion of 20 → 27). Using the methodology worked out for the titled compounds, a practical synthesis of several promising MDR reversal agents was possible. Biological data that provided the basis for selection of candidates for advanced study are presented. Preliminary profiling of the zones of the molecules that are responsive to changes while still retaining MDR reversal ability are described. On the basis of these findings, compounds 2, 50, and 51 were selected for more extensive biological follow-up.

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A model study of ergot alkaloid biosynthesis

Cited by 19 publications

References 9 publications

Multisite Prenylation of 4-Substituted Tryptophans by Dimethylallyltryptophan Synthase

Multisite Prenylation of 4-Substituted Tryptophans by Dimethylallyltryptophan Synthase

Mechanistic studies on the indole prenyltransferases

Total Synthesis of 5-N-Acetylardeemin and Amauromine: Practical Routes to Potential MDR Reversal Agents

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