Ergot alkaloids pathway intermediates

Since the last review on ergot alkaloids, important new alkaloids from different sources, mostly from new ergot strains, have been discovered. Their proposed structure could in some cases be confirmed by synthesis. Some of them seem to be intermediates in the biogenetic pathway from tryptophan to the peptide alkaloids. Others are considered as end products of secondary plant metabolism. In any case we find many interesting structures among these recently discovered substances. 

Many of the intermediates and several of the enzymatic steps involved in the biosynthesis of ergot alkaloids have been studied in Claviceps species (e.g., Floss, 1976 Waller and Dermer, 1981 Kozikowski et al., 1988 Shibuya et al., 1990) and are outlined in Figs. 1-3. However, much about the pathway remains to be investigated. A similar pathway is expected in Neotyphodium, Epichloe, and Balansia spp. given their phylogenetic relationship to Claviceps (Glenn et al., 1996 Craven et al., 2001) and the presence of similar DNA sequences for two of the genes in the pathway (described below). 

The early steps in the ergot alkaloid biosynthetic pathway are outlined in Fig. 1. The first determinant and rate-limiting step is the prenylation of tryptophan to 4-(y,y-dimethylallyl)tryptophan (DMAT), catalyzed by dimethy-lallyl-diphosphate L-tryptophan dimethylallyltransferase (DMAT synthase EC 2.5.1.34) (Heinstein et al., 1971 Gebler and Poulter, 1992). The prenyl group for the DMAT synthase reaction is provided in the form of dimethylallyl diphosphate (DMAPP), which is derived from mevalonic acid. After the formation of DMAT, the free amino group of this intermediate is N-methylated with a methyl group donated by S-adenosylmethionine (AdoMet). The N-methylated DMAT is then converted into chanoclavine I by closure of the... 

Kozikowski AP, Wu J-P, Shibuya M, Floss HG. Probing ergot alkaloid biosynthesis identification of advanced intermediates along the biosynthetic pathway. J Am Chem Soc 110 1970-1971, 1988. 

The proposed sequence of events in which 23 is acetylated to 24, followed by reverse prenylation to 10, is supported by two observations. The first is the existence of an acetylated, but nonprenylated, fumigaclavine (24) and the lack of a prenylated, but not acetylated, fumigaclavine intermediate. Fumigaclavine C (10) can be experimentally deacetylated to yield such a compound, but this compound has not been detected in cultures of A. fumigatus (52). The second observation is simply that 10 is the most abundant ergot alkaloid in A. fumigatus (52), consistent with its position as the ultimate and inconvertible product of the pathway. 

Kozikowski, A.R, Okita, M., Kobayashi, M. and Floss, H.G. (1988) Probing ergot alkaloid biosynthesis Synthesis and feeding of a proposed intermediate along the biosynthetic pathway. A new amidomalonate for tryptophan elaboration. /. Org. Chem., 53,... 

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