Tryptophan isoprenylation

The comQXP loci of a set of natural Bacillus isolates have been sequenced and shown to possess a striking polymorphism that determines specific patterns of both activation and inhibition of the quorum sensing response.217 Genetic and biochemical evidence demonstrate that all the ComX variants are isoprenylated by the posttranslational modification of a conserved tryptophan residue and that the modifications on the ComX peptide backbones vary in mass among the various phenotypes. 

Shibuya, M., Chou, H.-M., Fountoulakis, M., Hassam, S., Kim, S.-U., Kobayashi, K., Otsuka, H., Rogalska, E., Cassady, J.M. and Floss, H.G. (1990) Stereochemistry of the isoprenylation of tryptophan catalysed by 4-( Y, Y-dimethylallyl)tryptophan synthase from Claviceps, the first pathway-specific enzyme in ergot alkaloid biosynthesis. /. Am. Chem. Soc., 112, 297-304. 

Roquefortine, roquefortine C, a modified diketopiperazine produced by a number of Penicillium species. It is a common fungal metabolite, and is widely distributed in a range of blue cheeses. This diketopiperazine is derived from the condensation of tryptophan and histidine residues, and modified by heterocyclization and isoprenyl addition. Interestingly, roque-fortines A and B are structurally different from roquefortine C, and belong to the isofumigaclavines, whereas roquefortine D possesses the same core structure as roquefortine C [P. M. Scott etal, Experientia 1976, 32, 140 B. Clark et al., J. Nat. Prod. 2005, 68, 1661]. 

In 1976, two key intermediates in the biosynthesis of 12 were isolated from filtrates of Asp. chevalieri (Mangin) Thom and Church grown on potato extract medium (40,41). One is cyclo(L-alanyl-L-tryptophan) (CAT, 15), and the other is the 2-isoprenylated derivative (MICAT or preechinulin) (16). The latter was also obtained by using a partially purified enzyme which transfers the isoprene unit from 3-methyl-2-butenyl-1-phosphate to CAT (42). 

Tanabe (772) and Acklin et al. (173) independently, and results were in good agreement. They showed that these related metabolites are derived from tryptophan and geranylgeraniol. Acklin etal. (173) reported that the probable biosynthetic sequence is paspaline (93) paspalicine (97) — paspalinine (94) (Scheme 18). It might be further speculated that paspalinine is converted to aflatrem by addition of an isoprene unit at the 4 position of the indole aromatic ring and that paspalitrem A (98) is derived via isoprenylation at the 5 position. 

In the course of their studies on the biosynthesis of ergot alkaloids. Robbers and Floss isolated clavidpitic acid, a new indolic amino acid [89]. Based on the X-ray crystal data of the major isomer and the assumption that the stereocenter at C-5 retains its stereochemistry from L-tryptophan, the structure shown in Scheme 59 was assigned [90]. By performing feeding experiments on Claviceps sp. SD 58 with clavicipitic acid (biosynthetically labeled), the laboratories of Floss [90] and Anderson [91] independently determined that clavicipitic acid is not a precursor to elymoclavine. Instead, Floss argues that it arises from ... a derailment of the metabolism leading to the tetracyclic ergolines between the first and second pathway-specific steps, the isoprenylation of tryptophan and the N-methylation of 4-(y,y-dimethylallyl)-tryptophan (DMAT). Anderson and co-workers isolated an enzyme, DMAT oxidase, from Claviceps sp. which catalyzes the formation of clavicipitic acid from DMAT [92]. The enzyme, which requires... 

Other enzymes involved in terpene biosynthesis have also been harnessed for biocatalytic reactions of arenes. Prenyltransferase enzymes that can affect the addition of Cj isoprenyl units both at carbon and at heteroatoms have been used for biocatalytic arene alkylations. For example, L-tryptophan 49 undergoes prenylation at various positions on the indole core in a wholly regiose-lective fashion, depending on the enzyme used [28] (Scheme 32.6). 

The conclusion of Shibuya et al. (1990) from these experiments was that isoprenylation of L-tryptophan involved displacement of the pyrophosphate moiety of DMAPP by the indole residue with inversion at C-1 of the isoprene moiety. In the ternary enzyme substrate complex, dissociation of the C-1/ pyrophosphate bond of DMAPP would yield an ion pair or an allylic carbocation stabilised by the countercharge of the enzyme-bound pyrophosphate as shown in Figure 7. From C-4 of enzyme-bound L-tryptophan on the face opposite to the pyrophosphate, attack would create DMAT with inversion at C-1 and retention of double bond geometry. If the scrambling between allylic hydrogens occurred during these event, this can be readily accounted for by Figure 7... 

During the biosynthesis of ergoline alkaloids, tryptophan is decar-boxylated, isoprenylated at the 4 position, and methylated at the amino nitrogen. Neither tryptamine (Baxter et al., 1961 Floss and Groger, 1963) nor A"-methyltryptamine (Floss and Groger, 1963) was incorporated into the alkaloids. This ruled out decarboxylation as the first step. The tritium label from N -[side c/zam- C,m r/zj/- H]methyltryptophan was lost (Floss and Grdger, 1964). Only the tryptophan part was incorporated, the A-methyl... 

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