Prenylated indole derivatives from fungi: structure diversity, biological activities, biosynthesis and chemoenzymatic synthesis

Abstract

Prenylated indole alkaloids are hybrid natural products derived from prenyl diphosphates and tryptophan or its precursors and widely distributed in filamentous fungi, especially in the genera Penicillium and Aspergillus of ascomycota. These compounds represent a group of natural products with diverse chemical structures and biological activities. Significant progress on their biosynthesis has been achieved in recent years by identification of biosynthetic gene clusters from genome sequences and by molecular biological and biochemical investigations. In addition, a series of prenylated indole derivatives have been produced by chemoenzymatic synthesis using overproduced and purified enzymes.

CdpC2PT, a reverse prenyltransferase from Neosartorya fischeri with a distinct substrate preference from known C2-prenyltransferases

“…Prenyltransferases are a large family of enzymes found in all domains of life and are involved in the biosynthesis of primary and secondary metabolites (Heide, 2009;Li, 2010;Liang, 2009;Yazaki et al, 2009). One subgroup of the prenyltransferases from ascomycetes shares significant sequence similarities with dimethylallyltryptophan synthase (DMATS) in the biosynthesis of ergot alkaloids from Claviceps purpurea (Tudzynski et al, 1999); they are therefore classified as members of the DMATS superfamily.…”

Genome mining and biosynthesis of fumitremorgin-type alkaloids in ascomycetes

“…1,2 Fungal secondary metabolites derived from the diketopiperazine brevianamide F (1) consisting of L-tryptophan and Lproline ( Figure 1) represent a large group within the prenylated indole alkaloids. 1,2 The enormous structure diversity is only possible by prenylation and other modification reactions of the cyclic dipeptide skeleton.…”

“…1,2 Fungal secondary metabolites derived from the diketopiperazine brevianamide F (1) consisting of L-tryptophan and Lproline ( Figure 1) represent a large group within the prenylated indole alkaloids. 1,2 The enormous structure diversity is only possible by prenylation and other modification reactions of the cyclic dipeptide skeleton. Derivatives of the regularly C2-prenylated brevianamide F; that is, tryprostatin B (2), are classified as fumitremorgin-type alkaloids, which include tryprostatins (2 and 3), spirotryprostatins (4 and 5), cyclotryprostatins (for example 6), fumitremorgins (7-10) and verruculogen (11).…”

“…Derivatives of the regularly C2-prenylated brevianamide F; that is, tryprostatin B (2), are classified as fumitremorgin-type alkaloids, which include tryprostatins (2 and 3), spirotryprostatins (4 and 5), cyclotryprostatins (for example 6), fumitremorgins (7-10) and verruculogen (11). 1,2 Finding and proof of the genetic information for the biosynthesis of these compounds are focus of this review. Reversely C2-prenylated brevianamide F; that is, deoxybrevianamide E (12), is the biosynthetic precursor of brevianamides; for example, brevianamide A (13), austamide (14) and notoamides like notoamide A (15).…”

“…On the basis of the obtained bioinformatic, molecular biological and biochemical results, the following biosynthetic pathway has been postulated ( Figure 3). 1 The biosynthesis of fumitremorgin-type alkaloids begins by condensation of the two amino acids L-tryptophan and L-proline to brevianamide F, catalyzed by the non-ribosomal peptide synthetase FtmPS (also termed FtmA), which was proven by heterologous overexpression of the NRPS gene ftmPS in Aspergillus and identification of the accumulated product brevianamide F. 33 Brevianamide F is then prenylated by the prenyltransferase FtmPT1/FtmB in the presence of dimethylallyl diphosphate, resulting in the formation of tryprostatin B, as demonstrated by using the recombinant FtmPT1. 27 By gene inactivation in A. fumigatus BM939 and heterologous expression in S. cerevisiae, Kato et al 31 showed that the three cytochrome P450 enzymes, FtmP450-1/FtmC, FtmP450-2/FtmE and FtmP450-3/FtmG, are responsible for the conversion of tryprostatin B (2) to 6-hydroxytryprostatin B, tryprostatin A (3) to fumitremorgin C (8) and fumitremorgin C (8) to 12,13-dihydroxyfumitremorgin C, respectively.…”