A Methyltransferase Initiates Terpene Cyclization in Teleocidin B Biosynthesis

Abstract

Teleocidin B is an indole terpenoid isolated from Streptomyces. Due to its unique chemical structure and ability to activate protein kinase C, it has attracted interest in the areas of organic chemistry and cell biology. Here, we report the identification of genes encoding enzymes for teleocidin B biosynthesis, including nonribosomal peptide synthetase (tleA), P-450 monooxygenase (tleB), prenyltransferase (tleC), and methyltransferase (tleD). The tleD gene, which is located outside of the tleABC cluster on the chromosome, was identified by transcriptional analysis and heterologous expression. Remarkably, TleD not only installs a methyl group on the geranyl moiety of the precursor but also facilitates the nucleophilic attack from the electron-rich indole to the resultant cation, to form the indole-fused six-membered ring. This is the first demonstration of a cation, generated from methylation, triggering successive terpenoid ring closure.

Prenyltransferases as key enzymes in primary and secondary metabolism

“…In addition to LtxC mentioned above (Edwards and Gerwick 2004), the function of TleC in the biosynthetic pathway of teleocidin B in Streptomyces blastmyceticus was also characterized Table 5 Tryptophan-containing peptide or peptide-related prenyltransferases and their catalyzed reactions A. Aspergillus, N. Neosartorya, L. Lyngbya, Ant anthranilate, AA acetoacetyl, n.a. not available a Natural or if unknown the best accepted substrate was given biochemically (Awakawa et al 2014). Gene deletion experiments revealed the involvement of MpnD in the biosynthesis of methylpendolmycin in Marinactinospora thermotolerans (Ma et al 2012).…”

Streptomycetes: Surrogate hosts for the genetic manipulation of biosynthetic gene clusters and production of natural products

“…Another intriguing example is the heterologous production of a cyanotoxin lyngbyatoxin A (Figure 4). Genes ltxABC were identified to direct the biosynthesis of lyngbyatoxin A in cyanobacterium Moorea producens (Edwards and Gerwick, 2004); a similar gene cluster tleABC has been recently found in S. blastmyceticus NBRC 12747 (Awakawa et al, 2014). Expression of tleABC in three different hosts S. albus G153, S. lividans TK21 and S. avermitilis SUKA22 revealed unexpected host-pathway interactions.…”

Enzymkaskadenreaktionen in der Biosynthese

“…[39] Die Vorstufe von Teleocidin Bi st das Indolactam Lyngbyatoxin A, welches das aktive Agens bei Seetangdermatitis ist. [39] Die Vorstufe von Teleocidin Bi st das Indolactam Lyngbyatoxin A, welches das aktive Agens bei Seetangdermatitis ist.…”

“…[40] Die Biosynthese von Lyngbyatoxin Ai st mit einer bimodularen NRPS und danach mit einer P450-Monooxygenase (verhinderte Oxygenase;siehe Abschnitt 6zuradikalischen Kaskaden) verknüpft und geht mit der radikalischen Kupplung des Va lyl-Stickstoff-Atoms und des C4-Atoms der Indol-Einheit einher. Untersuchungen von Abe und Mitarbeitern [39] zeigten, dass die Methyltransferase TleD das Enzym ist, das die entsprechende chemische Kaskade auslçst. Untersuchungen von Abe und Mitarbeitern [39] zeigten, dass die Methyltransferase TleD das Enzym ist, das die entsprechende chemische Kaskade auslçst.…”