Discovery of a New Family of Dieckmann Cyclases Essential to Tetramic Acid and Pyridone-Based Natural Products Biosynthesis

Abstract

Bioinformatic analyses indicate that TrdC, SlgL, LipX2, KirHI, and FacHI belong to a group of highly homologous proteins involved in biosynthesis of actinomycete-derived tirandamycin B, streptolydigin, α-lipomycin, kirromycin, and factumycin, respectively. However, assignment of their biosynthetic roles has remained elusive. Gene inactivation and complementation, in vitro biochemical assays with synthetic analogues, point mutations, and phylogenetic tree analyses reveal that these proteins represent a new family of Dieckmann cyclases that drive tetramic acid and pyridone scaffold biosynthesis.

Identification of nocamycin biosynthetic gene cluster from Saccharothrix syringae NRRL B-16468 and generation of new nocamycin derivatives by manipulating gene cluster

“…SCSIO1666 involved in tirandamycin biosynthetic pathway [14]. TrdC and its analogues SlgC, KirHI have been determined as Dieckmann cyclases, and they catalyze the formation of tetramic acid or pyridone moiety [21]. Bioinformatics analyses revealed that NcmC also possesses the characteristic catalytic traid Cys-Asp-His (Additional file 1: Figure S4).…”

“…The core structure of nocamycin is bicyclic ketal unit and tetramic acid moiety. To date, tetramic acid structure has been identified in numerous natural products and four phylogenetically different family enzymes have been characterized to catalyze the tetramic acid formation through Dieckmann cyclisation reaction [21, 47–50]. In previous report, TrdC and its homologous protein SlgL have been characterized as Dieckmann cyclases to catalyze the formation of tetramic acid moiety in tirandamycin and streptolydigin biosynthetic pathway, respectively [21].…”

“…To date, tetramic acid structure has been identified in numerous natural products and four phylogenetically different family enzymes have been characterized to catalyze the tetramic acid formation through Dieckmann cyclisation reaction [21, 47–50]. In previous report, TrdC and its homologous protein SlgL have been characterized as Dieckmann cyclases to catalyze the formation of tetramic acid moiety in tirandamycin and streptolydigin biosynthetic pathway, respectively [21]. Thus, it is plausible to assume that NcmC, the homologous protein to TrdC, is employed to generate tetramic acid moiety through Dieckmann cyclisation during nocamycins biosynthetic pathway [21].…”

“…Some streptolydigin derivatives were generated by using combinatorial biosynthesis method [10]. In streptolydigin and tirandamycins biosynthetic pathway, a uniform strategy is employed to catalyze the formation of tetramic acid moiety [21]. The mechanism of bicyclic ketal structure formation remains unclear since no related gene candidates have been discovered in the two gene clusters.…”

Regio- and Stereocontrolled Dieckmann Approach to Treprostinil-Inspired, Polycyclic Scaffold For Building Macrocyclic Diversity

“…Compound 19 was subjected to acryloylation giving 28 in a high yield. Following the removal of the silyl group under mild acidic conditions, the free benzylic −OH group was then acylated using three different N-alloc protected amino acids giving the key precursor (29) to study the 15-membered ring formation by a ring closing metathesis stitching approach. As in the previous study, this reaction also worked-well, and in all the three cases, macrocyclic ring was obtained (see 30).…”