The Butenolide Signaling Molecules SRB1 and SRB2 Induce Lankacidin and Lankamycin Production in Streptomyces rochei

Abstract

New signaling molecules that induce lankacidin and lankamycin production in Streptomyces rochei were extracted from the culture filtrate and purified by Sephadex LH20 and silica gel chromatography with the help of bioassay. Chiral HPLC and ESI-MS analyses indicated the presence of two active components--SRB1 and SRB2--and their molecular formulas were established to be C15H24O5 and C16H26O5, respectively. By extensive NMR analysis, SRB1 and SRB2 were determined to be 2-(1'-hydroxy-6'-oxo-8'-methylnonyl)-3-methyl-4-hydroxybut-2-en-1,4-olide and 2-(1'-hydroxy-6'-oxo-8'-methyldecyl)-3-methyl-4-hydroxybut-2-en-1,4-olide, respectively. These structures were finally confirmed by chemical synthesis and the absolute configuration at C-1' was determined to be R in each case. The synthetic 1'R isomers induced production of lankacidin and lankamycin at around 40 nM concentrations. SRB1 and SRB2 are therefore distinct from the well-known 2,3-disubstituted γ-butyrolactone molecules such as A-factor, virginia butanolide, and SCB1 and and belong, like avenolide, recently isolated from Streptomyces avermitilis, to the γ-butenolide family.

Pseudonocardides A - G, Newγ-Butyrolactones from Marine-derivedPseudonocardiasp. YIM M13669

“… and plants . γ ‐Butyrolactones are reported as chemical signaling molecules or microbial hormones that regulate secondary metabolism and/or morphological differentiation in Actinobacteria especially in Streptomyces . The present study is the first report of isolation of γ ‐butyrolactones from a marine Pseudonocardia sp.…”

Identification of a butenolide signaling system that regulates nikkomycin biosynthesis in Streptomyces

“…However, this task is hindered by the low yield of autoregulators in producing strains, which makes their study by large-scale fermentation rather burdensome and inefficient (1). It has been evidenced that AfsA and its homologs as well as tailoring enzymes are responsible for the biosynthesis of various signaling molecules, such as GBLs, furans, and some butenolides (4,6,24). In this study, heterologous expression of afsA homologue sabA and two tailoring enzyme genes, sabP and sabD, of S. ansochromogenes significantly improved the signal molecule yield, and three different butenolides were characterized.…”

“…Recently, a butenolide signaling molecule, avenolide, was found to be essential for biosynthesis of the clinically important antibiotic avermectin, inspiring more interest in this family of regulators (5). Seven butenolides associated with antibiotic biosynthesis have been discovered so far, including avenolide from Streptomyces avermitilis and Streptomyces albus (3,5) and SRBs from Streptomyces rochei (6). Butenolide contains a five-member ring backbone, but with an unsaturated bond at C3-C4 and diverse side chains at C3, C4, or C5, which confer unique activities.…”

The International Conference of Natural Product Biosynthesis (ICNPB, 8th US–Japan seminar on the Biosynthesis of Natural Products)

“…9 Dr Kenji Arakawa (Hiroshima University) described the structural elucidation and biosynthesis of the butenolide signaling molecules that induce lankacidin and lankamycin production in Streptomyces rochei. 10 Professor Jürgen Rohr (University of Kentucky) reviewed a combinatorial biosynthetic enzymology, designated in vitro reconstitution of the biosynthetic pathway and recombination of enzyme components in type II PKS systems. In this study, glycosylation, dehydration and oxidation catalyzed by enzymes of the gilvocarcin and jadomycin biosynthetic pathways were characterized.…”