Inhibitor Report for: Vibralactone

Vibralactone is isolated from the basidiomycete fungus Boreostereum vibrans as one of the strongest lipase inhibitors. Its unusual beta-lactone-fused bicycle is derived from an aryl ring moiety via an oxidative ring-expansion prior to an intramolecular cyclization. Here, we report the discovery of the cyclase VibC which belongs to the alpha/beta-hydrolase superfamily and is involved in the vibralactone biosynthesis. Biochemical and crystal studies suggest that VibC may catalyze an aldol or an electrocyclic reaction initiated by the catalytic Ser-His-Asp triad. For the aldol and pericyclic chemistry in living cells, VibC is a unique hydrolase performing the carbocycle formation of an oxepinone to a fused bicyclic b-lactone. This presents a naturally occurring new enzyme reaction in both aldol and hydrolase (bio)chemistry that will guide future exploitation of these enzymes in synthetic biology for chemical diversity expansion of natural products.

A variety of novel natural products with significant bioactivities are produced by the basidiomycete Boreostereum vibrans. In the present study, we describe 16 novel natural oximes and oxime esters with a vibralactone backbone, vibralactoximes, which were isolated from the scale-up fermentation broth of B. vibrans. Their structures were determined through extensive spectroscopic analyses. These compounds represent the first oxime esters from nature. The hypothetical biosynthetic pathway of these compounds was also proposed. Seven compounds exhibited significant pancreatic lipase inhibitory activity, while ten compounds exhibited cytotoxicities against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480), with IC50 values comparable with those of cisplatin.

Four new natural products possessing vibralactone skeleton, 1,5-secovibralactone (1), vibralactone B (2), vibralactone C (3) and acetylated vibralactone (4), together with known compound vibralactone (5), had been isolated from cultures of the basidiomycete Boreostereum vibrans. The structures of 1-4 were elucidated on the basis of spectroscopic methods. The absolute configuration of 1 was suggested to be S by computational methods.

Vibralactone, a hybrid compound derived from phenols and a prenyl group, is a strong pancreatic lipase inhibitor with a rare fused bicyclic beta-lactone skeleton. Recently, researcher reported a vibralactone derivative (compound C1) that caused inhibition of pancreatic lipase with a half-maximal inhibitory concentration of 14 nM determined by structure-based optimization, suggesting a potential candidate as a new anti-obesity treatment. In the present study, we sought to identify the main gene encoding prenyltransferase in Stereum vibrans, which is responsible for the prenylation of phenol leading to vibralactone synthesis. Two RNA silencing transformants of identified gene (vib-PT) were obtained through Agrobacterium tumefaciens-mediated transformation. Compared to wild-type strains, the transformants showed a decrease in vib-PT expression ranging from 11.0% to 56.0% at 5, 10, and 15 days in reverse transcription-quantitative PCR (RT-qPCR) analysis and along with a reduction in primary vibralactone production of 37% to 64% at 15 and 21 days, respectively, as determined using ultra-high-performance liquid chromatography mass spectrometry analysis. A soluble and enzymatically active fusion Vib-PT protein was obtained by expressing vib-PT in Escherichia coli, and the enzyme's optimal reaction conditions and catalytic efficiency (Km /Kcat ) were determined. In vitro experiments established that Vib-PT catalyzed the C-prenylation at C-3 of 4-hydroxy-benzaldehyde and the O-prenylation at the 4-hydroxy of 4-hydroxy-benzenemethanol in the presence of dimethylallyl diphosphate. Moreover, Vib-PT shows promiscuity towards aromatic compounds and prenyl donors. .IMPORTANCE Vibralactone is a lead compound with a novel skeleton structure that shows strong inhibitory activity against pancreatic lipase. Vibralactone is not encoded by the genome directly, but is rather synthesized from phenol, followed by prenylation and other enzyme reactions. Here, we used an RNA silencing approach to identify and characterize a prenyltransferase in a basidiomycetes species that is responsible for the synthesis of vibralactone. The identified gene, vib-PT, was expressed in E. coli to obtain a soluble and enzymatically active fusion Vib-PT protein. In vitro characterization of the enzyme demonstrated the catalytic mechanism of prenylation and broad substrate range for different aromatic acceptors and prenyl donors. These characteristics highlight the possibility of Vib-PT to generate prenylated derivatives of aromatics and other compounds as improved bioactive agents or potential prodrugs.

Vibralactone is isolated from the basidiomycete fungus Boreostereum vibrans as one of the strongest lipase inhibitors. Its unusual beta-lactone-fused bicycle is derived from an aryl ring moiety via an oxidative ring-expansion prior to an intramolecular cyclization. Here, we report the discovery of the cyclase VibC which belongs to the alpha/beta-hydrolase superfamily and is involved in the vibralactone biosynthesis. Biochemical and crystal studies suggest that VibC may catalyze an aldol or an electrocyclic reaction initiated by the catalytic Ser-His-Asp triad. For the aldol and pericyclic chemistry in living cells, VibC is a unique hydrolase performing the carbocycle formation of an oxepinone to a fused bicyclic b-lactone. This presents a naturally occurring new enzyme reaction in both aldol and hydrolase (bio)chemistry that will guide future exploitation of these enzymes in synthetic biology for chemical diversity expansion of natural products.

Disclosed is a five-step synthesis of (+/-)-vibralactone, a biologically active terpenoid natural product. A key photochemical valence isomerization of 3-prenyl-pyran-2-one produces both the all-carbon quaternary stereocenter and the beta-lactone at an early stage. Cyclopropanation of the resulting bicyclic beta-lactone produces a strained housane structure that is converted to the natural product through a sequential ring expansion and reduction strategy. This concise and modular route to the natural product provides the shortest total synthesis of (+/-)-vibralactone reported to date.

A variety of novel natural products with significant bioactivities are produced by the basidiomycete Boreostereum vibrans. In the present study, we describe 16 novel natural oximes and oxime esters with a vibralactone backbone, vibralactoximes, which were isolated from the scale-up fermentation broth of B. vibrans. Their structures were determined through extensive spectroscopic analyses. These compounds represent the first oxime esters from nature. The hypothetical biosynthetic pathway of these compounds was also proposed. Seven compounds exhibited significant pancreatic lipase inhibitory activity, while ten compounds exhibited cytotoxicities against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480), with IC50 values comparable with those of cisplatin.

Despite their structural similarity, the natural products omuralide and vibralactone have different biological targets. While omuralide blocks the chymotryptic activity of the proteasome with an IC50 value of 47 nM, vibralactone does not have any effect at this protease up to a concentration of 1 mM. Activity-based protein profiling in HeLa cells revealed that the major targets of vibralactone are APT1 and APT2.

Three new compounds, named as vibralactones K-M (1-3), together with vibralactone (4) have been isolated from cultures of the Basidiomycete Boreostereum vibrans. Their structures were determined on the basis of spectroscopic evidences (1D and 2D NMR, HRMS, UV, and IR data), chemical methods and literature data. None of the compounds was cytotoxic against five human cancer cell lines and showed inhibitory activity on the pancreatic lipase.

Four new natural products possessing vibralactone skeleton, 1,5-secovibralactone (1), vibralactone B (2), vibralactone C (3) and acetylated vibralactone (4), together with known compound vibralactone (5), had been isolated from cultures of the basidiomycete Boreostereum vibrans. The structures of 1-4 were elucidated on the basis of spectroscopic methods. The absolute configuration of 1 was suggested to be S by computational methods.

The structure and absolute configuration of vibralactone (1) from the cultures of the Basidiomycete Boreostereum vibrans were established by spectroscopic methods and computational methods. Vibralactone, an unusual fused beta-lactone-type metabolite, was found to inhibit pancreatic lipase with an IC50 of 0.4 microg/mL. [structure: see text]