ABSTRACT
The biosynthetic gene cluster of the antifungal metabolite sporothriolide 1 was identified from three producing ascomycetes: Hypomontagnella monticulosa MUCL 54604, H. spongiphila CLL 205 and H. submonticulosa DAOMC 242471. A transformation protocol was established, and genes encoding a fatty acid synthase subunit and a citrate synthase were simultaneously knocked out which led to loss of sporothriolide and sporochartine production. In vitro reactions showed that the sporochartines are derived from non-enzymatic Diels-Alder cycloaddition of 1 and trienylfuranol A 7 during the fermentation and extraction process. Heterologous expression of the spo genes in Aspergillus oryzae then led to the production of intermediates and shunts and delineation of a new fungal biosynthetic pathway originating in fatty acid biosynthesis. Finally, a hydrolase was revealed by in vitro studies likely contributing towards self-resistance of the producer organism.
ABSTRACT
Two new 6-norpolycyclic polyprenylated acylphloroglucinols (PPAPs), hypermonins A (1) and B (2), featuring an undescribed decahydroindeno[1,7-bc]furan ring system, were isolated from the leaves and twigs of Hypericum monogynum. These compounds are a pair of epimers with opposite configurations at the C-5 position. Their structures, including their absolute configurations, were determined by extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. A plausible biosynthetic pathway of 1 and 2 was also proposed. Compound 1 exhibited a significant protective effect against corticosterone-induced injury in PC12 cells.
Subject(s)
Hemiterpenes/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Hypericum/chemistry , Neuroprotective Agents/pharmacology , Phloroglucinol/analogs & derivatives , Phloroglucinol/pharmacology , Animals , Cell Line, Tumor , Hemiterpenes/chemistry , Hemiterpenes/isolation & purification , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/isolation & purification , Models, Chemical , Neuroprotective Agents/chemistry , Neuroprotective Agents/isolation & purification , Phloroglucinol/chemistry , Phloroglucinol/isolation & purification , Plant Leaves/chemistry , Rats , StereoisomerismABSTRACT
Garmultins A and B (1 and 2), two polycyclic polyprenylated acylphloroglucinols characterized by the coupling of two novel cages, 2,11-dioxatricyclo[4.4.1.03,9]undecane and tricyclo[4.3.1.03,7]decane, along with five biogenetically related analogues (3-7), were isolated from Garcinia multiflora. Their structures and absolute configurations were determined by extensive NMR analysis, X-ray crystallography, and electronic circular dichroism calculations. Three compounds were capable of inhibiting oncogene expression and inducing apoptosis in human erythroleukemia cells.
