Novel key metabolites reveal further branching of the roquefortine/meleagrin biosynthetic pathway.
Metabolic profiling and structural elucidation of novel secondary metabolites obtained from derived deletion strains of the filamentous fungus Penicillium chrysogenum were used to reassign various previously ascribed synthetase genes of the roquefortine/meleagrin pathway to their corresponding products. Next to the structural characterization of roquefortine F and neoxaline, which are for the first time reported for P. chrysogenum, we identified the novel metabolite roquefortine L, including its degradation products, harboring remarkable chemical structures. Their biosynthesis is discussed, questioning the exclusive role of glandicoline A as key intermediate in the pathway. The results reveal that further enzymes of this pathway are rather unspecific and catalyze more than one reaction, leading to excessive branching in the pathway with meleagrin and neoxaline as end products of two branches.
From the Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden.
Marco I
MI
Ries
Hazrat
H
Ali
Peter P
PP
Lankhorst
Thomas
T
Hankemeier
Roel A L
RA
Bovenberg
Arnold J M
AJ
Driessen
Rob J
RJ
Vreeken
D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000378:metabolism; D007211:Indoles / Q000378:metabolism*; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D010408:Penicillium chrysogenum / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism
D005656:Fungal Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D010879:Piperazines; C012536:roquefortine; D008025:Ligases
Antibiotics; Anticancer Drug; Fungi; Natural Product Biosynthesis; Secondary Metabolism; Toxins