Biosynthesis of two dihydropyrrole-polyketides from a marine-derived Penicillium citrinum

Abstract

Experimentos de incorporação com precursores marcados com 13 C foram realizados objetivando-se estabelecer a biossíntese de dois dihidropirróis N-acilados, (8E)-1-(2,3-dihidro-1H-pirrol-1-il)-2-metildec-8-eno-1,3-diona (1) e 1-(2,3-dihidro-1H-pirrol-1-il)-2-metildecano-1,3-diona (2), isolados de culturas de Penicillium citrinum de origem marinha. A biossíntese de ambos, 1 e 2, procede através da incorporação de acetato, metionina e ornitina.Feeding experiments with 13 C-labeled precursors were performed in order to establish the biosynthesis of two N-acylated dihydropyrroles, (8E)-1-(2,3-dihydro-1H-pyrrol-1-yl)-2-methyldec-8-ene-1,3-dione (1) and 1-(2,3-dihydro-1H-pyrrol-1-yl)-2-methyldecane-1,3-dione (2), isolated from the cultures of a marine-derived Penicillium citrinum. The biosynthesis of both, 1 and 2, involves the incorporation of acetate, methionine and ornithine. Keywords: Penicillium citrinum, marine-derived fungus, mixed biosynthesis, dihydropyrrole IntroductionPyrrole, dihydropyrrole (pyrroline) and tetrahydropyrrole (pyrrolidine) alkaloids constitute a unique class of secondary metabolites, which include several bioactive members such as the tropane alkaloids, 1 tambjamines 2-4 and prodigiosin, 5 anatoxin-a, 6 as well as 2-alkyl or 2,5-dialkyl-branched pyrrolidine and pyrroline ant chemical defenses. 7 However, such alkaloids are extremely rare in fungi, the only examples found in literature 8 include the dihydropyrrole-bearing peptide brevigellin isolated from Penicillium brevicompactum, 9 the dihydropyrrole b-keto amides 1 and 2 also isolated from P. brevicompactum, [10][11][12] the mildly antibiotic scalusamides A−C (3-5), which have been isolated from a marine-derived P. citrinum, 13 as well as the tetrahydropyrrole-citrinin conjugate perinadine A, isolated from P. citrinum of marine origin. 14 Compounds 1 and 2 display insecticidal, fungicidal activities and induce precocious metamorphosis in the milkweed bug Oncopeltus fasciatus (Insecta). 12 We have recently isolated the same compounds 1 and 2 from a marine-derived P. citrinum, 15 and became interested to Braz. Chem. Soc. 1784 establish the actual biosynthetic pathway leading to 1 and 2. This is because while pyrrole, dihydropyrrole or pyrrolidine alkaloids isolated from non-fungal sources are typically derived from proline, 16,17 ornithine, 1 or even from acetate, 16 the biosynthesis of the above mentioned dihydropyrroles isolated from fungi have not yet been investigated. Particularly, we aimed to verify if the dihydropyrrole moiety in 1 and 2 is derived from proline or ornithine, and if the branched moiety is derived from propionate or from acetate plus methionine. To the best of our knowledge, this is the first report on the biosynthesis of fungal dihydropyrrole-bearing secondary metabolites. Results and DiscussionAfter toxicity evaluation with unlabeled sodium acetate, added to the growth medium of P. citrinum (up to 5 g L -1 ), for which no morphology alterations of the fungus in the growth medium or even alterations in the product...

Marine natural products

“…Feeding experiments utilising 13 C-labelled precursors established that the biosynthesis of both metabolites involves the incorporation of acetate, methionine and ornithine. 456 Reduction of emodin, a metabolite of both marine 457 and terrestrial 458 fungal origin, by sodium dithionite, resulted in the formation of two tautomeric forms of emodin hydroquinone. Subsequent conversion by the short-chain dehydrogenase/reductase (SDR) enzyme MdpC into the corresponding 3-hydroxy-3,4-dihydroanthracen-1(2H)-one implies that deoxygenation is the rst step in the biosynthesis of the marine 459 and terrestrial 460 fungal metabolite monodictyphenone.…”

Natural Products from Marine Invertebrates and Microorganisms in Brazil between 2004 and 2017: Still the Challenges, More Rewards

“…Biosynthesis of maleagrin (29) and oxaline (30) via roquefortine L (31). 40 isolated from cultures of Trichoderma sp., while cultures of the fungus P. paxilli provided pyrenocine A (37), B (38) and the new pyrenocine J (39), identified by analysis of spectroscopic data. 41 Compound 37 displayed antiviral activity against Herpes Simplex virus type-1 (HSV-1) and avian metapneumovirus (AMPV) with EC 50 at 4.2 and 63.27 µg mL -1 , respectively.…”

Thinking big about small beings – the (yet) underdeveloped microbial natural products chemistry in Brazil

“…69 The biosynthesis of both 258 and 259 proceeds via the incorporation of acetate, methionine and ornithine, as established by experiments using 13 Clabeled precursors. 102 Pyridovericin (260) isolated from the culture medium of Beauveria bassiana obtained from a soil sample, was evaluated as an inhibitor of mast cell degranulation and cytokine secretion. 103 Compound 260 was tested as a degranulating agent of RBL-2H3 cells, immortal cell line derived from rat leukemia basophil-like cells.…”