Insights into the Biosynthetic Origin of 3-(3-Furyl)alanine in Stachylidium sp 293 K04 Tetrapeptides

The marine-sponge-derived fungus Stachylidium sp. 293 K04 produces the N-methylated peptides endolide A (1) and endolide B (2), showing affinity for the vasopressin receptor 1A and serotonin receptor 5HT(2B), respectively. Both peptides feature the rare amino acid 3-(3-furyl)alanine. Isotope labeling experiments, employing several C-13-enriched precursors, revealed that this unprecedented heterocyclic amino acid moiety in endolide A (1) is synthesized from a cyclic intermediate of the shikimate pathway, but not from phenylalanine. Two new tetrapeptide analogues, endolides C and D (3 and 4), were characterized, as well as the previously described hirsutide (5).