Animal-Encoded Nonribosomal Pathway to Bursatellin Analogs

Abstract

The bursatellin-oxazinin family is a series of tyrosine-derived, nitrile-containing marine natural products from gastropod and bivalve molluscs. Although the first analogs were identified and associated with toxicity 40 years ago, their biosynthetic origins were unknown. During an investigation of published mollusc genomes and transcriptomes, we serendipitously identified a putative bursatellin biosynthetic gene cluster (referred hereafter as the bur-ox pathway). Through biochemical characterization of some bur-ox genes, we provide evidence suggesting that bursatellin-type metabolites are produced by molluscs themselves rather than by their microbial symbionts. We show that the reductive domain from a monomodular nonribosomal peptide synthetase (NRPS) protein FmtATR performs a four-electron reduction to produce tyrosinols from tyrosine derivatives. Moreover, an aminocarboxypropyltransferase enzyme, ACT, uses S-adenosylmethionine (SAM) to transform tyrosinols into their phenolic homoserine ethers, which in bursatellin is further modified to the nitrile. Widespread occurrence of bur-ox in molluscs suggests a common biosynthetic origin for bursatellins and oxazinins as well as an important but currently unidentified physiological role for this metabolite family in molluscs inhabiting diverse ecological niches. The presence of bur-ox pathway homologues in culinary bivalves, such as mussels and geoducks, calls into question the potential of oxazinins as toxins. As one of the few NRPS pathways of animal origin to be characterized, bur-ox sheds light on underappreciated chemical and biochemical diversity in animals.