Characterization of the Jomthonic Acids Biosynthesis Pathway and Isolation of Novel Analogues in GUA-06-05-006A

Jomthonic acids (JAs) are a group of natural products (NPs) with adipogenic activity. Structurally, JAs are formed by a modified β-methylphenylalanine residue, whose biosynthesis involves a methyltransferase that in has been identified as MppJ. Up to date, three JA members (A⁻C) and a few other natural products containing β-methylphenylalanine have been discovered from soil-derived microorganisms. Herein, we report the identification of a gene () coding for a putative methyltransferase highly identical to MppJ in the chromosome of the marine actinobacteria GUA-06-05-006A. In its 5' region, clusters with two polyketide synthases (PKS) (, ), a nonribosomal peptide synthetase (NRPS) () and a thioesterase gene (), possibly conforming a single transcriptional unit. Insertion of a strong constitutive promoter upstream of P1 led to the detection of JA A, along with at least two novel JA family members (D and E). Independent inactivation of , and abolished production of JA A, JA D and JA E, indicating the involvement of these genes in JA biosynthesis. Heterologous expression of the JA biosynthesis cluster in M1152 and in J1074 led to the production of JA A, B, C and F. We propose a pathway for JAs biosynthesis based on the findings here described.