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Mar. Drugs 2018, 16(8), 259; https://doi.org/10.3390/md16080259

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

1
Department of Functional Biology and University Institute of Oncology of Principado de Asturias (U.I.O.P.A), University of Oviedo, 33006 Oviedo (Asturias), Spain
2
Institute for Health Research of Principado de Asturias (IHRPA), 33006 Oviedo (Asturias), Spain
3
Drug Discovery Area, PharmaMar S.A. Avda. de los Reyes 1, 28770 Colmenar Viejo (Madrid), Spain
*
Author to whom correspondence should be addressed.
Received: 9 July 2018 / Revised: 26 July 2018 / Accepted: 28 July 2018 / Published: 31 July 2018
(This article belongs to the Special Issue Microbial Gene Clusters of Marine Origin)
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Abstract

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 Streptomyces hygroscopicus 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 (jomM) coding for a putative methyltransferase highly identical to MppJ in the chromosome of the marine actinobacteria Streptomyces caniferus GUA-06-05-006A. In its 5’ region, jomM clusters with two polyketide synthases (PKS) (jomP1, jomP2), a nonribosomal peptide synthetase (NRPS) (jomN) and a thioesterase gene (jomT), possibly conforming a single transcriptional unit. Insertion of a strong constitutive promoter upstream of jomP1 led to the detection of JA A, along with at least two novel JA family members (D and E). Independent inactivation of jomP1, jomN and jomM 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 Streptomyces coelicolor M1152 and in Streptomyces albus 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. View Full-Text
Keywords: biosynthesis gene cluster; molecular elicitation; heterologous expression; polyketide synthase; nonribosomal peptide synthetase biosynthesis gene cluster; molecular elicitation; heterologous expression; polyketide synthase; nonribosomal peptide synthetase
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García-Salcedo, R.; Álvarez-Álvarez, R.; Olano, C.; Cañedo, L.; Braña, A.F.; Méndez, C.; de la Calle, F.; Salas, J.A. Characterization of the Jomthonic Acids Biosynthesis Pathway and Isolation of Novel Analogues in Streptomyces caniferus GUA-06-05-006A. Mar. Drugs 2018, 16, 259.

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