Leptochelins A–C, Cytotoxic Metallophores Produced by Geographically Dispersed Leptothoe Strains of Marine Cyanobacteria

Avalon, Nicole E. and Reis, Mariana A. and Thornburg, Christopher C. and Williamson, R. Thomas and Petras, Daniel and Aron, Allegra T. and Neuhaus, George F. and Al-Hindy, Momen and Mitrevska, Jana and Ferreira, Leonor and Morais, João and El Abiead, Yasin and Glukhov, Evgenia and Alexander, Kelsey L. and Vulpanovici, F. Alexandra and Bertin, Matthew J. and Whitner, Syrena and Choi, Hyukjae and Spengler, Gabriella and Blinov, Kirill and Almohammadi, Ameen M. and Shaala, Lamiaa A. and Kew, William R. and Paša-Tolić, Ljiljana and Youssef, Diaa T. A. and Dorrestein, Pieter C. and Vasconcelos, Vitor and Gerwick, Lena and McPhail, Kerry L. and Gerwick, William H. (2024) Leptochelins A–C, Cytotoxic Metallophores Produced by Geographically Dispersed Leptothoe Strains of Marine Cyanobacteria. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (online). ISSN 0002-7863 (In Press)

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Abstract

Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A–C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus Leptothoe. Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three Leptothoe strains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.

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