A Maldiisotopic Approach to Discover Natural Products: Cryptomaldamide, a Hybrid Tripeptide from the Marine Cyanobacterium Moorea producens

• Published in: Journal of natural products (Washington, D.C.) Vol. 80; no. 5; pp. 1514 - 1521
• Main Authors: Kinnel, Robin B, Esquenazi, Eduardo, Leao, Tiago, Moss, Nathan, Mevers, Emily, Pereira, Alban R, Monroe, Emily A, Korobeynikov, Anton, Murray, Thomas F, Sherman, David, Gerwick, Lena, Dorrestein, Pieter C, Gerwick, William H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 26.05.2017; Amer Chemical Soc
• Subjects: Biological Products - chemistry; Biological Products - isolation & purification; Chemistry, Medicinal; Computational Biology; Cyanobacteria - chemistry; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Molecular Structure; Oligopeptides - biosynthesis; Oligopeptides - chemistry; Oligopeptides - isolation & purification; Pharmacology & Pharmacy; Plant Sciences; Science & Technology; GENE-CLUSTER; SAXITOXIN; ACIDS; BIOSYNTHESIS; CYTOTOXIC PEPTIDES; HEMIASTERLIN; INHIBITORS; SPECTRA
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.7b00019

Genome sequencing of microorganisms has revealed a greatly increased capacity for natural products biosynthesis than was previously recognized from compound isolation efforts alone. Hence, new methods are needed for the discovery and description of this hidden secondary metabolite potential. Here we show that provision of heavy nitrogen 15N-nitrate to marine cyanobacterial cultures followed by single-filament MALDI analysis over a period of days was highly effective in identifying a new natural product with an exceptionally high nitrogen content. The compound, named cryptomaldamide, was subsequently isolated using MS to guide the purification process, and its structure determined by 2D NMR and other spectroscopic and chromatographic methods. Bioinformatic analysis of the draft genome sequence identified a 28.7 kB gene cluster that putatively encodes for cryptomaldamide biosynthesis. Notably, an amidinotransferase is proposed to initiate the biosynthetic process by transferring an amidino group from arginine to serine to produce the first residue to be incorporated by the hybrid NRPS-PKS pathway. The maldiisotopic approach presented here is thus demonstrated to provide an orthogonal method by which to discover novel chemical diversity from Nature.