Isolation and Biosynthetic Analysis of Haliamide, a New PKS-NRPS Hybrid Metabolite from the Marine Myxobacterium Haliangium ochraceum

• Published in: Molecules (Basel, Switzerland) Vol. 21; no. 1; p. 59
• Main Authors: Sun, Yuwei, Tomura, Tomohiko, Sato, Junichi, Iizuka, Takashi, Fudou, Ryosuke, Ojika, Makoto
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06-01-2016; MDPI
• Subjects: Antibiotics; Antifungal agents; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Aquatic Organisms; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biological activity; Biosynthesis; Cell Survival - drug effects; Deltaproteobacteria - chemistry; Deltaproteobacteria - genetics; Deltaproteobacteria - metabolism; Gene Expression; haliamide; Haliangium ochraceum; HeLa Cells; Humans; Inhibitory Concentration 50; marine myxobacterium; Metabolites; Metabolome; Microorganisms; Multigene Family; Myxobacteria; Peptides - isolation & purification; Peptides - metabolism; Peptides - pharmacology; polyketide; Polyketides - isolation & purification; Polyketides - metabolism; Polyketides - pharmacology; Protein Structure, Tertiary; Sulfotransferases - chemistry; Sulfotransferases - genetics; Sulfotransferases - metabolism; Thiolester Hydrolases - chemistry; Thiolester Hydrolases - genetics; Thiolester Hydrolases - metabolism; Japan; marine myxobacterium; Haliangium ochraceum; polyketide; haliamide; biosynthesis
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules21010059

Myxobacteria of marine origin are rare and hard-to-culture microorganisms, but they genetically harbor high potential to produce novel antibiotics. An extensive investigation on the secondary metabolome of the unique marine myxobacterium Haliangium ochraceum SMP-2 led to the isolation of a new polyketide-nonribosomal peptide hybrid product, haliamide (1). Its structure was elucidated by spectroscopic analyses including NMR and HR-MS. Haliamide (1) showed cytotoxicity against HeLa-S3 cells with IC50 of 12 μM. Feeding experiments were performed to identify the biosynthetic building blocks of 1, revealing one benzoate, one alanine, two propionates, one acetate and one acetate-derived terminal methylene. The biosynthetic gene cluster of haliamide (hla, 21.7 kbp) was characterized through the genome mining of the producer, allowing us to establish a model for the haliamide biosynthesis. The sulfotransferase (ST)-thioesterase (TE) domains encoded in hlaB appears to be responsible for the terminal alkene formation via decarboxylation.