Deciphering the streamlined genome of Streptomyces xiamenensis 318 as the producer of the anti-fibrotic drug candidate xiamenmycin

Abstract

Streptomyces xiamenensis 318, a moderate halophile isolated from a mangrove sediment, produces the anti-fibrotic compound xiamenmycin. The whole genome sequence of strain 318 was obtained through long-read single-molecule real-time (SMRT) sequencing, high-throughput Illumina HiSeq and 454 pyrosequencing technologies. The assembled genome comprises a linear chromosome as a single contig of 5,961,401-bp, which is considerably smaller than other reported complete genomes of the genus Streptomyces. Based on the antiSMASH pipeline, a total of 21 gene clusters were predicted to be involved in secondary metabolism. The gene cluster responsible for the biosynthesis of xiamenmycin resides in a strain-specific 61,387-bp genomic island belonging to the left-arm region. A core metabolic network consisting of 104 reactions that supports xiamenmycin biosynthesis was constructed to illustrate the necessary precursors derived from the central metabolic pathway. In accordance with the finding of a putative ikarugamycin gene cluster in the genome, the targeted chemical profiling of polycyclic tetramate macrolactams (PTMs) resulted in the identification of ikarugamycin. A successful genome mining for bioactive molecules with different skeletons suggests that the naturally minimized genome of S. xiamenensis 318 could be used as a blueprint for constructing a chassis cell with versatile biosynthetic capabilities for the production of secondary metabolites.

Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase

“…AA0539. As shown previously, these three strains had identical 16S rRNA gene sequences and were tentatively assigned to S. xiamenensis 2. Moreover, counterparts of the characterized ikarugamycin gene cluster that consisted of ikaA, ikaB and ikaC were found in this group of S. xiamenensis strains (Supplementary Table S1).…”

“…Genome mining of a PTM biosynthetic gene cluster along with a chemical analysis of the targeted compound, ikarugamycin ( 1 ), demonstrated the production of PTMs by S. xiamenensis strain 318 in the fermentation broth2. In our ongoing phytochemical study of S. xiamenensis strain 318, the broth was extracted with ethyl acetate, fractionated by vacuum column liquid chromatography (guided by the ikarugamycin-like UV characteristic with absorption at 325 nm) and separated by semi-preparative HPLC.…”

“…Streptomyces xiamenensis 318, a moderate halophile isolated from mangrove sediment with a streamlined genome2, has been shown to be a cell factory that produces an anti-fibrotic drug candidate, xiamenmycin A. Nineteen gene clusters within the genome were predicted to be involved in secondary metabolism based on the antiSMASH pipeline23. Two biomolecule types, benzopyran1 derivatives and polycyclic tetramate macrolactams (PTMs), have been identified as the major secondary metabolites produced by S. xiamenensis 318.…”

A Novel AdpA Homologue Negatively Regulates Morphological Differentiation in Streptomyces xiamenensis 318

“…Streptomyces xiamenensis 318 was isolated from a mangrove sediment and represented a novel species of Streptomyces genus (20,21). Whole-genome sequencing shown that S. xiamenensis 318 has a linear chromosome 5.96 Mb in size, which is considerably smaller than other reported complete genomes of the genus Streptomyces (21).…”

Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2

“…A series of polycyclic tetramate macrolactams (PTMs), for example, ikarugamycin (1, denoted as IKA afterward), capsimycin (2), and capsimycin B (3), have been isolated from mangrove-derived S. xiamenensis 318. 14 The PTMs are structurally, biosynthetically, and pharmacologically unique natural products. 15 A broad variety of biological activities of IKA has been reported, such as immune regulation, 16 cytotoxic properties, 17,18 antitumor effects and other pharmacological effects.…”