N-methylphenylalanyl-dehydrobutyrine diketopiperazine, an A-factor mimic that restores antibiotic biosynthesis and morphogenesis in Streptomyces globisporus 1912-B2 and Streptomyces griseus 1439

Abstract

The cell-free extracts of a landomycin E-producing strain, Streptomyces globisporus 1912-2, were shown to contain a low-molecular-weight compound that, like A-factor, restored the landomycin E and streptomycin biosynthesis and sporulation of the defective mutants S. globisporus 1912-B2 and S. griseus 1439, respectively. The compound was purified by thin layer chromatography and HPLC. It had an absorption maximum at λmax=245 nm and a molecular mass of m/z 244. On the basis of NMR spectroscopy ((1)H, (13)C, HSQC, HMBC, COSY and NOE) the chemical structure of the compound was elucidated as 6-benzyl-3-eth-(Z)-ylidene-1-methyl-piperazine-2,6-dione ((L)-N-methylphenylalanyl-dehydrobutyrine diketopiperazine (MDD)). The sequences of arpA genes in S. globisporus 1912-2 and S. griseus NBRC 13350 are highly conserved. An explanation for the observed biological activity of MDD was proposed.

Similarity and dissimilarity of primary structures of some Streptomyces spp. genomes and the Streptomyces globisporus 1912-2 chromosomal DNA.

“…The sequencing of the genomic DNA of strain S. globisporus 1912-2 was carried out in BaseClear B.V., Leiden, Netherlands using described previously procedures [7]. The primary structure of the chromosomal DNA of S. globisporus 1912-2 was obtained as a result (in the form of 1438 contigs).…”

“…The wild type strain S. globisporus 1912 and its variants synthesize some carotenoids, antitumor antibiotics landomycin E and A and a new regulator of the antibiotics biosynthesis and morphogenesis [7,12,16]. The nucleotide sequence of S. globisporus 1912-2 chromosomal DNA was identified [7].…”

“…Nowadays many efforts are made to estimate this potential and to get access to the natural products, the biosynthetic pathways of which are encoded in the genomes of the corresponding Streptomyces strains [13][14][15]. The accumulation of high quality genome sequencing data will strongly contribute to implementation of this task [3,4,[6][7][8][9][10][11].…”

“…They are well known as producers of over two-thirds of cli ni cally useful natural antibiotics (e.g., neomycin, cypemycin, grisemycin, bottromycins, chloramphenicol and many others) [1][2][3][4][5] and some secondary metabolites, which are useful for people (regulators, pigments, proteins, vitamins and some others) [1,2,4,6,7].…”

Complete Sequence of Landomycin E Biosynthetic Gene Cluster from Streptomyces globisporus 1912

“…kiev.ua/images/doc/catalog/UCM_catalog.pdf). The strain 1912-2 is the more effective producer of landomycin E (200 mg/l) and a new regulatory diketopiperazine, generated by the action of nitrosoguanidine on the spores of the strain 1912 (14). The strain 1912-4Crt is the spontaneous mutant of 1912 producing beta-carotene (7.0 mg/l) and lycopene (3.24 mg/l), and not producing landomycin E [13].…”