Streptomyces diastaticus var. 108, a newly isolated strain, produces two closely related tetraene macrolides (rimocidin and CE-108) as well as oxytetracycline. A region of 19,065 base pairs of DNA from the S. diastaticus var. 108 genome was isolated, sequenced, and characterized. Ten complete genes and one truncated ORF were located. Disruption of these genes proved that this genomic region is part of the biosynthetic cluster for the two tetraenes. The choice of starter units by the loading module and the in vivo availability of the starter metabolites are crucial for the final ratio of the two macrolides. A second type I PKS, unrelated to tetraene biosynthesis, was also identified; disruption of these genes suggests that they would code for enzymes involved in the biosynthesis of a polyketide that might compete metabolically with rimocidin production.

Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular localization of these isoenzymes are also detected. All these alterations result in a reduced content of the moderate (MAT I) and high Vmax (MAT III) isoenzymes, whereas the low Vmax (MAT II) isoenzyme increases and nuclear accumulation of MAT I is observed. These changes derive in a reduced availability of cytoplasmic S-adenosylmethionine, together with an effort to meet its needs in the nucleus of damaged cells, rendering enhanced levels of certain epigenetic modifications. In this context, the putative role of protein-protein interactions in the control of S-adenosylmethionine synthesis has been scarcely studied. Using yeast two hybrid and a rat liver library we identified PDRG1 as an interaction target for MATα1 (catalytic subunit of MAT I and MAT III), further confirmation being obtained by immunoprecipitation and pull-down assays. Nuclear MATα interacts physically and functionally with the PDRG1 oncogene, resulting in reduced DNA methylation levels. Increased Pdrg1 expression is detected in acute liver injury and hepatoma cells, together with decreased Mat1a expression and nuclear accumulation of MATα1. Silencing of Pdrg1 expression in hepatoma cells alters their steady-state expression profile on microarrays, downregulating genes associated with tumor progression according to GO pathway analysis. Altogether, the results unveil the role of PDRG1 in the control of the nuclear methylation status through methionine adenosyltransferase binding and its putative collaboration in the progression of hepatic diseases.

In the search for strains producing antifungal compounds, a new tetraene macrolide CE-108 (3) has been isolated from culture broth of Streptomyces diastaticus 108. In addition, the strain also produces the previously described tetraene rimocidin (1) and also the aromatic polyketide oxytetracycline. Both tetraene compounds, structurally related, are produced in a ratio between 25 to 35% (CE-108 compared to rimocidin), although it can be inverted toward CE-108 production by changing the composition of the fermentation medium. This paper deals with the characterization of the producer strain, fermentation, purification, structure determination and biological properties of the new macrolide tetraene CE-108.