Elucidation of the glycosylation steps during biosynthesis of antitumor macrolides PM100117 and PM100118 and engineering for novel derivatives

Abstract

BackgroundAntitumor compounds PM100117 and PM100118 are glycosylated polyketides derived from the marine actinobacteria Streptomyces caniferus GUA-06-05-006A. The organization and characterization of the PM100117/18 biosynthesis gene cluster has been recently reported.ResultsBased on the preceding information and new genetic engineering data, we have outlined the pathway by which PM100117/18 are glycosylated. Furthermore, these genetic engineering experiments have allowed the generation of novel PM100117/18 analogues. Deletion of putative glycosyltranferase genes and additional genes presumably involved in late biosynthesis steps of the three 2,6-dideoxysugars appended to the PM100117/18 polyketide skeleton, resulted in the generation of a series of intermediates and novel derivatives.ConclusionsIsolation and identification of the novel compounds constitutes an important contribution to our knowledge on PM100117/18 glycosylation, and set the basis for further characterization of specific enzymatic reactions, additional genetic engineering and combinatorial biosynthesis approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0591-7) contains supplementary material, which is available to authorized users.

Biosynthesis and Heterologous Expression of Cacaoidin, the First Member of the Lanthidin Family of RiPPs

“…Despite the presence of three GTs in the cacaoidin BGC, only two sugar moieties in the form of disaccharide are detected in the structure. The three GTs could work in a cooperative manner to achieve effective glycosylation, as it has already been proposed [ 37 , 38 , 39 ]. Based on the “inverting” or “retaining” behavior of the glycosyltransferases, we propose that both Cao8 and Cao16, belonging to the “inverting” GT-2 family, might work cooperatively to attach the α- l -rhamnose unit, while Cao24, belonging to the “retaining” GT-4 family, would incorporate the β - l -6-deoxygulose unit [ 12 ].…”

Cooperative Involvement of Glycosyltransferases in the Transfer of Amino Sugars during the Biosynthesis of the Macrolactam Sipanmycin by Streptomyces sp. Strain CS149

“…However, reports on BGCs containing more GT genes than sugars in the molecule are scarce, with PM100117/PM100118 (42) and oleandomycin (43) being two examples of them. In the PM100117/PM100118 BGC, there is no clear role for a fourth GT in the biosynthesis pathway that otherwise involves the incorporation of three deoxy sugars (44). In the case of oleandomycin, which contains two deoxy sugars in its structure, the third GT acts as an inactivation mechanism (43).…”

Identification and engineering of 32 membered antifungal macrolactone notonesomycins

“…notonesogenes 647-AV1 in 1986 [17], from an assay against rice sheath blight disease. Characterization of similar compounds, such as brasilinolides [18,19], ibomycin [20], langkolide [21], novonestmycins A and B [22], PM100117 and PM100118 [23,24], demonstrates the bio-versatility of these 32-36 membered macrolactones. For this family of compounds, immunosuppressive, anti-tumor, and antifungal bioactivities have been reported.…”