Landomycin

The landomycins are a subgroup of the large family of angucycUne compounds characterized by possessing a unique phenylglycoside moiety in their structures. 

Figure 8.20 Landomycin derivatives generated by expressing glycosyltransferase genes into S. cyanogenus.

D-Olivose (2,6-dideoxy-D-arahiKo-hexose, 55D) is part of the glycosidically linked hexasaccharide in Landomycin A (66),144 a member of the angucycline antibiotic family.145... 

Production of several novel angucyclines referred to as urdamycins (Fig. 8) has been achieved through combinatorial expression of landomycin GT genes lanGTl... 

Luzhetskyy A, Zhu L, Gibson M et al (2005) Generation of novel landomycins M and O through targeted gene disruption. ChemBioChem 6 675-678... 

Erb A, Krauth C, Luzhetskyy A et al (2009) Differences in substrate specificity of glycosyltransferases involved in landomycins A and E biosynthesis. Appl Microbiol Biotechnol 83 1067-1076... 

Trefzer A, Fischer C, Stockert S et al (2001) Elucidation of the function of two glycosyltransferase genes (lanGTl and lanGT4) involved in landomycin biosynthesis and generation of new oligosaccharide antibiotics. Chem Biol 8 1239-1252... 

Luzhetskyy A, Fedoryshyn M, Durr C et al (2005) Iteratively acting glycosyltransferases involved in the hexasaccharide biosynthesis of landomycin A. Chem Biol 12 725-729... 

Roush and Bennett reported the consecutive removal of seven iodine atoms during their synthesis of the landomycin A hexasaccharide unit (46) (equation (25)151. 

This method was applied to the synthesis of the landomycin A hexasaccharide, which contains two p-D-olivose-(1 4)-p-D-olivose disaccharides [26], The 2,3-O- thionocarbonate of the olivosyl donor 30 was activated by MeOTf, leading to the... 

Luzhetskyy A, Taguchi T, Fedoryshyn M, Durr C, Wohlert SE, Novikov V, Bechthold A (2005) LanGT2 Catalyzes the First Glycosylation Step During Landomycin A Biosynthesis. Chembiochem 6 1406... 

SchemeSa. Feeding experiment with [U- Hjjglucose on landomycin A (12). Only the 1- and 6-positions show detectable amounts of label...

Scheme 6b. Favored hypothetical deoxygenation pathways to the deoxysugars of landomycin A,NDP-D-olivose (13a) and NDP-L-rhodinose (13b)...

Scheme 13. The antitumor antibiotics daunomycin (29 = daunorubicin) and adiiamycin (30 = doxorubicin) are polyketides with an attached deox ugar moiety. Polyketide oligodeoxy-saccharides characterized by one or more deoxysaccharide chains include the anthracyclines arugomycin (31) [73a] and viriplanin (32), the angucyclines landomycin A (see 12 in Scheme 6) and vineomycin A, (33 = P1894B [74]), and the aureolic acid antibiotics mithramycin (34) and UCH9 (35).Also,orthosomydn antibiotics, such as avUamycin A (36) can be considered as polyketide oligodeoxysaccharides...

Scheme 15. The biosynthesis of landomycin A (12) landomycinone (40) is the ultimate substrate for the glycosyl transfer cascade to 12...

Scheme 20a, b. Disaccharide transfers are thought to be involved in the biosynthesis of acarbose (16, transfer of maltose) and landomycin A (12, transfer of diolivoside units)... 

We favor the first alternative since further experiments with model substrates on S. fradiae revealed that presumably the same glycosyl transferase was able to C-glycosylate methylnaphthazarine (59). The resulting product, the olivosyl-naphthalinone 60, was also reduced by other enzymes of the urdamycin producer S. fradiae [81, 82]. The landomycin producer S. cyanogenus S-136, however, studied for reasons of comparison, was not able to glycosylate but only to reduce 59 to 61 (Scheme 22). This is a surprising result, since substrate 59 more closely resembles landomycin than the urdamycin chromophore in fact, it actually matches the western half of landomycinone (40). 

Additional evidence for an alternative pathway for the production of L-fucose came from experiments in mouse lymphoma cell lines blocked in the conversion of GDP-D-[ H]-mannose to GDP-L-[ H]-fucose. Reitman et al. observed that the block could be bypassed by growing the cells in the presence of L-fucose [119]. That this short activation pathway may be a general salvage mechanism is also indicated by the fact that 6-deoxy-D-glucose derivatives could be incorporated into neomycin [71]. The existence of a short activation pathway was recently proven in our laboratories [120] by successful incorporation of l-[2, 3--H2]-rhodinose [121] into landomycin A (12). In this experiment, NMR spectroscopy of the product showed, that only the four protons of the two L-rhodinose moieties were labeled. In a control experiment, d-[2, 2, 3, 3- H4]-rhodinose [121] was fed and, as expected, no incorporation into 12 was observed [120] (Scheme 27). 

Scheme 27. Successful incorporation of (2, S- HjJ-L-rhodinose [121] into landomycin A (12) provides evidence for a short activation pathway...

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