Pathway Engineering of Anthracyclines: Blazing Trails in Natural Product Glycodiversification

Abstract

The anthracyclines are structurally diverse anticancer natural products that bind to DNA and poison the topoisomerase II -DNA complex in cancer cells. Rational modifications in the deoxysugar functionality are especially advantageous for synthesizing drugs with improved potency. Combinatorial biosynthesis of glycosyltransferases and deoxysugar synthesis enzymes is indispensable for the generation of glycodiversified anthracyclines. This Synopsis considers recent advances in glycosyltransferase structural biology and site-directed mutagenesis, pathway engineering, and deoxysugar combinatorial biosynthesis with a focus on the generation of "newto-nature" anthracycline analogs.

Anthracyclines: biosynthesis, engineering and clinical applications

“…Anthracyclines contain a broad selection of 6-deoxysugar units that are typically associated with microbial natural products. 126,127 These include many 2,6-dideoxy-and 2,3,6-trideoxysugars, 104 but the two most common substrates used in glycosylation of the 7-position are the aminosugars TDP-L-daunosamine ( 18) 128 and TDP-L-rhodosamine (19), 129 which have been enzymatically synthesized using proteins from the nogalamycin pathway (Fig. 6).…”

“…103 Particularly significant are glycosylation steps, where anthracyclinones are decorated with diverse carbohydrate moieties originating from d -glucose-6-phosphate. 104 Other important tailoring steps include methylations and various redox reactions, which further modify the metabolites. Anthracyclines are thus formed by complex multi-enzyme pathways, which explain that they cannot easily be made by full chemistry.…”

“…The metabolic engineering efforts have focused particularly on expression of tailoring genes from related pathways 215 and glycodiversification. 104…”

A BioBricks Metabolic Engineering Platform for the Biosynthesis of Anthracyclinones in Streptomyces coelicolor

“…This result was expected since the glycoside moiety of the anthracyclines is essential for binding to DNA and inhibition of DNA topoisomerases. 66 Compounds 6 and 10 exhibited slight antiproliferative activity (6: 75−85% T/C; 10: 50−75% T/C). In the single dose experiment 1, 2, and 7 exhibited antiproliferative activity (<10% T/C) comparable to previously reported compounds 9, 11, 12, and 13.…”

Multi-strategy engineering unusual sugar TDP-l-mycarose biosynthesis to improve the production of 3-O-α-mycarosylerythronolide B in Escherichia coli

“…For example, by the inactivation of native gene dnrV and the expression of heterologous gene avrB or eryBIV , the TDP- l -daunosamine biosynthetic pathway of Streptomyces peucetius was modified to produce TDP-4′- epi - l -daunosamine that was the epimer at C4′ hydroxyl group of TDP- l -daunosamine, and the resulting glycosylated product epirubicin (4′-epidoxorubicin) possessed more effective antitumor property [ 11 ]. Besides, a series of undescribed deoxysugars were synthesized and attached to the anthracycline aglycones, resulting in the generation of unusual anthracycline analogues [ 12 ].…”