Identification of a C-Glycosyltransferase Involved in Medermycin Biosynthesis

Abstract

C-Glycosylation in the biosynthesis of bioactive natural products is quite unique, which has not been studied well. Medermycin, as an antitumor agent in the family of pyranonaphthoquinone antibiotics, is featured with unique C-glycosylation. Here, a new C-glycosyltransferase (C-GT) Med-8 was identified to be essential for the biosynthesis of medermycin, as the first example of C-GT to recognize a rare deoxyaminosugar (angolosamine). med-8 and six genes (med-14, -15, -16, -17, -18, and -20 located in the medermycin biosynthetic gene cluster) predicted for the biosynthesis of angolosamine were proved to be functional and sufficient for C-glycosylation. A C-glycosylation cassette composed of these seven genes could convert a proposed substrate into a C-glycosylated product. In conclusion, these genes involved in the C-glycosylation of medermycin were functionally identified and biosynthetically engineered, and they provided the possibility of producing new C-glycosylated compounds.

Chimeric natural products derived from medermycin and the nature-inspired construction of their polycyclic skeletons

“…OUCMDZ-4982 was sequenced, and the medermycin biosynthetic gene cluster ( med cluster) in this strain was compared with the reported cluster from Streptomyces sp. AM-7161 37 , 38 . The med cluster in Streptomyces sp.…”

Elucidation of the di-c-glycosylation steps during biosynthesis of the antitumor antibiotic, kidamycin

“…Alignment of the amino acid sequences of Kid7 and Kid21 with those of HedJ and HedL, respectively, also showed that the proteins are significantly identical (Kid7 vs. HedJ, 67.5% similarity; Kid21 vs. HedL, 71.8% similarity) ( Supplementary Table S4 ). Additionally, both Kid7 and Kid21 resemble Med-8 (52% and 59% similarity, respectively), a C-GT responsible for angolosamine transfer in medermycin biosynthesis ( Ichinose et al, 2003 ; Cai et al, 2021 ). However, Kid21 is believed to be responsible for angolosamine transfer, because of its high degree of identity with Med-8.…”

“…The late steps for angolosamine biosynthesis, which may be interchangeable, are catalyzed by 4′-keto-reductase and N-methyltransferase. The 4′-keto-reductase genes, med-ORF14 ( Cai et al, 2021 ) and gra-ORF22 ( Tornus and Floss, 2001 ), encode proteins 60% similar to the Kid23 enzyme. Kid4 is highly similar to AORI_1488 (76%), which catalyzes the C-methylation at aminohexose in the vancomycin biosynthetic pathway ( van Wageningen et al, 1998 ; Chen et al, 2000 ; Xu et al, 2014 ).…”

“…Additionally, Kid9 and Kid24 show high identity with med-15 (Kid9: 46% and Kid24: 50%), which catalyze the di-methylation at the amine moiety of angolosamine. ( Cai et al, 2021 ) ( Supplementary Table S7 )…”

Complete genome sequencing and in silico genome mining reveal the promising metabolic potential in Streptomyces strain CS-7

“…C -Glycosylation is a unique phenomenon in nature and is involved in the bioactivity of natural products. Only a small number of biologically important natural products are C -glycosides ( Cai et al, 2021 ). In the mayamycin gene cluster, we predicted the presence of genes for a rare C -glycosyltransferase and biosynthesis of a rare deoxy-amino sugar (angolosamine), which will be confirmed functionally and used for combinatorial biosynthesis of glycosides, to enrich the structural and bioactivity diversification of these therapeutically important compounds.…”