Biosynthesis of C-nucleoside antibiotics in actinobacteria: recent advances and future developments

Abstract

Epidemic diseases and antibiotic resistance are urgent threats to global health, and human is confronted with an unprecedented dilemma to conquer them by expediting development of new natural product related drugs. C-nucleoside antibiotics, a remarkable group of microbial natural products with diverse biological activities, feature a heterocycle base linked with a ribosyl moiety via an unusual C-glycosidic bond, and have played significant roles in healthcare and for plant protection. Elucidating how nature biosynthesizes such a group of antibiotics has provided the basis for engineered biosynthesis as well as targeted genome mining of more C-nucleoside antibiotics towards improved properties. In this review, we mainly summarize the recent advances on the biosynthesis of C-nucleoside antibiotics, and we also tentatively discuss the future developments on rationally accessing C-nucleoside diversities in a more efficient and economical way via synthetic biology strategies.

Experimental and computational snapshots of C-C bond formation in a C-nucleoside synthase

“…Both of these strategies often require the use of protecting groups, thereby increasing synthetic complexity. Biocatalysis offers an attractive alternative if we can understand the pathways that give rise to naturally occurring C-nucleosides and C-nucleotides [16][17][18].…”

C-Ribosylating Enzymes in the (Bio)Synthesis of C-Nucleosides and C-Glycosylated Natural Products

“…The pentose d -ribose is the main sugar building block of a large class of nucleosides and phosphorylated derivatives thereof (nucleotides). − Ribonucleotides are the precursors of RNA and play a central role in cellular energy and redox metabolism. ,, They are key molecules of various branches of natural biosynthesis. − The common nucleoside core structure has a β- d -ribofuranosyl unit attached to a nitrogen of the nucleobase aglycone. − In certain nucleosides, though, the canonical N -β-ribosyl pattern is replaced by a naturally rare C -β-ribosyl feature, as shown in Figure (e.g., 1a, 2a ). The chemical consequences of β-ribosyl attached to the aglycone by a carbon–carbon instead of carbon–nitrogen bond are of great biological interest. − …”

“…In RNA, U ( 1 a) to Ψ ( 2a ) substitution stabilizes the 3′-endo/North conformation. , The C -nucleoside is more resistant to degradation by chemical hydrolysis than the N -nucleoside. Biologically, the C -nucleoside may show unique , activity or mimic , the one exhibited by the relevant N -nucleoside counterpart. As an example, various RNA polymerases accept the 5′-triphosphate of Ψ ( 2e ) to substitute UTP ( 1c ) in transcription reactions. , …”

Characterization of the Oxazinomycin Biosynthetic Pathway Revealing the Key Role of a Nonheme Iron-Dependent Mono-oxygenase

“…C -Nucleosides are a small but unique class of natural products that include oxazinomycin ( 1 , also known as minimycin), formycin A ( 2 ), pseudouridine ( 3 ), pyrrolosine ( 4 ), showdomycin ( 5 ), and pyrazofurin ( 6 ). − As their name suggests, the characteristic feature shared by these nucleosides is a C -glycosidic bond between the ribofuranose and an sp 2 -hybridized carbon of the nucleobase (Figure ). The intrinsic stability of this C–C linkage renders C -nucleosides resistant to nucleoside phosphorylases and acid hydrolysis in contrast to N -nucleosides. − This important chemical property has thus inspired the design and preparation of many C -nucleosides as enzyme inhibitors in drug discovery efforts …”