The role of the maleimide ring system on the structure-activity relationship of showdomycin

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

“…Showdomycin ( 3 ) has antimicrobial activity and is cytotoxic. , It was shown to target several enzymes, including UMP-kinase, uridine phosphorylase, UDP-glucose dehydrogenase, and thymidine synthase. ,, When synthesized as the triphosphate, showdomycin can also be incorporated into RNA . The biosynthesis of showdomycin (Figure ) is initiated by cyclization of l -Gln ( 49 ) to give 2-amino-1-pyrroline-5-carboxylate ( 50 ) as an intermediate.…”

“…C -Riboside production by fermentation of natural strains yields showdomycin ( 3 ) (420 mg/L; Streptomyces showdoensis ATCC 15227), , oxacinomycin ( 4 ) (≥20 mg/L; Streptomyces hygroscopicus and Pseudomonas paucimobilis ) , and alnumycin C ( 5 ) (10 mg/L; Streptomyces sp. DSM 11575 and Streptomyces griseorubiginosus Mer-K1115). − A notable exception is indochrome ( 10a ) for which yields of up to 6 g/L ( Arthrobacter polychromogenes 161 and Pseudarthrobacter sp.…”

“…48,237,238 When synthesized as the triphosphate, showdomycin can also be incorporated into RNA. 49 The biosynthesis of showdomycin (Figure 15) is initiated by cyclization of L-Gln (49) to give 2amino-1-pyrroline-5-carboxylate (50) as an intermediate. Multistep conversion of compound 50 loaded onto the peptidyl carrier protein SdmD yields 2-amino-1H-pyrrole-5carboxylate (51) as the actual acceptor substrate for C-βribosylation catalyzed by SdmA.…”

“…In cases where the corresponding α-anomer was synthesized chemically, the C -α-riboside typically exhibited low biological activity . Various C -nucleosides have been discovered from the phylum Actinobacteria (Figure ) and are well known for the antimicrobial and antiviral activity they exhibit: showdomycin ,− ( 3 ), oxazinomycin − ( 4 ), alnumycin − ( 5 ), malayamycin , ( 6 ), pseudouridinemycin − ( 7 ), pyrazofurin − ( 8 ), and formycin , ( 9a, 9b ). Besides pharmaceutically active molecules, bacteria produce the highly water-soluble blue pigment indochrome ( 10 ) that has potential applications as a technical colorant in foods and other sectors of industry .…”

“…Figure16 7,50,51. They start with a mechanistically complex cyclization of L-Gln(49) to the pyridine heterocycle 3-amino-6-hydroxy-2-pyridinone (AHP, 54) catalyzed by OzmA. The purely enzymatic pathway to oxacinomycin (4) introduces the C-β-ribofuranosyl moiety (intermediate 65) by reacting compound 49 with Rib5P(22) in the presence of OzmB.…”