The Rieske Oxygenase SnoT Catalyzes 2′′‐Hydroxylation of l‐Rhodosamine in Nogalamycin Biosynthesis. (14th July 2020)

• Record Type: Journal Article
• Authors: Nji Wandi, Benjamin; Siitonen, Vilja; Palmu, Kaisa; Metsä‐Ketelä, Mikko
• Is Part Of: Chembiochem. Volume 21:Number 21(2020)
• Page Start: 3062
• Page End: 3066
• Publication Date: 2020-07-14
• Subjects: anthracycline -- hydroxylation -- biosynthesis -- Streptomyces -- Rieske enzyme; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202000229
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Nogalamycin is an anthracycline anti‐cancer agent that intercalates into the DNA double helix. The binding is facilitated by two carbohydrate units, l ‐nogalose and l ‐nogalamine, that interact with the minor and major grooves of DNA, respectively. However, recent investigations have shown that nogalamycin biosynthesis proceeds through the attachment of l ‐rhodosamine (2′′‐deoxy‐4′′‐epi‐l ‐nogalamine) to the aglycone. Herein, we demonstrate that the Rieske enzyme SnoT catalyzes 2′′‐hydroxylation of l ‐rhodosamine as an initial post‐glycosylation step. Furthermore, we establish that the reaction order continues with 2–5′′ carbocyclization and 4′′ epimerization by the non‐heme iron and 2‐oxoglutarate‐dependent enzymes SnoK and SnoN, respectively. These late‐stage tailoring steps are important for the bioactivity of nogalamycin due to involvement of the 2′′‐ and 4′′‐hydroxy groups of l ‐nogalamine in hydrogen bonding interactions with DNA. Abstract : Order ! The binding of nogalamycin to DNA is facilitated by its carbohydrate units. The 2"‐ and 4"‐hydroxy groups of l ‐nogalamine are particularly important for the bioactivity due to hydrogen bonding interactions. We have elucidated the biosynthetic steps for l ‐nogalamine formation and show that SnoT installs the 2"‐hydroxy group, followed by 2–5"‐carbocyclization and 4"‐epimerization by SnoK and SnoN, respectively.