ArticleProceedings of the National Academy of Sciences of the United States of America2015
Divergent evolution of an atypical S-adenosyl-l-methionine-dependent monooxygenase involved in anthracycline biosynthesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 43 citations in OpenAlex.
- Functional investigation of the SAM-dependent methyltransferase RdmB in anthracycline biosynthesis.Synthetic and systems biotechnology · 2025Article
- Structural and energetic analysis of stabilizing indel mutations.bioRxiv : the preprint server for biology · 2024Article
- Diverse Combinatorial Biosynthesis Strategies for C-H Functionalization of Anthracyclinones.ACS synthetic biology · 2024Article
- Insertion-Deletion Events Are Depleted in Protein Regions with Predicted Secondary Structure.Genome biology and evolution · 2024Article
- Biochemical and Structural Studies of the Carminomycin 4-Journal of natural products · 2024Article
- Metabolic engineering ofFrontiers in bioengineering and biotechnology · 2024Article
- Review
- Normal and Aberrant Methyltransferase Activities Give Insights into the Final Steps of Dynemicin A Biosynthesis.Journal of the American Chemical Society · 2023Article
- Evolution-inspired engineering of anthracycline methyltransferases.PNAS nexus · 2023Article
- Mechanisms of protein evolution.Protein science : a publication of the Protein Society · 2022Review
- Insights into methionine S-methylation in diverse organisms.Nature communications · 2022Article
- Article
- Biotechnological applications of S-adenosyl-methionine-dependent methyltransferases for natural products biosynthesis and diversification.Bioresources and bioprocessing · 2021Review
- Diversity of the reaction mechanisms of SAM-dependent enzymes.Acta pharmaceutica Sinica. B · 2021Review
- Whole-Genome Shotgun Sequencing for Nasopharyngeal Microbiome in Pre-school Children With Recurrent Wheezing.Frontiers in microbiology · 2021Article
- Evolutionary Trajectories for the Functional Diversification of Anthracycline Methyltransferases.ACS chemical biology · 2019Article
- Enzymatic Synthesis of the C-Glycosidic Moiety of Nogalamycin R.ACS chemical biology · 2018Article
- Confronting the catalytic dark matter encoded by sequenced genomes.Nucleic acids research · 2017Article
- New insights into bacterial type II polyketide biosynthesis.F1000Research · 2017Review
- Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways.ACS chemical biology · 2016Article
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5 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Bacterial secondary metabolic pathways are responsible for the biosynthesis of thousands of bioactive natural products. Many enzymes residing in these pathways have evolved to catalyze unusual chemical transformations, which is facilitated by an evolutionary pressure promoting chemical diversity. Such divergent enzyme evolution has been observed in S-adenosyl-L-methionine (SAM)-dependent methyltransferases involved in the biosynthesis of anthracycline anticancer antibiotics; whereas DnrK from the daunorubicin pathway is a canonical 4-O-methyltransferase, the closely related RdmB (52% sequence identity) from the rhodomycin pathways is an atypical 10-hydroxylase that requires SAM, a thiol reducing agent, and molecular oxygen for activity. Here, we have used extensive chimeragenesis to gain insight into the functional differentiation of RdmB and show that insertion of a single serine residue to DnrK is sufficient for introduction of the monooxygenation activity. The crystal structure of DnrK-Ser in complex with aclacinomycin T and S-adenosyl-L-homocysteine refined to 1.9-Å resolution revealed that the inserted serine S297 resides in an α-helical segment adjacent to the substrate, but in a manner where the side chain points away from the active site. Further experimental work indicated that the shift in activity is mediated by rotation of a preceding phenylalanine F296 toward the active site, which blocks a channel to the surface of the protein that is present in native DnrK. The channel is also closed in RdmB and may be important for monooxygenation in a solvent-free environment. Finally, we postulate that the hydroxylation ability of RdmB originates from a previously undetected 10-decarboxylation activity of DnrK.
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