ArticleThe Journal of biological chemistry2012
Characterization of SfmD as a Heme peroxidase that catalyzes the regioselective hydroxylation of 3-methyltyrosine to 3-hydroxy-5-methyltyrosine in saframycin A biosynthesis.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 35 citations in OpenAlex.
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- The β-subunit of tryptophan synthase is a latent tyrosine synthase.Nature chemical biology · 2024Article
- Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations.Beilstein journal of organic chemistry · 2024Review
- Hydroxytryptophan biosynthesis by a family of heme-dependent enzymes in bacteria.Nature chemical biology · 2023Article
- Combined spectroscopic and structural approaches to explore the mechanism of histidine-ligated heme-dependent aromatic oxygenases.Methods in enzymology · 2023Article
- Biosynthesis of DNA-Alkylating Antitumor Natural Products.Molecules (Basel, Switzerland) · 2022Review
- Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics.Nature communications · 2021Article
- Recent developments in the use of peroxygenases - Exploring their high potential in selective oxyfunctionalisations.Biotechnology advances · 2021Review
- A new regime of heme-dependent aromatic oxygenase superfamily.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- A novel catalytic heme cofactor in SfmD with a single thioether bond and aChemical science · 2021Article
- Structural and Biosynthetic Analysis of the Fabrubactins, Unusual Siderophores fromACS chemical biology · 2021Article
- Catalase Involved in Oxidative Cyclization of the Tetracyclic Ergoline of Fungal Ergot Alkaloids.Journal of the American Chemical Society · 2019Article
- Unusual Biosynthesis and Structure of Locillomycins from Bacillus subtilis 916.Applied and environmental microbiology · 2015Article
- Lincomycin biosynthesis involves a tyrosine hydroxylating heme protein of an unusual enzyme family.PloS one · 2013Article
- Complexity generation during natural product biosynthesis using redox enzymes.Current opinion in chemical biology · 2012Review
- Hijacking a hydroxyethyl unit from a central metabolic ketose into a nonribosomal peptide assembly line.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
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3 authors at 2 institutions in 1 country.
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Abstract
Saframycin A (SFM-A) is a potent antitumor antibiotic that belongs to the tetrahydroisoquinoline family. Biosynthetic studies have revealed that its unique pentacyclic core structure is derived from alanine, glycine, and non-proteinogenic amino acid 3-hydroxy-5-methyl-O-methyltyrosine (3-OH-5-Me-OMe-Tyr). SfmD, a hypothetical protein in the biosynthetic pathway of SFM-A, was hypothesized to be responsible for the generation of the 3-hydroxy group of 3-OH-5-Me-OMe-Tyr based on previously heterologous expression results. We now report the in vitro characterization of SfmD as a novel heme-containing peroxidase that catalyzes the hydroxylation of 3-methyltyrosine to 3-hydroxy-5-methyltyrosine using hydrogen peroxide as the oxidant. In addition, we elucidated the biosynthetic pathway of 3-OH-5-Me-OMe-Tyr by kinetic studies of SfmD in combination with biochemical assays of SfmM2, a methyltransferase within the same pathway. Furthermore, SacD, a counterpart of SfmD involved in safracin B biosynthesis, was also characterized as a heme-containing peroxidase, suggesting that SfmD-like heme-containing peroxidases may be commonly involved in the biosynthesis of SFM-A and its analogs. Finally, we found that the conserved motif HXXXC is crucial for heme binding using comparative UV-Vis and Magnetic Circular Dichroism (MCD) spectra studies of SfmD wild-type and mutants. Together, these findings expand the category of heme-containing peroxidases and set the stage for further mechanistic studies. In addition, this study has critical implications for delineating the biosynthetic pathway of other related tetrahydroisoquinoline family members.
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