9O35
Crystal structure of DoxA in complex with daunorubicin
Summary for 9O35
| Entry DOI | 10.2210/pdb9o35/pdb |
| Descriptor | Cytochrome P-450 monooxygenase DoxA, PROTOPORPHYRIN IX CONTAINING FE, DAUNOMYCIN, ... (5 entities in total) |
| Functional Keywords | p450 monooxygenase, hydroxylase, oxidoreductase |
| Biological source | Streptomyces peucetius subsp. caesius ATCC 27952 |
| Total number of polymer chains | 2 |
| Total formula weight | 94512.54 |
| Authors | Newmister, S.A.,Harte, R.J.,Kim, R.Q.,Metsa-Ketela, M.,Sherman, D.H. (deposition date: 2025-04-04, release date: 2025-12-24, Last modification date: 2026-02-25) |
| Primary citation | Koroleva, A.,Artukka, E.,Yamada, K.,Newmister, S.A.,Harte, R.J.,Boesger, H.,Londen, M.,Sanders, J.N.,Tirkkonen, H.,Kannisto, M.,Kuin, R.C.M.,Hulst, M.,Wang, R.,Leskinen, E.,Barillec, M.,Niemi, J.,van Wezel, G.P.,Neefjes, J.,Nybo, S.E.,Houk, K.N.,Sherman, D.H.,Kim, R.Q.,Metsa-Ketela, M. Metabolic engineering of doxorubicin biosynthesis through P450-redox partner optimization and structural analysis of DoxA. Nat Commun, 2026 Cited by PubMed Abstract: Doxorubicin, a widely used chemotherapy drug, is produced by Streptomyces peucetius ATCC27952. The biosynthesis relies on the cytochrome P450 monooxygenase DoxA, which catalyzes three consecutive late-stage oxidation steps. However, conversion from daunorubicin to doxorubicin is inefficient, necessitating semi-synthetic industrial manufacturing. Here, we address key limitations in DoxA catalysis. We identify the natural redox partners ferredoxin Fdx4 and ferredoxin reductase FdR3 by transcriptomic analysis. We discovered the vicinal oxygen chelate family protein DnrV to prevent product inhibition by binding doxorubicin. Structural analysis of DoxA and density functional theory (DFT) calculations reveal that inefficient C14 hydroxylation results from the unfavorable anti-conformation of the methyl ketone side chain of daunorubicin. We harness these advances for rational strain engineering, leading to an 180% increase in doxorubicin yields and an improved production profile. This study provides singular insights into enzymatic constraints in anthracycline biosynthesis and facilitates cost-effective manufacturing to meet the growing global demand for doxorubicin. PubMed: 41639599DOI: 10.1038/s41467-026-69194-6 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.19 Å) |
Structure validation
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