9S7F

Crystal structure of DoxA in complex with substrate DOD

これはPDB形式変換不可エントリーです。

9S7F の概要

• エントリーDOI: 10.2210/pdb9s7f/pdb
• 分子名称: Cytochrome P-450 monooxygenase DoxA, PROTOPORPHYRIN IX CONTAINING FE, (7~{S},9~{S})-7-[(2~{R},4~{S},5~{S},6~{S})-4-azanyl-6-methyl-5-oxidanyl-oxan-2-yl]oxy-9-ethyl-4-methoxy-6,9,11-tris(oxidanyl)-8,10-dihydro-7~{H}-tetracene-5,12-dione, ... (4 entities in total)
• 機能のキーワード: p450, oxygenase, reaction intermediate sanpshot, tetracyclin biosynthesis, transferase
• 由来する生物種: Streptomyces peucetius
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 101656.20

構造登録者

Kim, R.Q.,Metsa-Ketela, M. (登録日: 2025-08-04, 公開日: 2025-12-24, 最終更新日: 2026-03-25)

主引用文献

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, 17:-, 2026

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: 41639599
DOI: 10.1038/s41467-026-69194-6

実験手法

X-RAY DIFFRACTION (1.767 Å)