- Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones
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Previous studies showed that the FeII/α-ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine-2,5-dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine-2,5-dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate-directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance.
- Einsiedler, Manuel,Jamieson, Cooper S.,Maskeri, Mark A.,Houk, Kendall N.,Gulder, Tobias A. M.
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supporting information
p. 8297 - 8302
(2021/03/01)
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- Insights into the Desaturation of Cyclopeptin and its C3 Epimer Catalyzed by a non-Heme Iron Enzyme: Structural Characterization and Mechanism Elucidation
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AsqJ, an iron(II)- and 2-oxoglutarate-dependent enzyme found in viridicatin-type alkaloid biosynthetic pathways, catalyzes sequential desaturation and epoxidation to produce cyclopenins. Crystal structures of AsqJ bound to cyclopeptin and its C3 epimer ar
- Liao, Hsuan-Jen,Li, Jikun,Huang, Jhih-Liang,Davidson, Madison,Kurnikov, Igor,Lin, Te-Sheng,Lee, Justin L.,Kurnikova, Maria,Guo, Yisong,Chan, Nei-Li,Chang, Wei-Chen
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p. 1831 - 1835
(2018/01/27)
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- Structure of the Dioxygenase AsqJ: Mechanistic Insights into a One-Pot Multistep Quinolone Antibiotic Biosynthesis
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Multienzymatic cascades are responsible for the biosynthesis of natural products and represent a source of inspiration for synthetic chemists. The FeII/α-ketoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans is outstanding because it stereoselectively catalyzes both a ferryl-induced desaturation reaction and epoxidation on a benzodiazepinedione. Interestingly, the enzymatically formed spiro epoxide spring-loads the 6,7-bicyclic skeleton for non-enzymatic rearrangement into the 6,6-bicyclic scaffold of the quinolone alkaloid 4′-methoxyviridicatin. Herein, we report different crystal structures of the protein in the absence and presence of synthesized substrates, surrogates, and intermediates that mimic the various stages of the reaction cycle of this exceptional dioxygenase.
- Br?uer, Alois,Beck, Philipp,Hintermann, Lukas,Groll, Michael
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supporting information
p. 422 - 426
(2016/01/25)
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- The first total synthesis of (-)-benzomalvin A and benzomalvin B via the intramolecular aza-Wittig reactions
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The first total synthesis of (-)-benzomalvin A, which possesses 4(3H)-quinazolinone and 1,4-benzodiazepin-5-one moieties, was described. Both of 6- and 7-membered ring skeletons were efficiently constructed by the intramolecular aza-Wittig reactions as th
- Sugimori, Toshiyuki,Okawa, Tomohiro,Eguchi, Shoji,Kakehi, Akikazu,Yashima, Eiji,Okamoto, Yoshio
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p. 7997 - 8008
(2007/10/03)
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- The first total synthesis of (-)-benzomalvin A via intramolecular Aza-Wittig reactions
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The first total synthesis of (-)-benzomalvin A 1, which possesses quinazolin-4(3H)-one moiety and 1,4-benzodiazepin-5-one moiety, was described. Both of 6- and 7-membered ring skeletons were efficiently constructed by intramolecular aza-Wittig reactions as the key reactions.
- Sugimori, Toshiyuki,Okawa, Tomohiro,Eguchi, Shoji,Yashima, Eiji,Okamoto, Yoshio
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p. 869 - 870
(2007/10/03)
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- A ONE STEP SYNTHESIS OF 1,4-BENZODIAZEPINES:SYNTHETIC STUDIES ON NEOTHRAMYCIN
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A one step synthesis of 1,4-benzodiazepines from o-haloanilines and amino acids was achieved by use of palladium catalyzed carbonylation, by which application a synthesis of the model compounds (23a and 23b) of Neothramycin (A and B) was described.An efficient chemoselective reduction of the amide was provided.
- Mori, Miwako,Kimura, Masaya,Uozumi, Yasuhiro,Ban, Yoshio
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p. 5947 - 5950
(2007/10/02)
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